Hello and welcome to the ASLD-HBV-Sick Webinar, Current and Future Disease Burden of HBV, Global and Regional Perspectives, with a special tribute to Professor Din-Hsin Chen. I would like to first acknowledge my co-organizer, Dr. Ho-Lin Hsu from Ida University, Taiwan, and my co-moderator, Dr. Harry Jensen from the University of Toronto in Canada. We are also grateful today to have Dr. Anna Lok to join us and open our session with a special tribute to Professor Din-Hsin Chen, whom most of us know very well for his enormous contribution in the campaign against Hepatitis B and who passed away recently. Moving on to our main session, we are honoured to have experts representing the major continents to discuss the local-regional status of disease burden and treatment strategies. Africa, by Dr. Mark Sondera from Ushua Hospital, University of Cape Town in South Africa. East Asia, by Dr. Ji-Dong Cha from Beijing Friendship Hospital, Capital Medical University from Beijing, China. South Asia, Dr. Shiv Sarin from the Institute of the Liver and Biliary Sciences in New Delhi, India. Europe, by Dr. George Papadopoulos Dorogis from the Medical School of Athens University in Greece. North America, by Dr. Carla Coffin from the University of Calgary in Canada. And Central and South America, by Dr. Adrian Gargano from the Institute, University of Dell Hospital, Italiano, from Buenos Aires. These will be followed by a panel discussion and we look forward to lively discussion with everyone. Thank you once again for joining us today. From dear friends and family of my dear friend, D.S. Chen. It is an honor to be asked to pay a tribute to D.S. But it is also very sad to learn that he's no longer with us. D.S. is my role model, a respected colleague and a very dear friend. He has made so much contributions to our understanding of hepatitis and liver cancer. His accomplishments and his contributions will forever be remembered and will have the long lasting impact not only on the citizens in Taiwan, but worldwide. I'm gonna share with you a little bit but worldwide. I'm gonna share with you a few slides to show you my relations with D.S. and some of those fun times in recent years. This picture was given to me by D.S. when he was honored by ESO for the International Recognition Award. And I was so privileged to be invited to introduce him. Several years later, I was invited to attend this meeting to honor D.S.'s quote unquote retirement. We know that he never retired because he continued to work until the last day and he continued to do research and generate new information. So this was back in 2013 to celebrate his 70th birthday as well as his quote unquote retirement. You can see that D.S. was healthy, smiley and it was so nice to see so many friends flying in from different parts of the world to honor D.S. As you can see from here, the speakers came from the US, Australia, the UK and many, many countries in Asia in addition to obviously many of his colleagues in Taiwan. This was a picture of the two of us. You can see that I was a little younger at that time and D.S. as usual was always smiley. My most recent encounter with D.S. was December of last year. Therefore it was very shocking to hear that he got sick a few months after our meeting. This was the first TASO ASLD joint symposium. We're all up on the stage after a few drinks at dinner and we're all celebrating our accomplishments in conquering hepatitis, liver disease and liver cancer. This was actually a fun moment. I couldn't remember exactly what we discussed but evidently it was both serious as well as fun. You can see D.S. with his close colleague and longtime friend, young Ben and we had a good moment talking about science, talking about the future, talking about research. This stamp was very special. It's even more special now. This was a gift, a souvenir from D.S. in December and that was issued by the Taiwan government to celebrate the success of Taiwan as well as D.S.'s effort in conquering hepatitis B. We're here to celebrate D.S. and his accomplishments. We said that he's no longer with us but he would forever be in our mind and what he started, we'll all continue to carry forward and make sure that the goals that he set would be accomplished and we'll continue to control hepatitis B and cure hepatitis B and that liver cancer and hepatitis B would one day be in the past. Thank you. Hello, I'm Mark Sundrop from the University of Cape Town in Cape Town, South Africa and I'm gonna spend a few minutes with you sharing some thoughts on the current and future disease burden of hepatitis B in Africa and in particular, Sub-Saharan Africa and what perhaps still needs to be done to offset some of this burden. These are my disclosures. So let's start by looking at the global burden of hepatitis B and of the almost 260 million people chronically infected, just under 70% either reside in Africa or the Western Pacific region making these two areas HPV endemic. It is important to have some geographical perspective on Africa. It is a big continent and often one doesn't appreciate this from standard two-dimensional maps. When we look at the schematic, to appreciate the size, one can see that continental US, China, India and several European countries can comfortably fit into the landmass of Africa with some space to spare. It consists of 54 countries. There's North Africa and Sub-Saharan Africa conveniently divided into Western, Central, Eastern and Southern zones. Just over 40% of the