Next, I'd like to invite to the podium Dr. Tatiana Kushner, who is an associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell School of Medicine. She will present this year's hepatitis debrief. Well, thank you so much to the organizers and to ASLD really for the honor of presenting this year's viral hepatitis debrief. It has been a very exciting time in viral hepatitis. This year, we had approval of point of care testing for hepatitis C. We have now recommendations in the US for universal hepatitis B screening. And at ASLD this year, we saw many very engaging sessions on elimination, on our efforts towards getting there, and of course, on therapeutics. This is a brief outline of what I'll cover, but mainly I'll focus on hepatitis B, delta, and of course, hepatitis C. So I'll start with just one abstract that I'll highlight that addresses hepatitis B epidemiology and natural history. I thought this was an abstract that's relevant to our clinical practice and our current guidance on hepatitis B treatment. So currently, the recommendation is to treat individuals with hepatitis B viral load over 2,000. And we don't routinely treat those who have hepatitis B viral load under 2,000. And this abstract addressed two distinct groups in that population, those individuals who have low-level viremia, meaning viremia that's between 20 and 2,000 IUs per ml, compared to those with strictly undetectable hepatitis B DNA, which is less than 20. This was a multicenter retrospective study comparing significant clinical outcomes in these two patient populations, which included progression to E antigen negative indeterminate phase, which means HPV DNA over 2,000, surface antigen clearance, as well as progression to significant liver fibrosis and cirrhosis. And what they saw in these two distinct groups is that there were distinct clinical outcomes as they followed them over time. They saw that there was a higher likelihood of hepatitis B surface antigen seroclearance in those who had undetectable HPV DNA and a higher likelihood of progression to the indeterminate phase in those with low-level viremia. So this suggests that perhaps our treatment goals should be more aggressive and that we should really be aiming for undetected HPV DNA levels and really, in prognostication, know that these are distinct groups that may have different outcomes. So now I'll shift gears to hepatitis B and the interesting studies that were presented this year using approved therapeutics. This is a study that looked at a very important patient population. This is the pediatric patient population with hepatitis B. And really, the guidance about treatment in pediatrics is not entirely clear and varies. And this was a study that sought to investigate the efficacy and safety of antiviral strategies in the pediatric patient population and to explore factors associated with hepatitis B surface antigen loss. This was a prospective multi-center real-world study done in China in children age 3 to 18 addressing two strategies for treatment that were selected by the families and which chose which strategy they hoped to pursue. One of them was pegylator interferon alpha 2B combined with NA monotherapy and the other one was NA monotherapy alone. And in this study, they looked at almost 300 children and followed them over time. The goal for the study is treatment for 96 weeks. And here they reported outcomes at 48 weeks of treatment. And what you see, not surprisingly, is that in the combo arm, the kids did better. There was a 25% likelihood of surface antigen loss in children that were treated with pegylator interferon combination. Furthermore, when they stratified by age, it's the younger children that actually had higher rates of surface antigen loss, so 31% versus 20% in those children that were under age 7. So the conclusion here is that hepatitis B infected children can achieve significantly higher surface antigen, E antigen loss in treatment with pegylator interferon. Of course, the first question that came up in my mind is how do they tolerate this treatment? And actually, it appears that children tolerate pegylator interferon better than adults. And they really tolerated the treatment well, even for very long durations. Another study now shifting to adults also addressed the use of pegylator interferon combination with tenofovir in an adult patient population. And these were results from a multicenter randomized controlled phase 3 clinical trial also conducted in Asia. And here, they had four arms for treatment, three with NA experience patients and one with treatment naive patients, and compared tenofovir alone compared to different arms of pegylator interferon at the 180 and the 90 milligram dose. And what they saw here is that in almost 400 individuals in the full analysis set, that again, those individuals that were treated with pegylator interferon had significantly higher, well, had significant rates of surface antigen loss at around 30%. What they also saw is that baseline surface antigen titers are very important in predicting in who will have surface antigen loss. And so those with surface antigen titers of less than 100 were more likely to achieve surface antigen loss, which we'll see as a recurring theme as we move to novel therapeutics. Notably, I didn't mention, but this study looked at 24 weeks