Good morning, friends and colleagues around the world. Welcome to HPE Global Symposium. I'm Grace Wong from the Chinese University of Hong Kong. This is my personal disclosure. I'm very honored to co-chair this session with Dr. Joseph And from the Oregon Health and Science University. The newest global strategy to manage patients with hepatitis B virus will be discussed at this intriguing symposium. Topics include the current state of HPV research surveillance for hepatocellular carcinoma in HPV, HPV management during pregnancy, and novel and emerging therapies for both HPV and hepatitis delta. We are going to have these learning objectives, select populations to screen for, vaccinate and treat for HPV, cite surveillance recommendations for hepatocellular carcinoma in the setting of HPV, assess the emerging therapies for HPV. We are truly honored to have groups of world-leading experts around the world to be our speakers today. So let's get started. I would like to thank ASLD for the invitation to present at this conference. There are multiple important perspectives for hepatitis B. There's the lived experience of affected individuals and communities, and of course, clinical experiences. My presentation will look at this through a global health perspective, and this is the outline of the short presentation from the introduction to the 2021 progress report, and then highlighting the strategic shifts towards elimination in a new global healthcare era. And I will talk about the validation of viral hepatitis elimination and how to measure progress. And I will conclude by highlighting some important key techniques. So I'll just provide some background information on this slide. We know that viral hepatitis B is a small DNA virus that has a CCCDNA that is responsible for viral persistence and drug resistance. We know about the multiple disease outcomes with acute and chronic infections and the sequelae of cirrhosis and hepatocellular carcinoma. We understand that interruption of vertical and perinatal infection will have the greatest impact on reducing the incidence and prevalence of chronic hepatitis B infection. Testing by hepatitis B surface antigen and the hepatitis B vDNA is very important in making treatment decisions. And without treatment, the cumulative incidence of cirrhosis over 5 years is around 10-20% in people with active infection. And 2-5% of those with liver cirrhosis develop liver cancer each year. Those infected at birth are at a greater risk of disease progression to cirrhosis and liver cancer. The vaccination has been available since the early 1980s. So the Global Health Sector Strategy on Viral Hepatitis 2016-2021 and this is in response to the growing threat the World Health Assembly set goals for reducing the transmission and mortality of viral hepatitis before 2030. The elimination is defined as 90% reduction in incidence and a 65% reduction in mortality by 2030 from the 2015 baseline. This is a well-known slide. The goal is elimination as a public health threat by 2030 and the health outcomes, two basic health outcomes, one is reducing the incidence from new infections and the second is reducing the annual deaths from chronic hepatitis and sequelae from 884,000 to less than 310,000 deaths by 2030. This is also a very well-known slide and it identifies the five strategic directions of the Global Strategy and the six core interventions for viral hepatitis over the course of prevention, testing and treatment. The 2020 and the 2030 targets are also highlighted on this slide. All guidance available to support hepatitis B elimination, WHO guidelines informed by data and research is available to support all aspects of the viral hepatitis elimination program. The driving force behind these guidelines is to provide consensus for country program managers at all care settings, particularly in low and middle income countries and they differ from many liver society guidelines because they include elements of cost effectiveness, values and preferences and implementation considerations including human rights and equity. There are also guidelines for national strategic planning and for identification of standardized reporting and core indicators for the viral hepatitis response. This slide is taken from the 2021 Global Progress Report for Hepatitis HIV and STI, which assesses and reviews the progress in the health sector response according to the elimination targets established by the Global Strategy. The global burden of hepatitis B remains enormous with an estimated nearly 300 million people living with chronic hepatitis B. We can see significant regional differentiation with 90% of the burden in three of the six WHO regions. As we can see in the box on the left side of the chart, 40% in the Western Pacific region, 30% in the Africa region and 20% in the Southeast Asia region. Now the regional distribution of hepatitis B in low middle income countries has implications for the public health approach to elimination. We can see from this slide that 0.6% of the burden of hepatitis B resides in the Americas. So the 2021 Progress Report also establishes the status of the global hepatitis response and gives us new hepatitis B and C infection numbers and mortality and the hepatitis B prevalence amongst children. The chart on the left side shows that there were three million new infections in 2019, half of which were due to hepatitis B. There were 1.1 million deaths in 2019. 75% of these deaths from liver cirrhosis and liver cancer were due to hepatitis B. And the hepatitis B prevalence in under five in 2019 hit the target for SDG and for the global strategy. And all regions have hepatitis B prevalence in children under five at less than 1%. However, in the Africa region, the prevalence remains above 2% in children under the age of five years in 2019. This has implications for designing elimination programs and prevention of hepatitis incidents in different regions. Although a lot of progress has been made in the past few years, there's still significant gaps in hepatitis B testing and treatment. 10% of the estimated 300 million people were diagnosed in 2019 with variation by regions and less than 2% on treatment. There's a low rate of diagnosis, a low rate of treatment among the diagnosed, and this suggests that there might be bottlenecks to both testing and treatment. The availability of tools and effective treatment offers great potential for scaling up the response and requires a collective effect. Now, this systematic review was conducted to estimate the proportion of people with chronic hepatitis B infection eligible for hepatitis B antiviral therapy. The important points, nearly 150,000 participants from 162 studies were included in the analysis. Now, 32 of these studies reported eligibility for treatment as well as the number of people for treatment according to WHO or other guidelines with a pooled estimate of 19%, ranging from 12% eligibility in community studies to 25% eligibility in clinic studies. From this study, it was estimated that there are 26 million people in need of urgent treatment because of undiagnosed viral hepatitis B. This has implications for designing testing treatment programs. There are several programmatic barriers to hepatitis B elimination, and as shown on this slide, they are related to planning and to data. There are weak surveillance systems and there's definitely inadequate epidemiological data. It becomes important going forward to leverage the COVID-19 investments to improve reporting for hepatitis. There is a lack of engagement with ministries of health and national governments and partnerships to support policy development. There's also, as we know, lack of hepatitis specific fundings and lack of global investments. Advocacy, demand creation, translation of research to