population is urban and it's a mixture of low and middle income countries with low income countries facing the burden of poverty with low gross national incomes, low per capita health spend and this relates and translates into low physician and nurse to patient ratios of the population. This further compounds the burden of healthcare. With respect to hepatitis B, approximately 78 million people are chronically infected. The surface allergen seroprevalence is just over 6%. The lifetime risk of acquiring hepatitis B is enormous and of the more than 20 million people who meet eligibility criteria for treatment, only a fraction in fact are diagnosed and treated with almost no pregnant woman acquiring therapy. Importantly, just under 5 million children are chronically hepatitis B infected although within the vaccine era, there's been a clear decline in HPV surface antigen seroprevalence. This burden is exemplified in the Lancet Commission of 2019 showing countries such as Nigeria and Sub-Saharan Africa having significant burden and countries such as Egypt in North Africa carrying equally high burden. This burden is evident from the 2010 Global Burden of Disease Study where one can see that hepatitis B and to a lesser extent hepatitis C predominates as the leading causes of cirrhosis and HCC in Sub-Saharan Africa. Consistent characteristic features of the epidemiology of HPV in Africa is that it tends to predominate in rural versus urban areas. Men more than women and clearly from the Landmark Prolifica Study showed that almost 50% of adolescents in fact are e-antigen negative, very high annual e-antigen seroclearance rates and more than 85% of adults who in fact have biochemically and histologically active disease are e-antigen negative. Important perspectives of transmission patterns in Africa are that horizontal transmission and in particular early childhood transmission predominates as the major mode of transmission of HPV as shown in many studies. Perinatal transmission is another major factor and has become more important in the HIV era with HIV-HPV co-infection driving higher HPV DNA levels and thus increasing transmissibility. Whilst adult-to-adult transmission does occur, it is a minor component. Another characteristic feature are the lower perinatal mother-to-child transmission risks in pregnant women in Sub-Saharan Africa when compared to serologically similar women in another endemic portion of the world such as East Asia. The reasons for this are not entirely clear but may be genotype related or due to different perinatal practices. Despite these characteristics of hepatitis B in pregnancy, perinatal mother-to-child transmission of hepatitis B remains unacceptably high and considerably higher than the perinatal mother-to-child transmission risk of HIV. This is an important issue because as this data from the Gambia clearly showed that perinatal acquisition of hepatitis B is associated with significantly higher rates of long-term development of hepatocellular carcinoma and cirrhosis. This work from the Polaris Observatory shows that currently we still have significantly high rates of surface antigen seroprevalence greater than 1%. But more concerningly, if we carry on in the current trajectory in 10 years time, it will not be much different. Thus here in the red column, the majority of countries projected to have surface antigen rates greater than 1% are in fact in Africa. And this is clearly not a tenable situation. We are doing better with respect to full vaccine three-dose coverage. We're doing as well with respect to birth dose coverage, although globally rates consistently for full vaccine coverage and birth dose coverage are slowly increasing. And this schematic clearly shows if one is going to eliminate hepatitis B and hepatitis B related disease, there are clear areas one needs to target. And this includes prevention through vaccination, as well as identifying those who are chronically infected and linking them to care. Whilst prevention is key through vaccination, a critical aspect is prevention of mother to child transmission, given the risk of chronicity associated with perinatal acquisition. This modelling done by Imperial College in London and using Ethiopia as an example, reinforces the need for birth dose vaccination. One can see if we continue with full three-dose coverage, the rate to achieve the targeted less than 0.1 surface antigen seroprevalence takes an inordinately long time. With the introduction of birth dose, we achieve that so much faster. Equally linking people to care, despite the global reduction in the cost of generically available antivirals such as tenofovir has been exceedingly poor. If we are going to screen the number of people we need to and link them to care, traditional treatment models simply will not suffice. Plenty of data has supported the feasibility of scaled up test and treat programmes. And one of the most well-known studies, the prolific study from the Gambia has identified that simplified approaches for treatment evaluation eligibility demonstrates benefit and that you can achieve high coverage of community-based screening, good linkage to care, but there's only a proportion of people ultimately may require treatment. A more recent Ethiopian study demonstrated that decentralised care with simple treatment protocols was feasible, but also highlighted that limited performance of non-invasive tools for fibrosis assessment were a problem, as well as existing guidance