post-treatment. So these are results of surface antigen loss after 24 weeks being off any treatment. So their conclusion here was that pegylator interferon alpha combined with tenofovir can achieve durable surface antigen loss. Again, the question of tolerability comes up. Here, they used actually an intermittent treatment protocol where they took treatment breaks throughout the duration, which helped with improving tolerability for the patients that were on the pegylator interferon. And the last object I'll present in regards to approved therapeutics is a treatment of the pregnancy patient population. So this evaluated tenofovir alafenamide in pregnant individuals at a shorter duration of eight weeks compared to a longer duration of 12 weeks. Of course, in the pregnancy context, we like to minimize medication exposure if at all possible. So here, they looked to see if in those pregnant women with high-level viremia, if we can use eight weeks of tenofovir alafenamide and achieve the same results. The main endpoints here were safety as well as mother-to-child transmission. And what they saw here in the per-protocol analysis is that there was no mother-to-child transmission in either of the groups. In the intention to treat, you see some reported mother-to-child transmission, but that was really due to loss to follow-up as opposed to actual events of transmission. And so the conclusion here is that maternal TAF prophylaxis to prevent mother-to-child transmission is generally safe and effective, and we can use shorter duration of eight weeks, which is feasible. Recently, this week, also Calvin Pan published a paper in JAMA that actually looked at longer duration antiviral therapy, but without the H-big immunoprophylaxis. So I think as we move forward, we'll have individualized treatment regimens in the pregnancy population, depending on region and accessibility for antiviral therapy and immunoglobulin. Now I'll have a few slides about Hepatitis B novel therapeutics. This is a very exciting space, and this is a very busy slide that probably is not even entirely up to date. But just to show how much drug development is going on in the Hepatitis B and Delta space. You see here that we have Phase I, Phase II, and Phase III drugs that are in development, and that really we are looking at them as two categories of medications of the direct acting antivirals, where we're seeing a lot of siRNAs, capsid inhibitors, and then the immune-targeted therapies, such as monoclonal antibodies checkpoint inhibitors. In Phase III of drug development, we have two medications currently, which is very exciting. This is the first time in a while that we have Phase III drugs available. And we have BepiRiversin, or Bepi, for the treatment of Hepatitis B. And we have Bolivertide for the treatment of Delta hepatitis. And as many of you know, Bolivertide is already approved for use in Europe and is actively being used for the treatment of Delta hepatitis. So just a few studies about the novel therapeutics that updated data was presented at this meeting. The first one is from the company VIR, and it looked at a combination regimen with tobivibart, which is a monoclonal antibody, and alepsirin, which is an siRNA. So again, we're looking at combining a direct acting antiviral and immune therapy that have complementary antiviral and immunomodulatory effects to hope to achieve functional cure. The goal here was to investigate the safety and efficacy of this combination regimen with or without pegylated interferon. So we are seeing that pegylated interferon is still playing a role even in these novel therapeutic regimens. And what they did is they had three arms, which looked at monotherapy, dual therapy with these two agents, and then combination with interferon. And the results presented here are end of treatment. So these are not off-treatment results. These are end-of-treatment results. And what they found is that in the individuals on the combination therapy, there is a 16% likelihood of surface antigen loss at end-of-treatment, and a higher rate at 22% in combination with pegylated interferon. So the conclusion here is that these agents, in combination with pegylated interferon, possibly without, are promising. And follow-up is ongoing to determine functional cure rates after cessation of study treatment, which will be really important to see. The next study that I'll share updates on is from Arbutus. This is also a combination therapy with an siRNA imduceran, which was used every eight weeks with nucleoside analog therapy, leading up to a combination with a 24-week course of interferon. We already saw earlier in the year results at end-of-treatment. But here, they presented results at 24 weeks after end-of-treatment. They had 43 non-serotic, NA-suppressed, e-antigen-negative subjects that received initially four doses of this imduceran, and then potentially received two additional doses for a total of six doses with interferon, followed by a consolidation period of nucleoside analog therapy alone. And again, these are results off-treatment 24 weeks after treatment completion. And what they found, which is very exciting, was that in the group that received the six doses of the siRNA imduceran, 25% of the individuals achieved surface antigen loss. And in those that started with surface antigen less