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Where We Are and Where We're Going: Optimizing Hepatitis B Virus Care and Advancing Toward Functional Cure

What’s New: Expert Insights on the Current State of HBV Care in the US

Dr. Su Wang (Cooperman Barnabas Medical Center): My name is Su Wang, and I'm a medical director for the viral hepatitis programs at the Cooperman Barnabas Medical Center, which is here in New Jersey. I'm also a global health advisor [00:08:30] for the Hepatitis B Foundation, and I'm really excited to be here today to talk about where we are now and what's new, looking at expert insights on the current state of hepatitis B care in the US.

[00:08:45]

WHO: Global Call for HBV Elimination

So, first, we're going to start off with a global perspective... Whoops. Let me go back. And this is basically talking about where we are in terms of WHO's call for [00:09:00] hepatitis B elimination around the world. And this was signed on by 100/100 92 countries, basically saying that we are committed because we have the tools to eliminating viral hepatitis as a major global public health threat by the year 2030, which is around the corner.

And some of these targets include reducing new hepatitis B infections by 90% and reducing annual mortality by 65%. Unfortunately, [00:09:30] despite having vaccines and highly effective antiviral therapy, we are, unfortunately, nowhere near those goals, at least for treatment.

The latest Global Hepatitis Report, which just came out early this year, tells us that over 95% of people living with chronic hepatitis B worldwide still remain untreated. So, while we do have effective therapies, our biggest challenge today is still getting patients diagnosed, linked to care, and appropriately treated.

[00:10:00]

Global Deaths from Viral Hepatitis Exceeds Those from HIV Infection, Tuberculosis, or Malaria

So, this graph illustrates why hepatitis B deserves much greater attention than it has been getting. This is looking at the global deaths from viral hepatitis exceeding those from ‑ comparing them to HIV, tuberculosis, and malaria. And unlike those diseases, you can see that hepatitis deaths continue to rise while the deaths from the other diseases are actually on the decline because of the investments and the interventions that have been taking place.

So, as Margaret Chan, who [00:10:30] was the former WHO director general, said many years ago, "The world has ignored hepatitis at its peril, and it's now time to mobilize a global response to hepatitis." The Global Hepatitis Report, which I mentioned earlier, also cites that liver cancers from hep B continue to rise. And so, her statement remains true more than ever today.

[00:10:57]

Awareness of Chronic HBV Infection Status

So, one of the major reasons for what we are seeing [00:11:00] in terms of disparities and not being able to reduce mortality or morbidity is the lack of awareness.

Worldwide, about 90% of people with chronic hepatitis B don't yet know that they're infected.

Even here in the United States, about half remain undiagnosed.

And among Asian Americans who do carry a high burden of the disease, and the population that I work with closely, roughly two‑thirds of Asian Americans are unaware of being infected.

So, [00:11:30] we simply cannot treat patients we never diagnose. So, we want for everybody to be aware that everybody should have a one‑time hepatitis B test, regardless of risk factors. And this is a new CDC recommendation as of 2023.

[00:11:51]

2026 Data: Hepatitis B Testing and Treatment Remains Suboptimal

All right, so the WHO 2026 Report also highlights enormous gaps in both diagnosis and treatment across every region around the world. Although you do see [00:12:00] some countries doing better than others in terms of being able to diagnose and treat people. And that area is the Western Pacific region where there is a huge burden but also greater awareness.

What you see is some of the disparities in the African region where there's a huge burden, but still very little diagnosis and treatment.

And the Americas, it looks like much lower in terms of the number of people affected, but still very few people diagnosed and treated. And the issues with the Americas is large disparities. There's pockets [00:12:30] of populations that have much higher prevalence of hepatitis B. And so, a lot of them are people who are from these other regions who have immigrated over to our region. But it just shows that we have a lot of work to do all around the world.

[00:12:46]

What Can We Do to Close the Gaps?

So, what can we do today? Fortunately, the CDC recommendations are straightforward. Every adult should receive one lifetime hepatitis B screening panel using the triple panel, which includes the hepatitis B surface antigen, [00:13:00] the Anti‑HBs or hepatitis B surface antibody, and total anti‑HBc or the hepatitis B core antibody.

There is ongoing risk factor‑based screening in addition to the universal screening, where every pregnancy, there should be a screening in the first trimester and ongoing periodic risk‑based screening for people who are at higher risk, including those people who are incarcerated, people who have multiple sex partners or a history of STI, and [00:13:30] people who have a history of hep C or are being treated with a DAA if they have hep C.

Equally important, and especially for prevention, is vaccination for those who test negative, and those who are close contacts of those who test positive, and even those who have unknown status if they are at high risk that you can vaccinate even before getting the test results.

And the hep B vaccine is the first cancer prevention vaccine out there, and that's an important way to [00:14:00] frame it when talking to your patients.

So, besides the birth dose and the infant vaccinations that are recommended, the CDC also recommends universal hepatitis B vaccination for adults ages 19 to 59, and for anybody who requests it who is ‑ who are 60 years and older. Next.

[00:14:24]

New AASLD 2026 Guidelines: Removal of “Don’t Treat” Wording

So, what's very exciting is that the AASLD, or the American [00:14:30] Association for the Study of Liver Diseases, just updated their hepatitis B guidelines. And one of the big takeaways is that we've now removed the language of ‑ of who not to treat. So, previous guidelines really emphasized when not to treat. And the 2026 guidelines has expanded our ability to treat more people and has intentionally removed that language.

So, instead, what we see come out of these new guidelines is the emphasis in a shift towards [00:15:00] individualized care and shared decision‑making, especially among certain groups.

