Hello, I'm Joseph Lin from the Yale School of Medicine. I'd like to thank the ASLD for the very kind honor and privilege of presenting this year's Hepatitis D Brief 2022. In the next 30 minutes, I'd like to try to summarize some of the most impactful abstracts that aim to advance the science, clinical practice, and public health related to viral hepatitis. I'd like to also acknowledge the efforts of Dr. Peter Block, a gastroenterology fellow at Yale, who participated in the screening review of abstracts selected for this presentation. We will go sequentially, going through abstracts addressing Hepatitis B, C, D, as well as those that address aborsed abstracts at the end. I apologize, I wanted to have it checked to make sure these are the right slide sets for this presentation. I'm not sure if there's someone who can do that for me, I appreciate that. I'll go ahead and get us started with our first abstract, this abstract number 30. This is trying to address the issue of global incidence of Hepatitis B in 2022. Although this is a vaccine-preventable disease, we recognize that the incidence of Hepatitis B continues to be very significant, but with significant geographical and regional variability. In this Polaris Observatory analysis, they look at 160 country-specific data and make several observations. First is that the incidence is approximately 1.2 million persons of incident of Hepatitis B in 2022. Observation number two is that this appears to be concentrated in low, middle, and low-income countries, collectively representing about 95% of all incident cases globally. By continent, it's largely concentrated in Africa and Asia, and collectively this represents about 98% of all those globally. The route of transmission is still predominantly in young people. Perinatal represents about 35% of children under age 18, and a small proportion in adults age 18 or older. Interesting among adults that the incidence appears to be concentrated in upper, middle, and high-income countries, and by region, Europe has the highest incidence compared to other regions of the world. This is important data that helps to underscore that the work towards Hepatitis B elimination cannot be achieved unless we begin to address the new acute infections that continue to occur. The next abstract I'll present is abstract number one, presented by Calvin Pan, that tries to address the question about the role of Hepatitis B immunoglobulin related to Hepatitis B vaccine and tenofovir in mothers who are Hepatitis B positive and have high baseline viremia during pregnancy. The current standard of care is that for mothers who do not have high DNA, is to administer HBIG and vaccine at birth, followed by the second and third dose vaccine. And for mothers with DNA above 200,000 IU per ml, that they would have to receive tenofovir beginning at around week 28 to 32. However, in a global context, this is a very challenging task, both due to cost and logistics, and the authors raised the question, is it possible to achieve a decrease in maternal fetal transmission by removing the HBIG components and extending the duration of tenofovir during pregnancy? This is a randomized controlled trial involving 280 E-positive mothers, high DNA, 200,000 or higher, randomized in a one-to-one fashion to receive tenofovir, 300 milligrams, at gestational week 16 or week 28. And so, in effect, it's a comparison of the standard of care, HBIG, vaccine, tenofovir starting at week 28, versus HBIG removed, HPV vaccine, and starting tenofovir at week 16. And the authors report the results of their safety and efficacy analysis. In this group, there are 265 mothers and 209 infants who completed the trial, and the median duration of exposure was about 23 weeks and 11 weeks, respectively, between the two groups. Overall, they reported that there is no difference in maternal transmission between the two groups at 0% on a per protocol basis, suggesting that the regimen that removed the HBIG may be potentially and similarly safe as the arms that included all three components. Other maternal safety and infant safety parameters appear to be comparable between groups as well. In conclusion, this paper suggests that HBIG-removed regimen may be potentially feasible and safe and effective for this population, but may require further investigation, but has significant public health implications. The next abstract tries to address the question, what is the implication of low level of HPV DNA on ACC risk in untreated patients with compensated cirrhosis? We know that the current guidelines across societies do not have uniformity with regard to whether HPV DNA should be a factor for initiation of treatment or not, specifically whether a DNA cutoff of 22,000 is required. In this historic core study of 627 patients with Crohn's disease B untreated from Korea between 2007 and 2021, they were able to compare the risk of ACC between groups with low level of viremia, defined as between 15 to 2,000 IU per ml, and those with undetectable DNA. In this study, they report that low level of viremia was associated with increased incidence of ACC, with an adjusted hazard ratio of approximately 2.36. And in addition, there were other variables that were determined to be potentially predictive in the study, but I think that the main conclusion is that this suggests that compared to patients with undetectable DNA, that even low level of viremia may be associated with increased risk of ACC. This may have important implications for the decision to initiate antiviral therapy in this population. The next paper, abstract number 37, addresses the question about the role of integration in patients with functional cure. In patients with functional cure, we recognize that there