practice is definitely very limited. There is a role for AASLD in every aspect of this programmatic planning, from research to engagement and advocacy to support national planning and data collection for viral hepatitis elimination. The new global strategy is linked with HIV and STI. It's interlinked and it's currently in development and builds on the achievement of the 2016 to 2021 global health sector strategies to provide direction for the next eight years to address the remaining gaps. Now, the strategies emphasize the need for coordinated action that will transform the response in the post-COVID-19 era. And this strategy already has received multiple public consultation. There are five main strategic directions and I will just highlight the first one, which is people-centered, evidence-based services. This is about putting people at the center of health systems. Now, for hepatitis control, the implementation of decentralized care with integration and simplification provides a unique opportunity to develop comprehensive services to patients with non-complex needs at the primary health care. And it's an important strategy in resource-limited settings. This strategic direction 2, 3, 4, and 5 are important. It suffices to mention the need for innovation in hepatitis B elimination for accelerated action. This includes hepatitis B cure and point-of-care diagnostics for cirrhosis. WHO interim guidance for validation of viral hepatitis has been developed for countries seeking validation of elimination, and it's aligned with the Global Hepatitis Strategy. It defines the criteria for country validation for both hepatitis B and C and provides a pathway for countries seeking validation of elimination. The table on this slide summarizes the elimination targets. We do know now that the hepatitis B surface antigen prevalence in those age 5 years or less is a proxy of the true chronic hepatitis B incidence. An absolute annual incidence of hepatitis B is a proxy of the true chronic hepatitis B incidence. An absolute annual HBB-related mortality rate of less than 4 per 100,000 persons has been identified as the criteria. The programmatic targets are also shown for hepatitis B in the box below. Note that the guidance proposes the use of absolute impact targets below a specific threshold to validate elimination. And the rationale for adopting the absolute target is shown in the table on the right hand of the slide. So, in terms of incidence, measuring the prevalence of hepatitis B surface antigen in children less than or equal to 5 years old, the preferred approach is a national-level biomarker survey among young children. But it is recognized that this may be challenging in certain countries and various other methodologies are suggested in the slide. The post-vaccination serological testing of exposed infants can be used to calculate the mother-to-child transmission rate. Like I said, this is an additional indicator in countries that practice targeted timely birth dose. So, the liver-related mortality due to hepatitis B and or C, the measurement options are also provided. Preferred is the direct measurement of liver cancer mortality due to hepatitis B using national death registers and cancer registries. However, this is a challenge as most countries do not include a theology of hepatocellular cancer in the death certificates or in cancer registries. And implementing direct measurement requires significant change in coding practices, even in the format of the death certificates. Now, indirect estimates of liver-related mortality are also possible in three quick ways using hepatocellular cancer incidence as a country-level proxy for liver-related mortality. Now, there are challenges to this as well as shown in the slide. Sentinel surveillance in sites of excellence, including tertiary care centers and university hospitals, can generate data on the attributable fraction and then applying these estimates to national data. Ultimately, estimation of trends in mortality by mathematical modeling using various sources of data for triangulation can be done. So, to quantify deaths from the sequelae of hepatitis B infections or hepatitis C infections too, the WHO proposes to start from the mortality envelope for the sequelae, that is the deaths from cirrhosis and hepatocellular carcinoma from vital registration data, and to correct this on the basis of the fraction of this sequelae that are attributable to hepatitis B or C infections. These can be done in three short steps. Step one, reach out to the National Vital Registration System for deaths from cirrhosis and liver cancer, and this can be the cancer registry. Step two is get data on proportion of cirrhosis and HCC due to hepatitis B or C from Sentinel sites at a specialist or referral center, which can systematically collect this data by recruiting the patients and assessing for hepatitis B or hepatitis C status. And the third step is to connect the two to estimate the fraction of cirrhosis or liver cancer mortality due to hepatitis and monitor this over time. This is a collaborative study between ECDC and ESO using the WHO-developed protocol in three Sentinel sites in Bulgaria, Norway, and Portugal, showing that the etiological fraction estimate is feasible. Now furthermore, such Sentinel studies empower countries, assist the acquisition of up-to-date data, and closely monitor the changes in the attributable fraction at country level. So WHO is also currently conducting country elimination pilots in six countries across the six regions to evaluate the feasibility of different approaches and tools to assess and measure these impact and programmatic targets for both hepatitis B and hepatitis C, some of which we have highlighted in the preceding slides. Some key take-home points, four things to remember. The hepatitis B burden is huge with significant regional variation and gaps in treatment and prevention, and this has to be considered in development of elimination programs. Now the public health approach to scale up has the potential to save lives, millions of lives, to reach elimination targets by 2030. Now the proposed new strategic shift in the global strategy can transform the global response to reach elimination, and collaboration and partnerships are key. Lever organizations are important partners in the elimination agenda. Good morning friends and colleagues. I'm Grace Wong from the Chinese University of Hong Kong. The lecture is HCC Surveillance in HPV. I'm also the director of the Medical Data Analytics Center of CHK. This is my personal disclosures. Hepatitis B virus, HPV, is the key risk factors of HCC around the whole world, in particular in Asia and Africa. By now, there's still more than 230 million people chronically infected by HPV. We have more than 315,000 new cases of HPV-related HCC annually, and sadly, more than half of these patients are too advanced for curative therapy, which leads to more than 200,000 deaths every year. WHO set this very important target for reducing new cases and deaths from viral hepatitis, and in particular, it concerns the death. In fact, the majority of the deaths are related to HCC. So this is one of the key things we should work hard on to reduce the new case, as well as to reduce the death from HCC. Over the last decade or so, we have seen a lot of changes in the world. Over the last decade or so, we have a lot of very nice studies showing HCC surveillance improves survival. Early diagnosis of HCC improves survival. Many international guidelines recommend us to do regular surveillance with ultrasound scan and tumor markers, most commonly alpha-fetoprotein, every six months for our patient who are at risk. Patients under surveillance will have smaller tumor, fewer number of tumor, and longer survival. But still, around a third