So, now our approach, when we have patients in front of us, is to recognize that everybody is potentially eligible for treatment. And in theory, anybody who's surface antigen positive with any viremia should be offered treatment. But we should be asking "Would this patient benefit from treatment?" And instead of looking at who falls into our neat categories, maybe we should be thinking about who we don't need to treat. And so, while [00:15:30] it looks complicated here and there, you will see that there are more categories which I'm going to show you in the next table where there are more indications now for treatment.

[00:15:44]

Indications for HBV Treatment

All right. So, this just kind of simplifies the algorithm that you will see that still looks complicated, but it basically puts people in different buckets. So, our "Treat Now" bucket which is clear and some of this hasn't changed too much from the previous guideline, [00:16:00] is we're targeting people who do have active chronic hepatitis B or cirrhosis. So, those who are ‑ have active hepatitis B with ALT over or equal to two times upper limit. And the normal, again, for AASLD guidelines is 35 for men and 25 for women. If they have viral load over 2,000 IU/mL if they're e‑antigen positive, or if it's over 2,000 IU/mL if they're e‑antigen negative.

Anybody [00:16:30] with advanced fibrosis or cirrhosis should be treated. Anybody coinfected with HIV should be treated, and there are a number of special populations, including those receiving immunosuppressive or immunomodulator therapy that should be treated. And I'll talk later about the cut‑offs for pregnancy.

Currently, we're still deferring treatment for those who are inactive, less than 2,000 IU, and a normal ALT if they don't have other indications. [00:17:00] And we'll go into those as well. Next.

[00:17:07]

2026 AASLD Guidelines: Expanded Treatment Criteria, With Use of Shared Clinical Decision‑making

All right. So, what are the groups where now it's very explicit where we're talking about adding shared decision‑making or definitely taking into account the patient's values and preferences for treatment. So, where we see this is in three different groups.

So, the immune‑tolerant phase group, which is now you see the definition has changed [00:17:30] a little bit. People in the immune‑tolerant phase are those who are e‑antigen‑positive with a hep B DNA load of over 10 million or 7 logs, which is higher than what it was before, because we want to make sure they're truly immune‑tolerant and they have to have normal ALT to be considered immune‑tolerant.

So, for those who are age 40 or high fibrosis over F2 or a liver inflammation grade over 2, then those are [00:18:00] clear indications for treatment. But if somebody is immune‑tolerant and they're under 40 years of age, then we now have the ability to use shared decision‑making into deciding whether somebody should be treated. And some of those reasons may be, obviously, if somebody has very high viral load, they're more likely to transmit the infection. And so, perhaps if they're sexually active and unsure if their partner has been vaccinated or not, you know, that may be a concern. Or perhaps if they live [00:18:30] with somebody who is immunocompromised, you know, that would sway you into starting somebody on treatment earlier for somebody in this phase, especially to help with transmission.

That kind of goes into the third category. So, I'm going to go ahead and talk about that now. But this is a very new indication that's actually not in any of the other guidelines that have been updated. But the AASLD guidelines do include an indication for preventing horizontal transmission.

So, for those people [00:19:00] with hep B viremia and not necessarily meeting disease specific treatment indications, but if they are at high risk for transmission to others, you can use a ‑ utilize a shared decision‑making approach for starting antiviral therapy for the ‑the reason to prevent transmission. And so, this is something that is important to let patients know because if they are very concerned about transmission and they are living in a household or have ‑ are sexually active with somebody who they're concerned about [00:19:30] transmitting the virus this is something that will be important for them to know that they can be start antivirals for that purpose.

And then in the middle, we've got indeterminate phase, which is a big chunk of our population. So, those people who are not following into the criteria for being active, but may have ‑ maybe their ALT is elevated, or their ALT is normal, but the viral load is elevated. So, we can use shared decision‑making now for initiating treatment of people [00:20:00] in this group.

[00:20:04]

Immune‑Tolerant CHB

So, this is going back to the immune‑tolerant group, and where you may be... This kind of helps us think about, you know, what are the reasons you might initiate therapy and what are reasons you might defer therapy for somebody in the immune active phase. In terms of ‑ in terms of reasons, transmission to others, the risk of integrated hep B DNA because we now know that integration happens early in life. And the more integrants we have, [00:20:30] we have a higher risk of spontaneous development of mutations, and some of those mutations with clonal expansion can become hepatocellular carcinoma. We worry also if patients do not stay in close contact in terms of like having their every‑six‑month visits. We may miss them when they're transitioning to an immune‑active phase if they're not adherent to monitoring.

And there's some data showing that people who are not in treatment are more likely to fall out of care. One [00:21:00] reason may be that because now we have generic options, they are simple, safe, they're all oral, and they're affordable. So, for patients who really want to be proactive ‑ and I have patients who, you know, if they ‑ you know, they, if I don't ‑ if we're not going to take therapy, they're going to take potentially a supplement or something because they want to do something about their hepatitis B. And so, in those circumstances, you'd say, you know, "Let's put you on treatment because the antiviral treatments are quite effective. And we'd rather you do that than take something that has not been [00:21:30] proven to help your hepatitis B."

Now, some of the reasons to defer antiviral therapy until somebody becomes immune active are that we do see low rates of e‑antigen or surface antigen loss with people in the immune‑tolerant phase, and we may not fully suppress their HBV DNA because the viral load is so high. There is lack of data supporting HCC risk reduction in the current studies we have. And it's, you know, it's a real fact that adherence over a long period of time may be a challenge for [00:22:00] many people, and the pill burden is an issue, especially in younger individuals.

And below, we just kind of summarize the treatment recommendations for immune tolerant based on age differences using age 40. All right.