remains persistent virus that is traditionally active but non-replicative within the liver tissue. In this study, they aim to use novel capture sequencing and transcriptional sequencing that are performed for integration analysis and immunochemistry of intrapartic surface antigen in this core of patients with functional cure. The authors report that surface antigen capacities were confirmed in 21% of patients with functional cure, and that intrapartic residual surface antigen appeared to be derived predominantly from transcriptional HPV integration in these patients. These results are important and may have important implications for patients who may achieve surface antigen seroreversion and or reactivation. The next paper has addressed the question of high levels intrapartic integrated DNA that correlate with serum levels of surface antigen in E negative chronic hepatitis B. The primary aim is to correlate CCDNA integrated DNA from liver tissue in those who are E positive or negative with chronic hepatitis B and corresponding with serum markers. They used that liver tissue from 56 untreated patients with chronic hepatitis B from the HBRN network, evaluating for both CCDNA and integrated DNA. And the primary finding was that integrated DNA was, in fact, present in all patients in variable quantity. And interestingly, there appeared to be a higher proportion in the E negative patients of integrated DNA in the liver and with interpretation that this could be based on HPV host junctional read compared to those that are E antigen positive. So these conclusions, again, may provide important information that will be potentially important for future studies for investigation of these novel markers that may also have implications for future investigational therapies. Next paper, abstract 40, is trying to identify predictors of those who may achieve very low levels of surface antigen at the end who have resolved HPV. The next paper is looking at S antigen surface antibiotic complex levels that may persist after S antigen loss. This is looking at immune complex kinetics prior to and after spontaneous and or treatment induced S loss using a novel assay. In this study, they look at 31 E negative patients. This is largely from Alaska natives and tertiary care centers with either spontaneous or new conduced S loss. 17 of these patients achieved S antigen conversion with the development of surface antibody. Regardless of the S antibody status, immune complexes continue to be detectable after S loss. So in conclusion, I think that this is just further confirmation of the durability of the complexes long after S loss has been achieved. And I think this may have, again, consequences to require further investigation for the possibility of reactivation in the context of immune pressure, such as with immunomodulatory therapy. In this next study by Huang et al., this is a large multicenter Asian cohort study, combined U.S., Europe, and Asia, that tries to address the question, what is the risk of ACC in patients who meet the definition of indeterminate phase, often with low DNA and ALT in the real B cohorts? They looked at 855 patients, all adults, treated naïve, without advanced liver disease, in the determinate phase at 14 centers. What they report in a multivariate analysis is the following, that there appeared to be a significant relationship between antiviral therapy and ACC risk in this population defined as indeterminate phase, with a hazard ratio of 0.30, suggesting, conversely, that this may be associated with a significant risk reduction of ACC of approximately 70%. I do want to highlight, though, that the incidence rate in this population was fairly small, with larger numbers, that this observation may be even further enhanced, but it was overall 34% at 15 years and untreated, and 11% in the treated groups. This was found to be statistically significant. Next paper looks at functional cure based on PEG interferon in a very large study from China called the Everest Project. This is a four-year update. It is well known that PEG interferon can achieve functional cure in a small subset of patients, but in E-negative patients on NUKE therapy, the success rate of achieving functional cure with PEG as an add-on or switch is less well determined. In this study, they look at a very large cohort of patients that have been fouled over the course of at least one year after being enrolled with NUKE therapy, that's been stable for, again, a period of at least one year, who have achieved DNA level less than 100, E-engine negativity, and a S-engine less than or equal to 1500 IUs per ml. And what they report is that the cumulative S loss at 48 weeks of add-on or switch PEG interferon in this cohort approached one out of three, really quite striking results in this population. Further studies will be needed across different populations and patient subtypes to further clarify the role of PEG interferon in these patients. The next paper will be abstract 18. This is looking at a novel investigation regimen for hepatitis B. The context is that both VIR-2218, a short-interfering RNA, and VIR-3434, a neutralizing monoclonal antibody, have previously demonstrated efficacy against HPV parameters in monotherapy studies with or without PEG interferon with a 2218 compound. This represents the first study that looked at the combination of 2218 and 3434 to evaluate the efficacy and safety of this combination. The authors report in this phase two study that they have, along three different cohorts, this is looking at 2218, 200 milligrams, 3434, 75 milligrams at variable durations of anywhere between 12 to 20 weeks. And you'll see here that the number of weekly dosing varies for the 3434 up to weekly for 12 weeks or