of these patients died in five years, not just us. Many other groups around the world also show very similar findings that patients who have regular surveillance will have longer survival compared to those without regular surveillance for HCC. In order to provide adequate surveillance program, we first need to understand the risk of our patient who may develop HCC. These are the well-established risk factors for HPV-related HCC. Some are not modifiable, like age, gender, family history. Some will be quite readily modifiable, would be viral load, like high-HPV DNA, the coexistence of obesity, diabetes, hepatic steatosis, inflammation, fibrosis. All these, in fact, would be quite readily reversible or modifiable with adequate treatments. For a good HCC prediction model, it should be simple, objective, with clearly defined variables, not fixed but with modifiable variables, validated widely in various cohorts, acceptable to both academic and non-academic hospital, and also easily applied in real-life practice. There have been quite a handful of very well-known HCC prediction model or HCC risk scores around the world. I just named a few examples from our group. This HCC prediction score were derived more than 10 years ago with just very fine, simple, readily available data that we have that in our regular clinical practice, namely patient's age, similar albumin burden would be viral load and presence of surveillance. With this simple score ranging from zero to 44.5, we can stratify our patients into three level of risk. Patients with score between zero to four would belong to the lowest group with very minimal risk of HCC up to 10 years. But for those with median and high risk, they will have quite significant HCC risk down the line. We know that not just at a one-time shot at the baseline that we can predict the risk, but we know that when patients who have been put on antiviral therapy, their risk may change. Usually would be reduced because of the good control of the virus, as well as there will be some regression of a cirrhosis. In fact, our group also showed that if the patient would be able to have their risk score decrease from like more than one time, or decrease from like more than five at baseline to less than five at two year, represented by the blue line. In fact, these patients will have a much reduced risk compared to those remaining at the high risk, like remaining to have risk score five or above. But I also like to point out that even though the risk is reduced, but there's still a minimal residual risk there, which means that in fact, these patients may still need regular surveillance. CUHCC score is simple, but there's also one shortcoming that this diagnosis of clinical cirrhosis may be sometime not very reliable because some early cirrhosis may be missed by scanning. So we optimize this risk score with a more objective tool, FibroScan, to have the liver stiffness measurement, LSM. So we have this new score called LSM-HCC score. In fact, the score is even simpler with only four components. And again, we can nicely stratify our patient into three level of risk. And this LSM-HCC score have a much better sensitivity and negative predictive value to identify a group of patient with low risk of HCC. And lastly, machine learning approach has been a very hot topic in clinical medicine. Our group also adopted this machine learning models to predict HCC risk. In fact, during this meeting, our group also presented our work concerning various machine learning models. And among those, rich regression is one of the model with very consistently good performance in both training cohort and validation cohort. And with a dual cutoff approach, again, we can identify significant proportion of patient who belong to the low risk group, which we may reduce the intensity of HCC surveillance for them. Now, we would like to understand more about the surveillance strategy. So to improve the cost-effectiveness of HCC surveillance, we would like to reduce the cost by fewer screening tests, less frequent tests, cheaper tests, and also screen fewer patients by very targeted screening. And we also will hope to have better treatment for HCC, which I believe is now the case with improvement in HCC therapy. There will be some questions still remain a bit debatable. For example, whether we should screen every 12 months instead of every six months. And also, should we only use scanning to omit tumor markers like alpha-fetoprotein, or only perform screening in some selected high-risk group by the risk goal we just mentioned? So one of the proposed approach in our previous studies, like the LSM-HCC score, in fact, we can confidently identify a group of patients, they will have very low risk of cancer, like only 0.3% after three years, which means that their annual risk is less than 0.2, the threshold for HCC surveillance. So we may reduce the intensity of screening in these patients and try to reallocate the resources to those patients who are at higher risk, like the high-risk group that their risk will be up to 11% at three years. So we may even shorten the interval to every three months to hopefully identify the tumor much earlier to increase the treatment option of HCC. And concerning tumor markers, there's still a lot of research to identify some new novel tumor markers for HCC. But now we are still using alpha-fetoproteins in many parts of the world, especially in Asia, because it's still the most widely available biomarkers. But we also understand it's shortcoming is that around a third of the tumor would not secrete alpha-fetoprotein. So the sensitivity of this tumor is relatively low, ranging from like 20% to 65%. And there will also be some false positive findings because levels are sometimes elevated in patients with active hepatitis only or cirrhosis without HCC. And current evidence is in fact conflicting as whether alpha-fetoprotein provide additional value when added to ultrasound. But our study are looking to a group of patients who have zero alpha-fetoprotein before and after putting on antiretroviral therapy. And in fact, we realized that before antiretroviral treatment in fact, the alpha-fetoprotein level can be quite unstable and usually would be, tends to be elevated right before treatment because of the active inflammation. But after antiretroviral therapy, like six to 12 months, in fact, the necrosis inflammation will be under good control and the alpha-fetoprotein will be very stabilized. So that's why, in fact, we will advocate for patients who have been receiving antiretroviral therapy for at least 12 months, we may consider to use a lower cut off of alpha-fetoprotein like six instead of 20 in many other study recommended. With this low cut off, in fact, we can have full acquired satisfactory sensitivity and specificity near 80%. So that would be one approach we may better use alpha-fetoprotein in such a setting. We also know there have been a lot of other biomarkers being studied like alpha-14L3, DCP or endoname is PIVCA and so on. So I would say that some studies show that they may be a bit more sensitive or maybe a bit more specific, but I will have to say up to now, even there will be quite a long list of HCC biomarkers being found or being studied. The guidelines will still say that on one hand alpha-fetoprotein will lack adequate sensitivity and specificity, but there will also be no data supporting using other biomarkers at this stage. But now we have a lot of a more in-depth understanding about the biology of the HCC, be it like the tumor development and the progression and invasion. Amongst all, in fact, we have a lot of understanding about the genomic signature, genomic markers for HCC. So some scientists also advocates to use a genomic marker as one of the tool for HCC surveillance. Like