[00:22:16]

Antiviral Treatment in Patients with CHB in Indeterminate Phase (“Gray Zone”)

Let's go to our next group. So, the other ‑ the big group I mentioned was the indeterminate group, or people we've been calling in the gray zone, and we've seen that it's actually quite a lot of people. In some studies, 30 to 50% of those people [00:22:30] living with hep B actually fall into this ‑ into this group. And a retrospective cohort study showed here of 855 treatment‑naive individuals without fibrosis in the ‑ in the indeterminate phase in 14 centers showed that if you take a look at this, over the course of time, the HCC incidence was higher in this group of indeterminate people who were untreated versus those people who were treated, and antiviral therapy reduced [00:23:00] HCC risk by 70%.

[00:23:07]

Indeterminate Phase: 2026 AASLD Guidelines

And also, just didn't show in that slide, but many people who are indeterminate phase often stay in the indeterminate phase for ‑ for many years. And so, because of that, we don't necessarily want to wait too long if we see that they are, you know, that they fall into this category.

So, this is what the 2026 AASLD guidelines [00:23:30] now say, that you can consider treatment, and especially if people have certain risk factors. So, they're obviously indeterminates two categories. Those are the e‑antigen‑positive indeterminates where we're using a higher viral load of 20,000, and the ALT is one to two times upper limit, where you can consider treatment.

And then the other group of e‑antigen‑negative indeterminates. And those are people with a viral load of over 2,000 and ALT less than two times upper limit. And [00:24:00] in this group, the e‑antigen‑negative, we want to consider treatment based on shared decision‑making. And some of those factors that you would take into account when making the shared decision‑making are factors that are associated with increased risk for HCC. You would obviously recommend stronger that people go on treatment, but people over age 40, people who have F2 fibrosis or higher, if they're male, and if their platelet count is 180,000.

So, another really important caveat to these recommendations [00:24:30] is that if you're not starting treatment in this group, then monitoring for ALT and hepatitis D ‑ hepatitis B DNA every three, six months is critical. And you want to reassess the need for treatment at every visit. So, rather than people thinking that they've been told once they don't need treatment and they think that's a permanent state, we want people to know that every time we need to assess you, because things may change. And, you know, usually people are still asymptomatic when they're ‑ when they're ‑ when their labs change. And [00:25:00] so, they may need treatment at that point.

[00:25:03]

Indeterminate Phase Is Common in CHB

So, indeterminate phase is common. And this is a study kind of showing what percentage of people may have it. And so, in this one study we saw up to ‑ it was 38.7% were indeterminate, 40% were inactive, only 14% were immunoactive and 6.3% were immune‑tolerant. And this may vary ‑ vary in different parts of the world [00:25:30] and looking at different genotypes, but it does show you that the indeterminate group is quite significant.

[00:25:37]

Treatment During Pregnancy: 2026 AASLD Updates

So, now we're going to move to pregnancy. And this is not ‑ the cut‑off has not changed for treatment here. It still remains that if a ‑ if the viral load for the mother is over 200,000 IU/mL then you would start treatment at 28 weeks. And now we've [00:26:00] added TAF as an option. So, not just TDF. So, now tenofovir alafenamide can be used as an additional option based on some great studies to showing that it's safe.

And of course, critical to preventing mother to child transmission, along with treating those with high viral load are birth dose and HBIG within 24 hours ‑ 12 hours of birth [00:26:30] if the mom is pregnant, and then completing the vaccine series with the second and third shots in infancy after that.

All right. So, did I miss one? No. Okay.

[00:26:50]

Evolving Guidelines Treatment Paradigms: Treatment Expansion

All right. So, this is just to show you that we've been ‑we've had evolving guidelines. It's been a really exciting time over the past couple of years with the guidelines [00:27:00] all over the world changing. And all of them are moving towards treatment expansion, although there may be some differences in the specifics, but it's great to see this overall movement towards expanding ‑ getting people on treatment earlier.

And so, you can see that there were some kind of ‑ started ‑ this whole flurry of updates started in 2022 with a Chinese Liver Society and their ID society making some really big changes in theirs. In 2024, [00:27:30] WHO updated their guidelines, and they're targeted at lower‑middle‑income countries. And they allow for treatment even if there's not access to hep B DNA, which is often a very expensive test. So, you can treat alone even if there's just abnormal ALT and you don't have a hep B DNA test.

And this is, I believe, quite relevant in a lot of high‑income settings, because sometimes patients can't afford to get a viral load test, or they may not have access to viral load tests. So, I would say the WHO guidelines can be followed in some of those circumstances. [00:28:00]

And then the World Hepatitis Alliance, a patient group, and Hepatitis B Foundation both put out statements ‑ sorry about that ‑ put out statements basically saying that patients wanted to be treated and they wanted the right to be able to ask for treatment. And so those were really important patient‑empowerment statements. And so, you know, we want patients to know that they can ask for treatment. And patient preference is equally important to some of the lab considerations [00:28:30] and clinical considerations.

So, in 2025, we saw the European Liver Society, the AASLD, and IDSA update their guidelines. And then just this year, actually just a month ‑ actually, this month, the Asian Pacific guidelines were updated just a month ago. So, those will be ‑ those are exciting to see because they're also very expansive. And they also include a treat‑all indication.

And a lot of this has changed because we've seen really [00:29:00] solid evidence that these antivirals are safe, that we're seeing really great treatment impact from them, the longitudinal studies on disease progression, and we're also seeing falling costs of the diagnostics and the treatment so that they are much more accessible. And we've also seen little resistance develop with the ‑ with long‑term use of the antivirals.

[00:29:27]

Monitoring While on Oral Antiviral Therapy

So, important to remember is that while on anti‑therapy ‑ [00:29:30] oral anti‑therapy, we want to continue monitoring. So, what you want to do is test people for the HBV DNA and ALT every three to six months. You know, once people are stable, every six months is okay. And now that we have these quantitative hep B ‑ sorry ‑ the second one is actually just to do a surface antigen test to monitor for seroclearance annually. If somebody's undetectable, to do about once a year to see if you've ‑ somebody's loss of surface antigen.