than 1,000, 50% achieved functional cure. On the right, you see the viral kinetics picture, which showed that most of the individuals that had surface antigen loss also mounted surface antibody. So very encouraging data, and it will be important to see how they do further out after treatment. And I'll just mention one quick abstract that I just saw recently that was presented yesterday. And this is really investigating a novel immunotherapy. So many of the data and abstracts that I shared until now included interferon as part of their treatment regimen. And really a question in the field is, will we stay with interferon, or will there be other effective immunotherapies that can take the place potentially of interferon? So VTP300 is a targeted investigational immunotherapy designed to elicit AG-specific T cells. And this was a phase 1b2a study that showed sustained reductions in surface antigen when given alone. And in this particular study, they combined it with a low-dose checkpoint inhibitor. They did see some promising early data that there was surface antigen loss in some of the individuals on these treatments. And the conclusion here was that this preliminary safety data showed that VTP300, in combination with low-dose nivolumab, is well-tolerated. There were no significant treatment-related adverse events observed. And perhaps this may be an important component of future functional cure regimens. So now let's shift to delta hepatitis. A lot of abstracts this year on delta hepatitis. We saw many updated looks at local, regional, national, global epidemiology. I'll share just a few of them here. There was one abstract that was from the country Georgia, where they looked at prevalence of delta among hepatitis B-positive individuals in Georgia. And this was a national seroprevalence survey. They found a 3.7% HDV positivity rate among samples that they tested from this national survey. Similarly, there was a national study from Canada that looked at prevalence from referred versus non-referred specimen that were sent to their national lab, and saw 4.2% versus 1% HDV positivity. And then there was updated data from a U.S. database from the U.S. veterans, which looked at prevalence, but also association with long-term outcomes. This was a large retrospective study, which identified a 3% prevalence of delta among patients with hepatitis B, very high prevalence of substance use among these patients with delta hepatitis in this U.S.-based cohort. And they saw significant association with long-term liver-related events, including HCC, hepatic compensation, all-cause mortality, and liver-related mortality. And really, one of the key messages that we've seen here in the U.S. is that we're really not testing enough in order to be able to link these patients to care and optimize their outcomes. We presented data from our system in terms of implementing reflex testing, which is one potential solution. There were significant barriers in getting this done, but it was effective in improving our delta hepatitis testing rates within our health system. So now let's turn to therapeutics for delta hepatitis. So we saw many abstracts at this conference on Bulaveritide, probably maybe 10 abstracts on Bulaveritide, both clinical trial outcome data, as well as real-world data that we're now accumulating largely from Europe. This is the SAVE-D study. This is long-term Bulaveritide monotherapy in patients with HDV-related compensated cirrhosis. So this is a group of individuals with cirrhosis that many of them had a history of ascites, varices, even a few with active HCC. And this is long-term, long-duration treatment up to 120 weeks in patients with delta hepatitis and cirrhosis. And they saw really positive results with at 120 weeks, 74% having virologic response and almost half having combined response virologic with ALT. Furthermore, given the long-term follow-up, they were actually able to look at clinically relevant endpoints, including HCC and hepatic decompensation. They saw low rates of these events, and another poster compared events in the Bulaveritide treated arm compared to those who were not treated, and found that there was a trend towards decreased hepatic decompensation in individuals on Bulaveritide. So this is very promising to see that long-term duration therapy with Bulaveritide is well-tolerated even in patients with cirrhosis. In regards to other novel therapeutics, there was updates from the SOLCIS trial. So this is week 24 primary endpoint analysis from the VIR combination, which is, again, a virbite monoclonal antibody and an siRNA. Here they randomized individuals one-to-one to either mono or combo therapy versus rollover, meaning they started with monotherapy, then rolled over into combination therapy and had longer duration follow-up. And here they present week 24 results of the two top arms, and then week 60 results of the rollover arm. Again, we're seeing very promising results in terms of endpoints. So 100 percent of individuals had HDV RNA response. And then in regards to the combined endpoint, high rates that were sustained even in the combination rollover arm that showed that longer duration of treatment has sustained response. So very exciting that this combination regimen is now planning to move into phase three with the phase three trial to start in 2025 