here, we may use the cancer epigenomics, including the tumor suppressor gene hypermethylation or even the global hypermethylation for all the chromosome in the patients because it is a kind of pervasive changes and also potentially more sensitive to detect with low coverage sequencing. So like in this study by our chemical pathologists in our university, they identify tumor-derived DNA concentration in the plasma and the normal genome-wise hypermethylation patterns. So here, like this is the pattern of the tumor. So you can see there's some genomic aberration, be it deletion or duplications. And the pre-treatment plasma sample is very similar to the tumor samples. But after treatment, in fact, all these aberration has disappeared because the tumor burden has been removed. And we also can look into their methylation analysis. There will be quite some hypermethylation patterns can be identified before treatment, but not after treatment. So with that, we find that this actually genomic markers would be very sensitive and also very specific in order to identify HCC. I would say at this moment, maybe the main issue is about the cost. The current cost of this analysis would be around $1,000 per sample. I think with technology advances, in fact, the cost can be reduced in the near future. So in conclusion, chairperson, ladies and gentlemen, we are facing a new era of HCC surveillance because we know that we will have more personalized risk stratified approaches to really first identify the risk level of our patient and then to have very personalized, tailor-made HCC surveillance strategy for them. And we are now also studying and identifying some novel approaches, novel biomarkers. First, we may adopt some machine learning models for HCC risk prediction with better accuracy. We also have HCC genomic markers, which would be potentially more sensitive and specific to identify HCC earlier. So with that, I thank you very much for your attention and I look forward to have more discussion during the Q&A session. Thank you. Hi, thank you so much for joining us today on the discussion of hepatitis B in pregnancy. This is my disclosure. I like to focus on two discussion. One is for the acute hepatitis B during pregnancy and the second part, we'll dive into chronic hepatitis B in pregnancy, particularly how to manage the mother-to-child transmission of hepatitis B. Now, even though we don't know the true incidence of acute hepatitis B in pregnancy, but in general population, the acute hepatitis B incident has been declined. In the United States, in 2007, it was about 1.5 per 100,000 cases in the population. So compared to non-pregnant women, mothers who have hepatitis B acute infection actually have some unique features, which include a higher mortality, a higher incidence of fulminant hepatitis, and more likely to develop pregnancy complications. But more importantly, it will increase the risk of mother-to-child transmission, particularly during the third trimester, because as you know, acute infection increase the level of viremia. Even though majority of the mothers, they could get well with observation and supportive care, but some mothers at high risk group, you probably want to offer antiviral treatment, particularly in those mothers with co-infection, emerald compromise, or have a protracted cause, such as persistent symptoms, or even shows the synthetic function compromise. The treatment should be offered with TDF for four weeks or longer, and one exception is even mothers are doing well, but if they infected with acute hepatitis B during the third trimester, you want to offer a TDF treatment to reduce the chance of mother-to-child transmission. Now, besides acute infection, there are some mothers might develop acute exacerbation of chronic hepatitis B. The definition is all over the place. There is no consensus at this point. Some studies use ALT more than five times up and then with normal. The others have a higher bar using 10, but most of the studies would define any elevation of ALT associated with synthetic function compromise, such as prolonged bilirubin, lower albumin, or prolonged PTINR. You should consider this is acute exacerbation of chronic hepatitis B. And in terms of differential diagnosis, we want to be sure patient doesn't have co-infection or super infection of hepatitis E. The other cause commonly can cause elevation of ALT, including NASH, DUTY, and other liver disease should be ruled out. The management is pretty straightforward. If you make the diagnosis, you want to provide antiviral treatment, and usually they have a good outcome. There are no large clinical trial support the data, but this experience usually come from case report or case series. Now let's discuss a little bit on the prevention of mother-to-child transmission. As you all know, right now the standard of care would be providing immunoprophylaxis for the infant, including birth dose of HPV vaccine and HPAID. Now I want to draw your attention to the data at the blue, with the blue background. So if you look at year in positive patients, mothers give a child birth, and then 78% of them without intervention will get into chronic hepatitis B. If you provide vaccine, that will reduce about 20%. And vaccine projects big, now it's very effective. However, about five to 10% of those patients E antigen positive, they can still get the virus transmitted to the newborn. So therefore, in the last 10 years, many study explore the risk factors have defined mothers with viremia more than 200,000 IU, actually at risk of transmission. In a randomized control trial placebo arm, they observed a 7% in this group. If the maternal viremia more than 200 million, actually the transmission rate could be as high as 12%. So the question is, are there any rooms that we can optimize emerald prophylaxis with vaccine and HVAC? Let's take a look at the data in early use of vaccines many years ago, about two decades. In this randomized clinical trial, they look at patients with different regimens. The first group would be intensified vaccine and HVAC time seven. And the second group would be vaccine time three with burst dose of HVAC, which would be the current standard of care. So let's focus on this group. And if you look at the transmission rate and year antigen positive, even though this infants will receive the burst dose of vaccine and HVAC within 38 minutes with a standard deviation, 40 minutes, they still have 7% of transmission. So I think even though we can do a bigger clinical trial with a better design and earlier use than 38 minutes, I doubt that we can produce a better result. And in addition, I don't think it's practical. Even in China now have the most, biggest system to monitor putting the first dose of vaccine on HVAC. You can hardly guarantee that 80 or 90% of patients or newborns receive vaccine within one hour or 30 minutes. So I think it's impractical, even though this regimen might work with early dose, but we'll face a lot of challenge when you implement that. Now, what are the other better options? For the last two decades, since the risk factors has been explored in antiviral therapy has been proven a very effective treatment for e-antigen positive mothers or mothers with high level of viremia. This is a meta-analysis just published by the WHO group and further look at the studies on the risk of transmission or immunoprophylaxis failure. And HPV DNA maternal level more than 200,000 a year have been documented as the best indicator for immunoprophylaxis failure. And therefore it's no doubt in my mind now, any mothers with such level of viremia or above should get antiviral treatment. Now, are there any other markers that we can identify high risk mother, particularly in the resource limited area? The answer is yes. If you look at a couple