And then the third point is about the [00:30:00] quantitative hep B surface antigen, which Jordan will actually talk about. So, I'll leave that for him. But this test is much more available now. And add some more information too.

And then, of course, we don't want to ‑ don't want to forget about HCC surveillance, so that we can monitor and make sure if there is liver cancer, we detect it early, but this entails ultrasound and AFP every six months for at‑risk individuals, those with cirrhosis or a family history of liver cancer.

So, the AASLD guidelines now have [00:30:30] expanded the criteria for HCC surveillance and has added people with hepatitis delta or HIV coinfection, and also those who have cleared hepatitis B surface antigen should continue to get HCC surveillance if they have cirrhosis, a family history of HCC, if they're men over 40 or women over 50. So, even if they don't need to be treated, they should still be monitored for liver cancer in those cases.

[00:31:00]

2026 AASLD Guideline Recommendations for Stopping Treatment

So, guidelines for stopping therapy. So, of note, the new guidelines do not recommend stopping treatment until surface antigen loss. If people wish to stop treatment, they should engage in shared decision‑making with their HCP and must meet all of these criteria below, which include not having history of cirrhosis, hepatic decompensation, HCC or extrahepatic complications. They should be antigen‑negative and e‑antibody‑positive for more than a year because sometimes people can flip [00:31:30] back. Their viral load should be undetectable for more than two years. And the quantitative surface antigen level should be less than 100 IU/mL. They should not have HIV or hepatitis delta because those people should remain on therapy, and they should agree to frequent monitoring.

[00:31:50]

HBRN Immune Active Treatment Trial: Predictors of Severe Flares After NA Cessation

So, this is just kind of a warning in terms of, you know, why we want to make sure somebody gets close monitoring if they stop their medication. This is the HBRN, which [00:32:00] is a large hepatitis B research network. And it was a ‑ the prospective study kind of looking at people with hep B without cirrhosis, who stopped tenofovir after four years of lead‑in Peg interferon.

And so, of those who stopped, 100 of them, of which five of them had sustained surface antigen loss, 97 were included in this analysis. And we saw that 37% of them had ALT flares of more than five times upper limit [00:32:30] of normal. And they were not necessarily associated with surface antigen decline or loss, and therefore not necessarily beneficial loss ‑ flares, sorry ‑ that led to surface antigen loss.

And some of the predictors of ALT flares, which you see here on the right are people who have ‑ are older age. And if they have a viral load that's greater than 4 logs. So, the potential criteria for restarting therapy is included in the new guidelines.

[00:33:00]

[00:33:02]

WHO Guidelines: HBV Treatment

So, just so you know, and I alluded to this, that the WHO guidelines for hep B treatment are targeted for low‑ and middle‑income countries or resource‑limited settings. And so, they do include ‑ their recommended treatment is actually for everyone age 12 and older, which is new that it includes adolescents and some of their indications, which are very similar to AASLD and some of the other guidelines are people with [00:33:30] fibrosis or cirrhosis. And looking at non‑invasive measures such as APRI or transient elastography with APRI score of over 0.5 and transient elastography over 7 Kilopascals. Or if they have cirrhosis, you know, they should be treated. If they simplify it to the indications based on lab criteria to not include e‑antigen antibody because the WHO's guidelines are simpler. So, regardless [00:34:00] of your e‑antigen status, anybody who's got viral load of over 2,000 IU/mL or ALT over upper limit of normal, and they use 30 and 19 can be treated.

And then there's a number of risk factors below, including coinfections, family history, immune suppression, and comorbidities. And they include diabetes or MASLD, previously known as fatty liver, as reasons to start treatment and extrahepatic manifestations such as glomerulonephritis and vasculitis. [00:34:30]

And as I mentioned before, if there's no access to DNA, hep B DNA, you can treat those who have persistently abnormal ALT levels.

[00:34:42]

2026 AASLD Guideline Updates: Faculty Discussion

So, I would love to start a discussion with Jordan just to talk about what you think of all these evolving guidelines. And do you have one in particular that you align with, or how do you ‑ how do you approach the many guidelines we have now?

Dr. Jordan Feld (University of Toronto): Thanks. Great ‑ great overview [00:35:00] of ‑ of all the changes that have been happening. And as you said, it's sort of an exciting time in the field. And I think it can be challenging to figure out which guideline to use. You know, I'm probably partial to the AASLD and IDSA guidelines. I think they're a little more evidence‑based, if we're strict about it, than some of the other guidelines. But I think the key point, and you really highlighted it nicely, is that they've taken out the word "don't treat". So, we're now really listening to patients discussing with them.

And I think the shared decision‑making really has shifted us towards [00:35:30] treating more people. And that ‑ that's a conversation that evolves. I think you really stress the point that it's not a one‑point‑in‑time discussion, and these ‑ these things may evolve over time. But it's probably led me to be ‑ people that are in the indeterminate phases where we were previously watching, I'm now having a more fulsome conversation with people, really listening to them, seeing how ‑ where they fall in this. Some people like [00:36:00] to be treated, some people really don't want to be treated unless they need it, "unless they need it," so to speak. So, it's really helpful to have these conversations, but it probably has shifted me a little towards treating more people, I think. How about you?

Dr. Wang: Yeah, I think that's great. And I think you brought up, which is the ‑ the next question right away, which is in what you said about how we navigate shared decision‑making conversations when you said, you know, looking at exactly what the patient wants, right? And you can have two people in front of you with exact same lab tests, and one person really wants to be treated, [00:36:30] and the other one doesn't, right? So, we all, you know, know our patients, and the question, you know, the ‑ it's really important to elicit what is important to them, right? Sometimes we don't ask, and it's important to ask them, you know, and to say, especially in the areas where the shared decision‑making is recommended, which is really areas where it's like not definitive, right? And we are right, the data, you can go either way, and you're not wrong picking either one of them, which I think is ‑ has been challenging for physicians because people don't want to do the wrong thing. And we're [00:37:00] kind of telling them, you, you know, there's ‑ you can go either way and still be okay. So, I ‑ you know, hopeful that patient, you know, physicians see that as an invitation to also invite patients to be a part of that decision‑making.