for a total of five weekly injections that follow after the 2218 exposure over five months with 2218. The results basically show similar results across the three groups with a mean surface antigen reduction of over 2.5 logs across all three cohorts. Furthermore, these patients also achieve S antigen reductions of at least 1.5 from baseline and absolute levels less 100 at the end of treatment. This is well tolerated overall without major SAEs reported in the study. Further investigation is needed for this protocol with variable doses and duration and potential need for a combination with other novel strategies. The next paper, Abstract 19, we're looking at preliminary data from the Virtu218 alone or in combination with peg interferon in patients chronic hepatitis B. This is looking at a non-steroidal cohort of patients who are stable on NUCC therapy who are randomized to one of five cohorts to receive either 200 milligrams subcutaneous weekly and or peg interferon subcutaneous weekly. As you'll see here, along these five cohorts, cohort one is looking at Virtu218 as monotherapy and then cohorts two, three, four, five are looking at variable combinations of peg interferon for durations anywhere from 12, 24, 48 or 44 weeks with variable duration of 2218 in the fifth cohort of up to 13 doses. So the results are reported as follows that there is excellent response regards to the 2218 alone, which has been previously reported at about 1.9 log drop and with a combination with peg interferon-containing arms, this range anywhere from 2.1 to 2.4 log drop median for the S antigen titer. Importantly, in this cohort, four of these patients appeared to achieve S antigen loss accompanied by S antibiotic conversion, which really suggests that this may be associated with potential functional cure. Although this is 40-week data and a follow-up of 24 weeks duration was required to assess the durability of this response. This again demonstrates that the sRNA alone is not likely to be associated with S antigen loss in isolation, but the combination with peg interferon appears to modulate the response that may be associated with S antigen loss. The next paper, episode 23, is looking at 2829 and 6779 as a therapeutic vaccine looking at immune responses. This is aimed to look at specific immune markers and viral parameters that are expressed within this vector. And what they aim to show here is the activity of immune responses that they describe as a very high magnitude in this vector that suggests antiviral activity and immune stimulation or augmentation. And this provides additional data that may help to support future studies with this individual components and combination. The next study is looking at late-breaker oral abstract 5013. This is looking at a long-term follow-up study looking at boulevertide monotherapy in patients with chronic hepatitis delta infection. This is also known as the HEP4DI Italian multicenter study. These are patients who've been dosed with boulevertide subcutaneous daily for up to 72 weeks. Overall, there are 130 patients randomized, including 85 active, 45 control, of whom 121 completed at the time of the abstract presentation. The preliminary results include the following. First is that there was a higher decline in the S antigen in the active versus control group both at end of treatment and at follow-up week 48. As you see here, the difference are 71 versus 2% and 47% versus 15%. The second endpoint is decrease in surface antigen to less than 100. Again, similar responses here. I just want to correct myself here is that the S antigen decline, rather, is about 1.9 log drop at end of treatment and 1.5 log drop at follow-up week 48. And then finally, in terms of the proportion that meet a much lower threshold for S antigen titer of less than 10 that we see here is that it was about 20% versus 0% at end of treatment and 15 versus 7.5% at follow-up week 48. None of these patients achieved S loss without restoring the new inhibitor. This is a late-breaking oral abstract and therefore full details will be presented in the next hour by the author. This is a paper from Block et al. that is trying to provide updated global epidemiology. How are we doing in regards to elimination? And this is an update through 2021. I won't dwell on the specifics of this particular slide because there are several iterations in post-reform, but I think that this was really focused on where we are in terms of the proportion of countries that have what's described as political will for financing of national programs focused on hepatitis B and C elimination. And the authors report that, although we are making progress towards these goals, that only very few countries are actually on target to achieve the targets for hepatitis C and even fewer for hepatitis B. And in fact, they report that not a single country is currently on track to achieve all targets for hepatitis elimination by the year 2030. Next paper is Abstract 47, looking at hepatitis C virus re-infection after successful treatment with DA therapy in Canada. It is well-recognized that re-infection may occur in a very small proportion of patients after achieving SVR 12, 24, or 48. This appears to be concentrated in those who have new exposures to viral hepatitis C. In this cohort from British Columbia, they looked at their hepatitis testers cohort and follow these patients with DAs who achieve SVR and had subsequent measurement of HCV RNA. In this cohort of 8,400 patients that achieve SVR, about 20% had recent injection drug use and 17% with past injection drug use. In this group, they report 176 re-infections during follow-up of 11,800 person years. And that basically translates to re-infection rate of 1.49 per 100 person years. What