of studies on surface antigen level as shows here in the AUROC of accuracy 80% by using a cutoff surface antigen 4.1 log. And this have been shown in other study consistently that surface antigen level could serve as alternative marker to identify high risk mother, put them on antiviral. Now, how about surface antigen level now available? Then antigen status, even though it's very sensitive can identify 99% plus mothers at risk. However, the specificity was low as a 62%. So in summary, the best way to identify mothers would be using HPV DNA. If not available, try surface antigen level or alternatively less accurate would be e-antigen status. However, using e-antigen status, you may overtreat some mothers. Since antiviral treatment have been recommended by many dynamics, including the recent published WHO, I would not spend too much time on discussing individual antiviral. In the next couple of slides, I just want to get some example of antiviral treatment for the discussion. The first antiviral treatment used for mothers would be lamivudine. It shows that in this large real-world study, terpivudine and lamivudine were equally effective in terms of reducing mother-to-child transmission. As you see in the right side, 7% control group, the treatment goes 2.2 in ITT analysis, and there was no transmission in the on-protocol analysis for antiviral experimental arm. Now how about tenofovir? Now it's the first line or preferred agent for all the guidelines. It's because lamivudine might have resistant issues and also terpivudine, but some studies show TDFA is more effective in terms of reducing viremia compared to lamivudine. So this is a randomized control trial, more than treatment on the third trimester, enrolled 200 patients. It shows that treatment arm compared to no treatment, immunoprophylaxis failure occurred 18% versus 5% at ITT. It shows at least three-fold reduction on the transmission rate. On protocol analysis, there was no transmission in the TDF arm, whereas the 7% patients infected in the control. So this study actually was extended to a four-year long-term follow-up on the safety data. So here shows TDF exposure during the third trimester compared to the control arm. There was no difference between the bone mineral density score, physical growth, and also neurodevelopment scores measured by Bayley 3 system. So this study actually suggests that TDF exposure showed no safety concern in long-term, and it actually raised the comfort level of using TDF in pregnancy. Now are there any new treatment for mother-to-child transmission? Lately, TAF have been available for general population. Lately, there are three studies published by using TAF treating highly virulent mothers. They're all done in China. And the first was a retrospective study enrolled more than 70 patients during the third trimester or second trimester using TAF. There was no transmission in this single arm study, and there was no safety signals compared to the non-treated mother's historical control. And the second study was a randomized control trial, even though it's a small sample kind of pilot study, enrolled 36 patients in each arm, compared TDF treatment with TAF treatment, and there was no difference. All patients receive either TDF or TAF, have no transmission, and the safety profile were comparable between the two drugs. And lastly, this is a real-world study, also compared TAF and TDF for highly virulent mothers, over 100 patients in each arm, and saw the similar results. There was a zero transmission. So lastly, let's discuss some challenges in the field of preventing mother-to-child transmission. If you look at the association guineye, usual guineye recommend that the antiviral should be initiated at the second trimester, whereas the in contrast AASLD or WHO guineye recommended the antiviral treatment should be started at the third trimester. So what is the bottom line here? Now, some reasons that actually suggest that second trimester have a better efficacy in terms of reducing antiviral load before delivery. This is a meta-analysis sponsored by WHO, and look into the second trimester versus third trimester. It shows the third trimester actually have a better efficacy with an OR of 0.23. Another study published more recently, looking at the antiviral kinetic of TAF versus TDF in terms of 12-week treatment versus 24-week treatment. I know this is a study on the child-bearing age woman, but if you look at the viremia reduction, 12 weeks have particularly in highly viremic female, more than eight lots, 12 weeks is not enough in this data set. It's showing that 12-week was inferior to 24 weeks in terms of helping patients to reach the target level of 200,000 IU. And also particularly those patients have baseline level more than eight lots, that you are talking about 80 or 85% can achieve the target level at 12 weeks, versus 90% plus in 24 weeks. So putting all this together, our data suggests that we probably should modify our current treatment algorithm, should initial the antiviral treatment for highly viremic mothers or e-energy positive mothers at the second trimester. I would, in my practice, I would propose a study at 14 to 16 weeks of pregnancy, particularly if they have HPV viremia more than eight lots. So ESOGAN, I actually suggest second trimester would be more suitable and supported by the new data. Now another challenge would be in the resource limited area, HPV may not be available, or even first dose of HPV vaccine may not be available. The second or the third, probably you can get it from Gavi's vaccine program. So let's talk about this global challenge. I don't have time to list all the countries, but if you look at, just cut and paste the data from Central Asia, many of these countries on the table actually show there is no HPV available or flu vaccination regimens. So therefore it may potentially increase the chance of mother to child transmission during the implementation of so-called triple therapy for highly viremic mothers. Are there any new developments? Yes. Actually in this year, EPASO, the Cambodian group, present a study on patients highly viremic mothers or e-antigen positive mothers without HPV treatment and shows that in the TDF treated e-antigen positive patients, the transmission rate could be reduced to 1.2%, which is comparable to e-antigen negative, serve as a control arm. Now another big study in China is a randomized control trial, enrolled 280 patients and half of them randomized to mothers taking antiviral from second trimester to the third, then the infant received no HPV. The control arm is the current standard, mothers started with antiviral treatment at the third trimester and infant received HPV vaccine. The study have enrolled 280 patients, 233 complete with no transmission. So hopefully this data will be available next year in ASLD. And with all this new data, I would propose in the area that have limited resource, we probably can, based on e-antigen's data, stratify those patients receive antiviral treatment started from second trimester, at least the third trimester if the HPV is not available. Of course, this proposal would open to the group discussion. With that, I thank you for your attention. Hi, my name is Maria Butti. I am professor of medicine at Hospital Universitario Vallebron in Barcelona, and I would like to thank Grace Wong and Joseph Ann for inviting me to the Hepatitis B Global Symposium. My task today is to comment on emerging hepatitis B therapies. These are my disclosures. And this is the outline of my presentation, Limitations of the Current Treatments, Goal of Emerging Treatments, and New Drugs, and I am going to focus today on a selection of different compounds in phase two. The current therapy for hepatitis B, the majority of cases are oral antivirals. These drugs