Dr. Feld: There was actually a question in the Q&A relevant to this, where it says, "I follow the SABA simplified approach to hep B algorithm. The treatment is generic. Why follow these more conservative AASLD guidelines? Treat people so they do not fall out of care." And I think that's an important perspective to consider, but I would just highlight, as, [00:37:30] you know, Su and I both have acknowledged seeing a lot of people with hep B, is ‑ it's really variable. There are some people who really don't want to go on treatment unless they need it. And I think it's important to acknowledge the evidence isn't super strong in some of these areas. So, for someone who doesn't want to take pills every day, and even ‑ even for generic medications, especially if people fall in and out of coverage, what their insurance caps are, that can still be a significant financial burden. So, I think the ‑ I don't think it's wrong to [inaudible] on the side of treatment when you're uncertain, but I [00:38:00] really do think this shared decision‑making approach, taking into account everything, not just the disease, but also where the person is at, what their financial coverage, other circumstances are, can ‑ can lead to different decisions.

Dr. Wang: Yeah, I see that question now. So, yeah, I was involved with the SABA guidelines as well, which used 2,000 viral load cut‑off abnormal ALT in the age of 30 as a risk factor. And I think, you know, if it gets more physicians willing to take on hep B, especially if you're a primary care provider, I [00:38:30] think, you know, we do need some simplified guidelines. And I would encourage people also look at ‑ we put out ‑ actually, I'm a primary care provider, an internal medicine doctor, and we put out a new set of guidelines, which we did base a lot on the ASLD guidelines, but it's called the Hepatitis B Primary Care Guidance. It's hosted by the University of Washington, and it's got a lot of those things from AASLD, but also tailored for the primary care setting.

And I agree, like, I think if you know your patient [00:39:00] is more likely to stay in care and willing, you know, seeing you anyway, they may be on meds already for hypertension or something, you know, it may be ‑ follow up may be fine, but if there's somebody who's, you know, got challenges with getting meds and stuff, like you may want to reconsider, at least really have a serious discussion about compliance with them. But yeah, staying ‑ keeping people in care is really our goal here. And I ‑ and I think, you know, I think physicians often do know their patients [00:39:30] best, but I think sometimes we have to ask them because they will not tell us these things unless we ask them.

Dr. Feld: Absolutely.

Dr. Wang: All right. Well, let's move on because we've got some more exciting things. But we're going to go through our posttest first.

[00:39:43]

Posttest 1

So, this is the question that we looked at earlier. How likely are you to offer hep B treatment to a 40‑year‑old? And remember that the key is offer, to a 40‑year‑old non‑cirrhotic person with hepatitis B e‑antigen‑negative chronic hepatitis B with viral load of [00:40:00] 9,000 IU/mL, but a normal ALT. And your options are:

A. Extremely unlikely

B. Unlikely

C. Neutral

D. Likely, and

E. Extremely likely

So, let everybody put in their answers. And then let's see what we get.

[00:40:23]

Rationale

So, the rationale is that guidelines suggest considering treatment for people e‑antigen‑negative with [00:40:30] hep B viral load over 2,000 and ALT less than two times based on shared decision‑making.

And I had gotten the results, but now they've disappeared, so I cannot see them. I don't know if you guys can pull them up for me.

Okay, so now we have 55% saying that they're likely to offer. So, I think that's good. We've moved on that. And 18% saying extremely likely. So, we now have like almost 70 ‑ 70% of people saying that they are likely or extremely likely to offer treatment. [00:41:00]

[00:41:02]

Posttest 2

All right. And the Posttest 2. How likely are you to offer treatment to somebody 50 years old, non‑cirrhotic, with antigen‑negative hep B but a viral load of 10 million, but normal ALT. And same categories:

A. Extremely unlikely

B. Unlikely

C. Neutral

D. Likely, and

E. Extremely likely

[00:41:24]

Rationale

All right. I'm going to catch the answers before they disappear here. So, it is recommended [00:41:30] to treat people who are in the IT phase if they're over 40. And here we've got 53% saying likely, and 27% extremely likely. Great job.

[00:41:44]

What’s Coming: Progress Toward Functional Cure

All right. I'm going to hand it over to Jordan now. Thanks.

Dr. Feld: All right. Thanks, Su. Well, thanks for setting the stage for moving us, talking about what we have now to talking about what's coming. So, I'm going to be talking about the ‑ what we're looking into the future [00:42:00] and progress towards functional cure.

[00:42:03]

Shifting Therapeutic Goals

And so, when we think about our current goals, I think Su really laid it out nicely that our goal is to really get people to sustain viral suppression. And the reason for that is that that's been associated with really long‑term benefits of reducing the risk of cirrhosis and liver‑related complications, including cancer. But it isn't quite where we want to be. It does require long‑term therapy, and it also does leave people, even who are on therapy, still at risk of cancer. And that's why there's been a move [00:42:30] to try to improve on what we have and try to get to functional cure. And you could say, "Well, why are we even talking about this? What is functional cure? Why not complete cure?"

And I think the reason we've struggled with complete cure, like we've done for hepatitis C, would be that the goal there would be to actually get rid of all traces of hepatitis B from the liver. But the reason that's proving to be extremely challenging is because of two aspects of hepatitis B virology that make it a little more difficult. One is this long‑lasting reservoir [00:43:00] of the virus, the so‑called covalently closed circular, or cccDNA, which stays in infected hepatocytes, maybe for the length of the cell and maybe even survive cell division. And then even more challenging is that this virus, again, unlike hep C, can actually integrate into the host genome. So, you can get bits of hepatitis B DNA that get into the DNA of the hepatocytes, and that will survive replication of the cell.