for the treatment of delta hepatitis. The last agent that I'll present on is the BlueJ agent. So this is a monotherapy for delta hepatitis, a monoclonal antibody, BGT778. The goal here, again, was to evaluate safety, virologic response, and ALT normalization and combined response in patients with HDV. They had three courses of treatment with this monoclonal antibody. And what you see, again, is promising results that over time there was increase in virologic response, including to target not detected in all three arms, as well as promising data regarding up to 75 percent combined response in these individuals. All right. So in the last three minutes, I'll move to hepatitis C. So just an update here about how we're doing in terms of our efforts towards hepatitis C elimination. This was an abstract presented by Tushaly from the CDC. And it looked at our treatment rates to date with direct acting antiviral agents using the IQVIA database. So overall, the estimated number of individuals that have been treated in the U.S. with DAAs is estimated to be about 1.3 million. Treatment rates peaked in 2015, soon after the DAAs became available. And although we're really not close to achieving our hepatitis elimination goals, we are seeing some promising trends where there are an increased number of individuals that are being treated that are covered by Medicaid. In addition, although most individuals who are treated are over age 60, we're seeing a rise in treatment of younger individuals. So the conclusion here was that despite overall low treatment numbers, increase in the number of younger persons and those covered by Medicaid is encouraging. However, we really need to make more efforts to get to our elimination goals, which includes actual implementation of the newly approved point of care RNA testing, removal of any Medicaid restrictions and specialist provider restrictions, and innovative programs to reach young individuals with hepatitis C. So not too much in regards to novel therapeutics, but a lot that we saw in regards to novel therapeutic settings and important new therapeutic settings for the treatment of hepatitis C. So this was a study presented by Faladi Nwulia and colleagues, and this was a multi-center randomized controlled trial that evaluated the difference between treatment on-site in an OTP program and standard of care off-site. And what they saw is that there was a clear benefit in hepatitis C rapid treatment initiation in those that were treated on-site compared to those with standard of care, as well as higher SVR rates. So this is the type of strategy that really we should try to think about moving forward in order to optimize treatment and working towards elimination. In addition, there was another abstract by Tony Martinez and colleagues that looked at same day rapid start of hepatitis C treatment, which also was very encouraging in terms of our ability to achieve SVR in difficult to reach populations. The last abstract that I'll present is abstract about treatment and what I think is the last frontier patient population, which is the pregnancy patient population. This was interim results from the STORC study, which is a multi-center phase four open label study for hepatitis C treatment in pregnant individuals from 20 to 30 weeks gestation. And this data was very promising. We're halfway done with our recruitment goal of 100 individuals with 50 patients that are currently enrolled. Of the patients that completed follow-up, 100% achieved SVR 12. There were no significant adverse events related to the drug. And notably, there were some benefits. For example, 0% of individuals had intrahepaticolostasis of pregnancy, which is an associated issue with hepatitis C, suggesting that there's actual clinical benefit aside from hepatitis C cure in these individuals. One question that came up is who will take on treatment of pregnant individuals moving forward? Will it stay in the obstetric realm or will hepatologists do this? And so we have an ongoing survey that all of you are welcome to participate in to share with us if you would be willing, given the expanding data, to treat hepatitis C in pregnancy. If you are treating hepatitis C in pregnancy, there's also an online registry that you can submit your cases to as we continue to accumulate real-world data. Just a few additional late-breaker abstracts that I wanted to quickly highlight, that there are other agents in the hepatitis B space. Unfortunately, I couldn't cover everything. Another agent called Viron, which is an immune therapy, as well as capsid assembly modulators are actively being investigated as another mechanism. With hepatitis C, we saw other abstracts. One focused on the use of a glaucoma-revered preventive sphere, multicenter single-arm prospective study in the acute hepatitis C patient population, as well as another abstract that looked at difficult-to-treat patient population with genotype 3 compensated cirrhosis. So I'd really like to thank all of the presenters who made the presentations available for inclusions. Really like to thank the people listed here for helping me bring together this debrief, and thank you very much. Thank you. Thank you very much, Dr. Kushner.

viral hepatitis

hepatitis C testing

hepatitis B screening

pegylated interferon

novel therapeutics

treatment strategies