achieve suppression of viral replication with an excellent safety profile and are indicated in patients with chronic hepatitis B for both the positive and negative with cirrhosis and also decompensated cirrhosis. However, this type of treatment needs longer therapy, achieve a very low HVS antigen clearance, and patients still have risk of hepatocellular carcinoma and are not indicated in patients with chronic hepatitis B infections such as immune tolerance or inactive carriers. The goals of hepatitis B therapy is to achieve HVS antigen loss functional cure that is associated with a decrease in CCCDNA and integrated HPV DNA. However, the goals of these studies with new drugs in phase two and in phase three is in addition to achieve HPV DNA suppression to have HVS antigen decline, some degree of immune response with a finite duration of treatment. Here, we have different guided antivirals and drugs, immunomodulatory drugs, that target different steps of hepatitis B replication cycle, such as entry inhibitors, targeting CCCDNA, RNA interference, capsid assembly modulators, inhibition of HVS antigen relays, and new compounds focused on inactive and adaptive immunity modulation. In order to be more directive, I am going to review these new compounds looking at those who suppress viral replication, those devoted to reduce hepatitis B antigens, and some new compounds related to inactive and adaptive immunity. So, looking at drugs to increase suppression of viral replication, there are several capsid assembly modulators and core inhibitors, the majority in phase one or preclinica, but some of them in phase two and even one entering in phase three, that is Bebe Corvir. This is a phase two study that evaluates Bebe Corvir and a nucleoside analog combined versus nucleoside analog for 24 weeks in E-negative and E-positive patients, and then those with response. The study was extended until week 76 with combination therapy. On the right, you can see the response in HPE antigen positive patients and a deeper reduction in HPV DNA and in pre-genomic RNA in those treated with the combination, but a moderate reduction in HVS antigen levels, and only 40% of them achieved more than 0.5 log decline. Similar results were observed in E-negative patients, but what is important in this study is that after this continuation of treatment, these patients were followed for an additional six months, and during this follow-up, all patients had a biological relapse increasing HPV DNA levels. None of the patients achieved sustained biological response. None of the patients experienced HVS antigen loss, and at the time of this continuation, some patients experienced 10% of the ALT elevations, and the majority of them need the reintroduction of nucleoside analog. Let's now look at new compounds trying to reduce HPV antigen levels that are small interference RNA and antisense olinucleotides. Here we have listed the compounds, the small interference RNA in phase two, and looking at VIR-2218, this is targeting RNA interference evaluated in viral-suppressed chronic hepatitis B, two doses at day one and day 29 in NUC-suppressed patients, and the endpoint was HVS antigen reduction, and there is a reduction of dose-dependent reduction in HVS antigen levels during the first 16 weeks of treatment. Then there is a plateau, and after stopping treatment, HVS antigen levels rebound, and similar in other viral biomarkers, and half of them of the patients treated reached HVS antigen levels below 100, but none of them HVS antigen loss. Another compound used for longer treatment duration is AB-729, another RNA interference in non-serotic patients, and in this study, these different doses of this drug was administered every four weeks or every eight weeks in these three cohorts of patients, and you can see that the drug is safe and well-tolerated. There is decline in HVS antigen levels, but no differences were observed between doses and dose interval, and the majority of subjects reached HVS antigen levels below 100 international units. What is important of this study is that in a subset of patients, the investigators look at the immune response, particularly HVB-specific T cell activations markers and interferon gamma, and those patients with HVS antigen reduction have an upregulation of HVB-specific T cell activation markers after multiple doses of this compound. So it's a drug that potentially that can be used for longer duration and can facilitate the recovery of host immune response, and this is another type of drug. This is an antisense oligonucleotide, GSK-836, and also in NUC-naïve and NUC-suppressed patients. These patients were treated with different doses of this compound, and we can see particularly with the high dose with 300 milligrams, there is a reduction in HVS antigen levels during treatment that is maintained, but after treatment, this continuation, there is a rebound and increase in HVS antigen levels, as well as an increase in ALT levels, suggesting that longer treatment duration were needed using this compound. Again, in this study, there is a dose-dependent changes in acute phase proteins and markers of inactive and adaptive immune activation, suggesting, again, that reduction decline in HVS antigen levels are associated with increase in ALT levels and with markers of immune response. Now let's look to innate immunity. There are several drugs under investigation. Due to the short time, I am going to touch only toll-like receptor 8 agonist, and this is the phase 2 randomized double-blind placebo-controlled study with Selgan Tolimot in viremic patients with chronic hepatitis B, and in this study, a patient received two different doses of this compound versus placebo plus oral antivirals, and you can see particularly with the dose of 3 milligrams, some decline in HVS antigen levels, but none of these patients achieved HVS antigen loss. This is an oral drug that is safe and well-tolerated. And finally, looking at adaptive immunity, there are also several therapeutic vaccines under investigation. I am just going to focus on one, B.1.7.9, and this is a small study in phase 1, phase 2A study, non-cirrhotic patients, viral suppress with chronic hepatitis B, and this therapeutic vaccine is given different doses at day 1, 4, 8, and 12, and we can see at week 20, after discontinuation of the vaccine, there is an increase in HVS-specific B and T cell response, particularly when this vaccine is administered together with interferon as has been in a subgroup of these patients. The last part of my talk is focused on the potential of combination therapy combining new compounds to induce the inhibition of viral replication and antigen reduction or even immune stimulation. Just two examples, this is the first clinical experience with triple combination therapy combining an RNA interference and a capsid assembly modulator and a nucleoside analog, so three drugs in patients with chronic hepatitis B. Twelve patients received this combination for 12 weeks, and the data on efficacy show a decline in HBs antigen levels. Treatment is very well tolerated, and this reduction in HBs antigen levels were very similar between E antigen positive and E antigen negative patients. There is another study looking at combination of two different drugs, and this is the combination of an RNA interference, BIR2218, with an approved drug for hepatitis B, that is PEC interferon alpha 2B. This is a phase two study, three different cohorts of patients, one treated with the BIR2218, another 12 weeks with this new compound, and after combination with PEC interferon, and the third cohort, the two compounds together from starting treatment. You can see, particularly in the cohort three, that this combination from the beginning, a more deeper decline in HBs antigen levels, and this