So, getting rid of every trace of hepatitis B in someone who's been infected [00:43:30] is perhaps beyond what we can do, at least with current technology. And I will talk about maybe some tantalizing ideas that this might be possible in the future, but so we've settled for this idea of functional cure. And what does that mean? Well, it means getting rid of surface antigen, the hallmark of the infection that persists for at least six months off therapy with undetectable hepatitis B DNA levels, and ideally with seroconversion to the development of anti‑HBs.

[00:43:56]

Benefits to Functional Cure vs Long‑term Suppression

So, why have we chosen this? Well, for people, why is ‑ why is functional cure better? [00:44:00] Well, if you take it from the patient perspective, first of all, as I'll show you, it is associated with a reduced risk of complications, but it also allows people to be off therapy. We're talking about lifelong treatment for most people once they start.

And it's also important for the ‑ the people with hepatitis delta coinfection, if you clear surface antigen, then generally delta can't replicate. So, people will also clear that.

And finally, for many people, just being surface antigen‑positive, even if they have inactive disease or on long‑term suppressive [00:44:30] therapy, is associated with stigma. And that's particularly true in many countries around the world. But it's true also here in North America, sometimes within families, certain communities. And so just being surface‑antigen‑negative and having this sense of ‑ of not being infected and not being ‑ and not being able to transmit the virus is something that's really beneficial for patients as well.

But it also has some public health benefits because when people clear surface antigen, they have a much lower risk, if not completely eliminated [00:45:00] risk of transmission, and that also reduces their risk of negative health outcomes with health and economic benefits.

And from a provider perspective, if we can actually cure people, just like with hep C, where we cure people, and we don't follow those who necessarily don't have advanced liver disease, we may be able to take people and cure them and ‑ and not take them out of the need for long‑term follow‑up.

[00:45:23]

Goals of New HBV Therapy

So, if we really look at the data to support this, on the left side, you look at what happens [00:45:30] in people who are surface antigen‑positive. And there's no question that if you look at the dotted line at the top, people who remain inactive have a really low risk of long‑term negative consequences. But if you look at the right graph, where you look at the risk of liver cancer, it's only in that orange line at the bottom, where people are surface‑antigen‑negative, where that risk of cancer is really, if not eliminated, reduced dramatically.

So, the reason that we focused on functional cure is data from the long‑term natural history show [00:46:00] us that this really has added benefits for patients.

[00:46:03]

HBV Treatment Pipeline

But how are we going to get to functional cure? It's proving to be a lot more challenging than it was for hepatitis C. This is a different virus and not so easy to cure. And part of it is that issue of the long‑lasting reservoir, the cccDNA and this integrated DNA. But you can see in this intentionally complicated version of the life cycle of the virus, you can see that there are a lot of targets or potential places to interfere. So, you can [00:46:30] actually going from ‑ starting from the right side of the screen, you can try to block entry, prevent the virus from getting into cells. And this is a potentially attractive treatment, particularly for delta with the approval of bulevirtide. That is an entry blocker. It doesn't work as well for hep B on its own, but could be an adjunctive therapy.

You can actually target the cccDNA directly, either trying to destroy it or to just silence it. Even if it's there, you target it so that it doesn't become a replication [00:47:00] competent. And there are a number of strategies. And what's exciting about this is some of the gene‑editing tools that have been used in other areas, like gene therapy, are being potentially applied to hepatitis B to target cccDNA, with the hope that this could potentially cure the infection and even target integrated DNA to get to that complete cure. That would be really nice to achieve, but these are still in early days.

If you continue through the life cycle, you can target the hepatitis B RNA. So, the transcripts of the ‑ of the [00:47:30] virus. And remember this goes ‑ it's a DNA virus, but it goes DNA, RNA, back to DNA. And the RNA is also messenger RNA to make the viral protein. So, when you target the HBV RNA, either with small interfering RNAs or antisense oligonucleotides, you prevent the production of the proteins and also block replication.

You can look at targeting DNA synthesis, which is what our current therapies do, but you can also go downstream in the life cycle and target... Sorry, just ‑ before DNA synthesis, you can target packaging. And so that's the capsid [00:48:00] assembly modulators, or CAMs, you might hear about, that block the encapsidation of the viral RNA. And these look like promising agents that are sort of like "nukes" that can be taken as oral drugs and inhibit ‑ inhibit viral replication very potently. And I mentioned that targeting DNA synthesis with our current "nukes". And finally, you can target assembly or export of the virus.

And so, you can see there's lots of different strategies. I'm not going to go through all of the data for all of these different strategies that are in different stages of development, but it's a pretty exciting [00:48:30] time in the hepatitis B field.

And to add even one extra layer, even if you don't target the virus, you can target the host and try to stimulate either the innate and/or the adaptive immune system to clear the virus.

[00:48:43]

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

Now, it's very exciting that we've had the first phase III trial for hepatitis B in a couple of decades, and this was just reported at the recent EASL meeting with the B‑Well 1 and B‑Well 2 studies that evaluated bepirovirsen, which is an antisense oligonucleotide, [00:49:00] and this was added on to nucleotide analogue therapy.

It was a large international randomized, double‑blind, placebo‑controlled trial in people who were stable on "nukes", did not have advanced fibrosis, and, importantly, had a surface antigen level less than 3,000 but above 100. So, between 100 and 3,000. And patients stayed on their "nukes" and were randomized to either get placebo for six months or to get bepirovirsen injections, subcutaneous injections weekly, as well as their [00:49:30] "nukes". They stayed on therapy ‑after the end of the active treatment, they stayed on their "nukes" for 24 weeks, and then if they met the "nuke" withdrawal criteria, they stopped all therapy. And then we were looking at their responses 24 weeks after stopping "nukes" if they were eligible for that criteria.