they report in terms of predictors are on the right here, and that not surprisingly, the leading risk factor is that of illicit opiate use history. And they also highlight that younger age is associated with a higher risk as well on multivariate model with a judge-to-judge ratio of 3.26. These are likely the consistent theme in terms of the route of transmission of hepatitis C, both for new infection and for re-infection as implications for public health measures to blunt this effect in our efforts for hepatitis C elimination. The next abstract is looking at risk factor for HCV occurrence after SVR, but specifically in the core patients who do not have advanced liver disease. So this is a cohort of around 1,700 patients with hepatitis C all with low FIFOR score, at least less than 3.25 to help exclude advanced fibrosis or cirrhosis. And without a prior history of ACC, all these patients started DAA therapy and achieved SVR. There were ACCs observed in 28 patients during a follow-up of 42.5 months from the time of SVR with cumulative incidence of ACC of approximately 1.8 and 2.5% at years three and five. Using this data set, the goal of the authors was to develop a scoring system to predict ACC occurrence after SVR using three variables that were found to be predictive in the multivariate analysis, including age. This is as described here. This is defined as greater than or equal less than age 65. So if you're over 65, you get a point. ALT at SVR, that's greater than equal to 30. That counts as a point. And third, AFP at SVR of at least 5.0 nanograms per milliliter, also a point. And what the report is that you had a score of zero that the likelihood of ACC during this period of observation out to five years was zero in this cohort. A score of one amount to incidence of 2.9%. And a score of two or three, 7.9%. This is a somewhat interesting and novel model that is a simplified approach for predicting ACC in a cohort of patients with hepatitis C. Specifically, these are patients without advanced liver disease at the time of SVR. The next paper is aiming to look at questions on diagnosis and screening, the care cascade for hepatitis delta. This is from Robert Wong et al, looking at two populations, one of which is urban safety net population, and the other is looking at national VA data as a comparator. And what they show here is that I'm left with a safety net cohort of 884 patients that with chronic hepatitis B, 30% were screened for hepatitis delta, and 7.8% of those patients were found to be hepatitis delta positive. In contrast to the national VA cohort, where among 12,000 patients with chronic hepatitis B, the reporting of approximately 20% testing, of which 3.1% were confirmed to be delta positive. And so this provides additional data points as to the epidemiology of delta among a cohort of patients with chronic hepatitis B infection in the United States. Clearly, additional studies are needed to further characterize the epidemiology that may be divergent based on population in Americans with hepatitis delta co-infection, and identifying whether we can eventually move from a risk factor-based screening approach, which is currently recommended, to one that may be more universal in the hepatitis B population. The next paper, looking at Abstract 28, Treatment of Bulivertide in HIV-infected Patients in a Real-Life Setting. This is aiming to look at the efficacy and safety of bulivertide tumor grams daily with or without peganin for a period of 18 to 24 months in a population with hepatitis delta, hepatitis B co-infection. This was an open-label perspective study performed at multiple centers. This was not performed with randomization, and what they report here are the proportion of patients who achieve undisclosed DNA, sorry, hepatitis delta RNA, or a composite endpoint of greater than two log decline in delta PCR and normalization of ALT, consistent with current regulatory criteria for virologic response. What they report here is, as noted on the pictorial on the right, the increasing rate or proportions who achieve this endpoint with bulivertide in green, as you can see, ranging from 38 to 52%, bulivertide PEG, 21 to 42%, and then the combination of bulivertide and PEG in 50% across month 12, 18, and 24. So in conclusion, I think that we've been able to briefly summarize that there are ongoing advances in regards to our understanding of hepatitis B, epidemiology, natural history, prevention, and therapy. We understand that there's still a need for improvement in our ability to halt and break the cycle for transmission of hepatitis B, particularly from mother to child, novel methods that we've discussed that may help to alleviate the need for HPEG, particularly in real-world or resource-limited settings. Discussed a number of novel investigational therapies focused on functional cure, which are associated with improving efficacy and safety with really exciting data, which I really hope provide a framework for additional studies that will help us move the needle towards functional cure. Although oral DAs are highly effective in achieving sustained viral response in patients with chronic hepatitis C, much work needs to be done to address ongoing issues in regards to special populations, including persons who inject drugs, as well as addressing post-SVR outcomes, most notably HCC. Significant deficits remain in the care cascade, both for hepatitis B and C, but as we note today that we are seeing this for hepatitis delta as well, we're all very excited that novel therapies are currently in development that will hopefully change the treatment paradigm.

Hepatitis B

vertical transmission

Hepatitis B immunoglobulin

hepatocellular carcinoma

Hepatitis B viral load

reinfection