decline in HBs antigen level occurs during the 12 weeks of treatment, so that it's preliminary results on treatment, and it is associated, in some cases, with an increase in ALT levels. The drug is well-tolerated, and no new or different side effects not related to interferon has been observed. So promising results, but we need to wait to the end of treatment results. So in summary, ladies and gentlemen, the majority of emerging hepatitis B therapies are in phase two or one, or even preclinical, have been evaluated in very selected patients with chronic hepatitis B in terms of age. The majority with my disease, no cirrhosis and no comorbidities. Several studies with these new drugs show an increase in viral suppression and a reduction in HBs antigen levels, and some partial modulation of immune response. Safety seems relatively good, but there is a lot or very, very few data of treatment response to support final duration of therapy. These last studies looking at new drug combinations are ongoing, and I am sure that they will help on the design of better strategies for treatment of hepatitis B. Again, thank you very much for the invitation and for your attention. Good afternoon. I'd like to thank the organizers for the opportunity to speak about hepatitis D. This is a rapidly moving and exciting field. I have no disclosures. Hepatitis D was discovered in 1977 by Dr. Mario Rossetto and colleagues, where they described a new antigen antibody system, which they called delta and anti-delta, associated with hepatitis B. And since then, we've known that delta or hepatitis D is completely dependent on hepatitis B for its existence. However, unlike hepatitis B or hepatitis C, there's a much faster progression to cirrhosis. 10 to 15% of patients with hepatitis D develop cirrhosis within two years, and 70 to 90% will develop cirrhosis over 10 years. There's an increased risk of hepatocellular carcinoma compared to hepatitis B. This is thought to be three to six-fold higher than hepatitis B alone. And the mortality, when compared to hepatitis B, is approximately two-fold higher. When looking at the epidemiology, we have to think a little bit about a number of caveats. First of all, some studies look at antibody alone, and others look at antibody and the presence of virus. Usually, in most studies, the presence of virus is about two-thirds that of the antibody. It's also different if one looks at the clinic, a liver clinic, versus the general population. And even amongst hepatitis B surface antigen carriers, the incidence or prevalence of hepatitis D is different, depending on whether patients fall into a high-risk or low-risk categories. There's tremendous assay variability, and perhaps the biggest barrier or obstacle to knowledge has been the lack of testing. These are quotes taken from a wonderful paper by Dr. Rossetto et al. earlier this year, where they say, despite 40 years of surveys, the number of infected patients remain undefined. And they quote, three of the most recent studies where the numbers are estimated at between 48 to 60 million, 62 to 72 million, and 12 million. They then state that these widely different figures emphasize the heterogeneity of reports on hepatitis D and a lack of sufficient quality data. Thus, inadequate screening, technical limitations, and a lack of testing to confirm ongoing viral replication all affect studies on the epidemiology and clinical impact of hepatitis D. With that as background, let's look at some epidemiology. This slide shows two important features of hepatitis D. The first is the genotype distribution. Genotype one is found globally, genotype two in Asia, three in the Amazon basin, four in Asia, and five through eight in Western Central Africa. This map also isolates and identifies hotspots like the Amazon basin, Central Africa, Mongolia, Pakistan, and parts of Europe. This figure was taken from a recent publication by Stockdale et al. And the important point here is when we look at the prevalence in the general population in panel A, it's different to the prevalence in a hepatology study It's different to the prevalence in a hepatology clinic in panel B. And I'll highlight particularly Turkey and Africa where it goes from a lower prevalence to a higher prevalence when going from the general population to a liver clinic. To further emphasize some of this, when 588 patients in a North American cohort who had been tested for hepatitis D were assessed in a multivariate analysis, the presence of low level hepatitis B DNA and elevated ALT were found to be significant. Predictors of hepatitis D, this is already well known. Hepatitis D is spread through blood and body fluids. And thus it wasn't a surprise that intravenous drug use was a significant risk factor. Hepatologists have become very good at looking for risk factors related to blood and body fluid transmission. However, the fourth feature, the country of origin and looking for countries or areas of the world that have higher endemicity for hepatitis D is less appreciated. And I'd like to emphasize this in particular. When we see patients in the developed world, we have to consider the country of origin and whether or not patients come from an endemic area. Challenges are that patients often present with advanced disease, that there are flares on withdrawal of treatment. Hepatitis D suppression is associated with hepatitis B flares. There's a lack of standardization of testing and also the definition of responses. And sometimes what we have thought to be relapse after therapy was really a problem with insensitive assays. There's a lack of awareness of hepatitis D and there's also often confusion with autoimmune hepatitis because hepatitis D often presents with a florid inflammation on liver biopsy and highly elevated liver enzymes. There's no talk which addresses treatment for hepatitis D without this, which should not include this statement. Vaccination for hepatitis B is the ultimate cure for hepatitis D. This will lead to eradication of hepatitis D. The history of the treatment for hepatitis D is interesting. The first papers came out 10 years after the discovery or description of hepatitis D and they were back-to-back papers in the same journal, one at the NIH led by Dr. Hofnagel and the second by Rossina et al in Italy, looking at the use of interferon to treat hepatitis D. The use of interferon has been studied in a number of settings and is well-established. Interferon has been used alone with anti-hepatitis B therapies as well as long-term. A seminal paper by Dr. Fauci and colleagues in the New England Journal in 1994 looked at the treatment of 41 patients for 48 weeks with interferon alpha at 9 million international units versus 3 million international units three times a week or no therapy. And 71% of patients in the high-dose group appeared to respond versus 36% in the low-dose versus 0% in the placebo group in terms of hepatitis D RNA. However, on follow-up, a relapse was common. And in longer follow-up of almost 10 years of 36 of the previous patients, there was a statistically significant benefit in terms of survival for the high-dose versus low-dose and high-dose versus controls. Most interesting was that there was regression of cirrhosis in four patients. There've been multiple studies using interferon trials for hepatitis D. I've highlighted just some of them. And in general, the response rates range between 20 and 30%. Interferon has also been given over the long-term. When it was given for five years to 13 patients, three seroconverted within five years by anti-HPS and one after five years. In a follow-up study, when patients were followed for 8.8 years on average after stopping therapy, just found that six of seven responders were still alive versus one out of five non-responders. In a really