And the primary endpoint of this the study was functional cure in people with baseline surface antigen level less than 3,000, with a whole host of secondary endpoints. And I'll touch on a few.

[00:49:59]

[00:50:00]

B‑Well 1 and 2 Primary Outcome Results: Functional Cure

So, we were excited to see these final results, where we had patients achieving high rates of ‑ higher rates of functional cure than we see with "nukes". Now, remember with "nukes", we're looking at maybe a 1‑2% chance of surface antigen loss per year. And here with a six‑month finite therapy, you can see that in both trials was about the same, roughly 20%, so 19% overall, cleared surface antigen and remain surface‑antigen‑negative after stopping "nukes" for over [00:50:30] six months.

So, this was pretty exciting. And you can see that not surprisingly, that didn't happen in any of the over 600 patients in the placebo arm.

[00:50:38]

B‑Well 1 and 2 Key Secondary Outcome Results

And this was an important achievement, but it's also important to highlight that even for those who didn't clear surface antigen and didn't achieve functional cure, there were some people that still had some benefit. So, you can see in both bars ‑ these are the ‑ in the ‑ on the left in the orange is people who started with the surface antigen level less than 1,000, and on the right are those who started with [00:51:00] the surface antigen level less than 3,000. And as you can imagine, those with lower S levels had a higher chance of functional cure. So, you can see those dark orange bars are higher. But even in people who didn't clear ‑ who didn't achieve functional cure, there was an additional group who were able to have undetectable HBV DNA off of their "nukes" for six months. And you can see that that now gets to above 30%.

And in addition to this group, there were a group of people who ended up with a surface antigen level less than 100. And as Su highlighted, [00:51:30] that's associated with a lower risk of bad outcomes and a higher chance of S loss in the future. And if you look at the whole group, that was about ‑ including ‑ so 19% had functional cure and about 30% ended up with an S level below 100 off "nukes", which is a pretty exciting and, I think, holds promise. We'll have to see if that's a durable outcome, but it could be an added benefit even in people who don't achieve functional cure.

[00:51:56]

B‑Well 1 and 2 Results: Safety

Now, overall, this was a safe therapy, but there's a couple of points that are [00:52:00] important to highlight. So, this is the overall high‑level view. And you can see relatively few patients that needed to stop therapy. The most common issues were injection site reactions, but very few people needed to stop therapy. But the one thing I do want to highlight is that the way this drug works, the bepirovirsen is it's targeting the viral RNA, but it's also probably stimulating an immune response. And with that, you see a rise in the ALT. So, there were very predictable ALT flares that [00:52:30] accompanied the surface antigen decline and surface antigen loss. And indeed, patients who had bigger ALT flares were more likely to go on to S antigen loss. And if you didn't have ALT flare, very low chance of S antigen loss.

So, this is important because as you're monitoring patients, you're going to see these ALT flares. And it's important to recognize that at least in the trial, they look to be generally well tolerated and safe, with no evidence of liver failure or other complications. But it is still something to keep a close eye on, especially [00:53:00] if we move into patients with more advanced liver disease.

[00:53:04]

Future HBV Treatment: Mix and Match Combination Therapies

Now, this is the first step, and I would say bepirovirsen is an important ‑ and this was a landmark study to have a phase III trial showing this efficacy. But we hope that this is going to be the first step in a long way to getting to high rates of functional cure. And to do that, we're likely going to need to combine multiple of those therapies that I showed you.

And the general paradigm is we're going to use something to suppress HBV DNA. And this may be our current "nukes", but we may add things like capsule [00:53:30] ‑ capsid assembly modulators, or potentially things like small interfering RNAs that could also work to deplete viral proteins, the antisense oligonucleotides like bepirovirsen and others in development, or we could bring down the viral proteins by targeting them with things like monoclonal antibodies.

Gene editing is sort of the holy grail that might actually lead to a clearance of cccDNA and integrated DNA, but lots of concerns there about safety, and it's still early days.

And then finally, targeting the immune system to stimulate [00:54:00] viral clearance. And you can imagine that figuring out how to combine these different approaches and the timing et cetera, can be challenging.

[00:54:08]

Getting Ready for New Therapies: Practical Considerations

But it's important now, as we are on the cusp of having, we hope, the first new therapy for a while, that people get ready for these new therapies. And one important point is to become familiar with quantitative surface antigen. This hasn't been widely used for a long time, but it's really important that you start measuring this test and becoming used to the value so that you understand who's going [00:54:30] to be eligible for the new treatments, which are all going to have surface antigen cut‑offs. And I'll show you some other utility of this in a moment.

In addition, most of these therapies are being used in people who are already on "nukes" with suppressed HBV DNA. And as Su nicely highlighted, the guidelines are now being more permissive for expansion of treatment. So, if people are going to be ready for these new therapies, you need to be making sure that those who are eligible and want therapy are already treated.

And finally, these therapies may be a little more complex than prescribing [00:55:00] a once‑a‑day pill. So, things like injectable therapies, you may need support in your clinic, things like nursing and monitoring. And so those are things you've got to be thinking about as we move towards a new era of hep B treatment.

[00:55:12]

What Can qHBsAg Be Used for in Clinical Practice?

Now, what else can ‑ why is quant surface antigen useful? You might say, "Well, until I have these therapies, I don't need it." But I would argue that it can be useful for predicting outcomes. So, it's associated with a higher risk of ‑ high surface antigen levels are associated with a higher risk of cancer and other bad outcomes.

It can help you identify the phases. [00:55:30] So, people with a very low surface antigen level can help you understand who's really more in an inactive phase and may not need treatment.

It can also help you understand who's likely to clear surface antigen. And as Su pointed out, if the surface antigen level is below 100, they have a high probability of spontaneous S loss. So, this is a group you can reinforce that message and may not even need some of the newer therapies.