instructional case report published by Dara Lau and colleagues, a single patient was given peg interferon for 12 years. And this patient seroconverted to anti-HPS and a complete resolution of cirrhosis with loss of hepatitis D. Problems are that these are all small studies and there's limited experience with different gene types. Mostly genotype one has been treated and there are different hepatitis D RNA assays, different doses, duration, follow-up and endpoints used. To be complete, I just want to show you a couple of studies looking at treatment of hepatitis B in an effort to improve outcomes for hepatitis D. Suffice it to say, in four different studies, including one in the New England Journal, so therefore it must be true, there was no additional benefit to treating hepatitis D in an effort to improve outcomes for hepatitis D. Treatment guidelines say that, by the SLD, say that peglet interferon should be used for 12 months. And if hepatitis B levels are elevated, therapy should be given using nucleoside or nucleotide analogs. And that consideration should be given to referring patients to specialized centers. There is no currently approved FDA therapy for hepatitis D. Future therapies really reflect the success of molecular biology and cell biology. And understanding the hepatitis D life cycle is really one of the opportunities. I'd like to address four investigational treatment options. And I'll go through each of these in detail. Peglet interferon lambda, entry inhibitors, specifically bilivertide, which is now EMA approved and is often drug status in the United States. Nucleic acid polymers, REP2139, and peronylation inhibitors, lornafonib. Much of the data has only been presented in abstract form. Much of the data is dose, duration, and optimal administration discovery. I'll focus on the highlights. And I'd also like to point out that treatment trials have looked at surrogates. And remember that we treat really to prevent death, cirrhosis, and clinical outcomes in hepatocellular carcinoma. Here, the studies have used ALT, more than a two log decline. And there's a robust debate as to what constitutes a durable biologic response. The first agent I'd like to address is peglet interferon lambda. This is a type three interferon and activates the JAK-STAT pathway, similar to interferon alpha. It has been shown to have similar efficacy in hepatitis B and hepatitis C with less side effects. And this is probably because the receptors have a greater hepatic restriction. This was a phase two study done with lambda monotherapy, where 36 patients were treated with a high dose or low dose of 120 or 180 micrograms subcutaneously weekly for 48 weeks. And shown on the right is a graph of the HDV RNA response. At 24 weeks of post-therapy follow-up, 36% of patients had undetectable HDV RNA. And this is being explored in further studies. When we look at the life cycle, there are three areas which are currently being exploited to develop therapies. The first is entry inhibitors. The second is assembly and release inhibitors. And the third, renylation inhibitors. The first are HPV and HDV entry inhibitors. The human sodium torocholate cotransporter peptide, or NTCP, is a transmembrane protein receptor for hepatitis B and therefore for hepatitis D as well. And it inhibits entry of both viruses in in vivo models. And I'll just highlight one of the studies, the most recent presented at Eazl this year, where bilivertide monotherapy at low and high doses at two and 10 milligrams in patients with chronic hepatitis D, who were treated for 24 weeks was presented. You can see in the upper left panel that the average patient experienced the more than two log decline in HDV RNA by 24 weeks. And when assessed further, ALT normalization occurred in between 38 and 53% of patients. And I'd point out that in the higher dose group, 68% of patients had a virologic response that is more than a two log decline from their baseline. The secretion inhibitors are nucleic acid polymers. These are oligonucleotides with activities against the diverse array of infectious agents. The specific mechanisms or actions are still unknown. It's thought to relate to assembly and secretion in this case. Rep 2139CA was given to 12 patients in conjunction with pegylated interferon. The mean hepatitis D RNA decline was 5.34 logs. And at 3.5 year follow up, seven out of 12 patients were still HDV RNA negative. And this was published by Bazanet et al and Lancet Gastroenterology and Hepatology in 2017. What about viral assembly and packaging inhibitors? These are perennulation inhibitors. Perennulation is a post-translational lipid modification involving the covalent addition of perennial lipids to proteins, which promotes membrane interactions. And although this promotes biological activities of a variety of cellular proteins, in this case, it is specifically the assembly of the hepatitis D variant into the HBV envelope that is being blocked. And the most recent study presented was a combination study using pegylated LAMD interferon, monofanab and rotonavir for 24 weeks. And the interim data was presented at the liver meeting last year, where 22 patients were treated. 17 patients achieved more than a two log viral drop from baseline. And 11 patients were undetectable or below the limit of quantitation at the 24 week mark. This also holds promise and the complete data should be released soon. So in summary, hepatitis D is fascinating. 44 years later, we are still struggling. Interferon is suboptimal, but it's wonderful for responders. We have to suppress hepatitis B to prevent flares, but not to improve outcomes of hepatitis D. Science reveals opportunities, combinations, dose, duration, endpoints are a work in progress, but these novel therapies hold real promise. I'd like to thank all the people I work with, the patients, the fellows, the nurses, and for this opportunity to speak. Thank you for your attention. Hello, my name is Joseph On and on behalf of the program chairs, Dr. Grace Wong and myself, we'd like to thank you for attending the Hep B Global Symposium. This symposium has been sponsored by the AASLD's Global Outreach and Engagement Committee. And we're very glad that you could join us to explore further the latest in hepatitis B from a global and international framework. As we heard today, we had a outstanding overview of the global perspective regarding Hep B by Dr. Lassie. We thank her for bringing the WHO perspective to show us what is going on from Hep B in an international perspective. We then heard the latest on hepatocellular carcinoma surveillance in chronic hepatitis B. Knowing that we are heading and are already in the world of precision medicine, we heard the latest in how to provide HCC surveillance. We then turned to hear Dr. Calvin Pan from New York to give us an update on Hep B in pregnancy, both on the acute and chronic hepatitis B in pregnancy. We heard the latest on utilizing antiviral therapy, including TAF, for the use of Hep B vertical transmission prevention. We then shifted to Dr. Butte from Spain to learn about emerging Hep B therapies this exciting time. And finally, from Dr. Heller from the NIH to discuss the latest on hepatitis Delta, which still remains with us as a unseen and under-recognized and under-treated disease. For which we hope to see newer and further therapies develop. On behalf of the ASLD and the Global Outreach and Engagement Committee, and Dr. Wang and myself, we thank you for your interest and your attendance. Thank you very much.

HPE Global Symposium

hepatitis B virus

emerging therapies

global epidemiology

pregnancy management

treatment options

hepatitis Delta virus

accurate testing

personalized treatment strategies

ongoing research

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innovation