[00:55:54]

Faculty Discussion: Functional Cure

So, I am mindful of time. I want to get to our ‑ our next ‑ just do [00:56:00] our posttest questions. So, I ‑ I think it is when we're discussing this with patients, how we're talking to them about functional cure and who will likely be eligible for the regimens, people are asking a lot about this. So, we are talking to patients about ‑ explaining what's in the pipeline. And one of the key things that we've really become very used to is using quant surface antigen levels to really stratify the patients. Is that true for you as well, Su?

Dr. Wang: Yeah, [00:56:30] and I'm having these discussions already with patients who are hearing about, you know, bepi and the fact that it's ‑ we're hoping it will be FDA‑approved in October, that ‑ like, we are talking about, you know, whether they fall into those categories, right? So, we're looking at quant S if it's over 3,000 or under 3,000. Even just doing it more has been really helpful for ‑ for me to understand. You know, I explain to people that you may have undetectable viral load, but the quant S helps us understand the amount of viral activity in the liver, and that [00:57:00] helps them understand the differences. The two tests. Yeah, I would love to hear how you explain it to patients.

Dr. Feld: Yeah, no, that's exactly what I said, especially for people who've been on long‑term "nukes" and they keep coming back, and the DNA is undetectable, but they still have a high quant surface antigen level. That can be really important for reinforcing that there's still a lot of virus in the liver and that they're likely to relapse if we were to stop. And ‑ and I think that's a challenge.

I'm just going to move on to our final posttest questions just to make sure that we get them covered. [00:57:30] And we'll try to address some of the questions in the Q&A in written responses.

[00:57:37]

Posttest 3

So, this was a question your patient was e‑antigen‑negative, chronic hepatitis B has surface antigen result of 50 IU/mL. What can you tell them about this result.

A. It indicates a low surface antigen level

B. The result is only prognostic in people receiving peg interferon

C. The result is only prognostic in people with e‑antigen positive CHB, or

D. A confirmatory test is needed before interpreting [00:58:00]

Please go ahead and answer. Okay. So, yeah. So, it looks like about a third of people are recognizing that this means it's a low surface antigen level. And I can tell you that we've had this test for a while. It took us a little while to get used to these results, [00:58:30] but a level of 50 is low. And so, this is, you know, anything under 100 is really quite a low level. And that's probably the most important thing to remember with this. Although there are other tests that we can do, we don't actually need any other tests to interpret this on its own.

[00:58:46]

Rationale

Let's move to the next question. Sorry. Here's the response that below 100 is really ‑ is low and predicts a higher chance of S loss.

[00:58:56]

Posttest 4

Based on the results of the B‑Well study, which of the following patients are most likely [00:59:00] to be considered for investigational functional cure regimens?

A. All patients with hep B

B. Patients with lower surface antigen levels on NA therap

C. Patients with chronic hep B e‑antigen‑positive, high HBV DNA, and normal ALT, or

D. Those with chronic HBV with cirrhosis

Please go ahead and answer.

[00:59:30]

[00:59:35]

Rationale

Okay, let's look at the responses. So, we saw that ‑ good ‑ about half of people... Oh, sorry. Okay. No, about half people said with positive disease. So, remember this is a group ‑ this is for functional cure. We're going to be looking at people with lower surface antigen levels who are on "nuke" therapy. So, that's why it's important to be measuring surface antigen levels.

Now the magic number for these ‑ most of these trials [01:00:00] is less than 3,000 or maybe less than 1,000. And people need to be on stable "nuke" therapy for most of these new therapies. And some of those other groups probably are going to be less likely for at least the first therapies that we have.

[01:00:14]

Posttest 5

And finally, which counselling point best describes the potential benefit of investigational HBV functional cure compared with long‑term viral suppression?

A. Functional cure is the standard of care for patients with chronic hep B

B. Functional cure reduces the risk of clinical [01:00:30] outcomes compared to viral suppression alone

C. Long‑term viral suppression and functional cure provide identical clinical outcomes, or

D. Long‑term viral suppression is associated with a large reduction in HBV related complications

Please go ahead and answer.

Okay, [01:01:00] good. So, about half of people recognize the functional cure reduces the risk of clinical outcomes compared to viral suppression alone.

[01:01:09]

Rationale

And that is the correct answer. And that's the reason ‑ it's the main reason that we want to get this antigen loss is there really is clinical benefit to this compared to just long‑term antiviral suppression.

[01:01:23]

Q&A Session

So, with that, we're going to close. We are right on the hour. So, a bit tight for time, but we want to do make sure [01:01:30] that people claim your CME credit, and we'll just ask you some general questions.

[01:01:36]

Poll 3

Do you plan to make any changes in your clinical practice based on what you learned from today's program?

A. Yes

B. No, or

C. Unsure

And Tammy[?] has put in the chat. You can get the link to the ‑ to claiming [01:02:00] the CME credits. And... Oops.

Poll 4

Please take a moment to text in one key message that you plan to make in your clinical practice based on this education. We'd love to hear. So, if you can put that in, that would be great for us to see. Thanks so much. [01:02:30]

[01:02:35]

Go Online for More Coverage of HBV!

So, with that, we'll thank everybody for your attendance today. It was great to see a big turnout, and I hope we covered what's ‑ what the current and what's coming. And we'll try to address any of the remaining questions in the chat. And you'll be able to get more coverage here from Decera Clinical Education. You can go online to have more coverage of hepatitis B with downloadable slides of all the [01:03:00] key data, as well as today's program. And there are on‑demand webcasts with expert faculty commentary on all the key studies. So, here you can see the link. Well, thank you all for your participation, and wish you all the best. Thanks.

Dr. Wang: Bye‑bye.

[END OF TRANSCRIPT]