in terms of eligibility for treatment may in fact underestimate those who need care. Looking at the Ethiopian study more closely, two important issues emerge. Firstly, when using the WHO criteria to assess treatment eligibility and comparing that to the ESL criteria or their own in-house study criteria, almost 50% of patients would have failed eligibility for linkage to care. Secondly, the APRI score performed quite poorly in terms of assessing those who would have advanced fibrosis. Sensitivity was poor, and although it improved as the sensitivity cutoff was lowered from 1.5 to 1 to 0.5, it still performed quite poorly as compared to fibroscanning. Core issues going forward include whether there's a need for true African-specific HPV treatment guidance, given what we now know about the limitation of some guidance in the African context. Key is full three-dose coverage of vaccine, but crucial is introducing hep B birth dose. We can cover excess perinatal risk through scaling up mother-to-child transmission prevention, but underpinning all of this is diagnostics, and we should be looking at potentially sharing platforms for viruses such as HIV, hep B, and hep C, and maybe layering in hep B and even hep C care into existing HIV programs. Here, I just want to highlight the importance of the diagnostics costs issue. As you can see in all these potential modeling scenarios, diagnostics remains a significant portion of the cost and something we clearly have to target and intervene to achieve the reality of upscaled care. In summary, hepatitis B remains endemic in Africa. There's a large reservoir of untreated people who need to be identified and linked to care. To do this, you're going to need affordable diagnostics, as well as validated and well-performing non-invasive means of assessing fibrosis. Consideration has to be given to whether existing systems and platforms need to be utilized for delivering this care, and ultimately, we need to be asking ourself whether simplified treatment algorithms need to be developed that are truly applicable to Africa. Good morning, good afternoon, all. Good evening, everyone. I'm very glad to be here to speak to you about the epidemiology and disease burden of hepatitis B in East Asia. This is my disclosure. I have nothing to disclose. I will not discuss the available use of any medication. Now, this slide shows the prevalence of hepatitis B in the West Pacific region, where it has the highest prevalence of surface allergen in the world. We can see actually in this area, including the Asian countries, have 6.2% in surface allergen, which is almost double the 3.5 in the world general population. Now, let's look at prevalence of surface allergen in Japan. For historical reason, the prevalence of hepatitis B in Japan has been very low. You can see as early as in 1978, the prevalence of surface allergen among young children less than 1%, whereas as late as 2011, we can see the prevalence of surface allergen in those between four-year and 15-year-old of age, actually less than 0.2%. So this is translated into the total number of patients with chronic hepatitis B, cirrhosis, and LCC. Actually, the number is very small. In this country, you can see only 257,000 in total. So that means the disease burden of hepatitis B in Japan is relatively small compared with other viral hepatitis, such as viral hepatitis C. Now let's turn to another country, South Korea, where we can see in this country the prevalence of cervical dandruff also declining since the adoption of universal vaccination of hepatitis B among all newborns. You can see the prevalence of cervical dandruff in younger age group markedly declined to 2.2 in 1998 and further declined to 0.3 in 2016. So overall we can see the prevalence of cervical dandruff in the general population declined from 8 to 10% in 1980s to around 5% in 1990s to currently around 3% since 2010. Well now let's look at the prevalence of hepatitis B in Mongolia. This is only maybe the first, I'm not sure if the only nationwide survey in Mongolian adults in 2013. We just look at the right panel, we can see the red bar showing the prevalence of hepatitis B in general population were 11%. So this translates into around 200,000 persons who lived with chronic infection of viral hepatitis B. From this slide you can also see the prevalence of hepatitis C is also very prevalent. Now just look at another, that's the general population in Mongolia, where we can see the urban Mongolia like the capital, Ulaanbaatar, you can see that the prevalence is also high, a little bit lower in general population, around 9.3% in 2008. Now also due to the universal recognition declined into 8% in the general population between 2015 and 2016 in the capital, Ulaanbaatar. Now in China, you can see the prevalence of hepatitis B in China also was very high before the adoption of universal recognition of hepatitis B among all newborns. Actually there's three lines, we can see the red line, the blue line, and the green line. We can see three national sero-epidemiological survey of viral hepatitis B. Well, in general we can see as the increase of the coverage and timely birth dose of viral hepatitis B, the prevalence of surface energy in the general population declined from nearly 10% in 1992 to around 7% in 2006, further decline to around something between 6% and 7% in 2014 in the general population, whereas in those younger than 15 years old, the prevalence of surface energy around less than 1%. Now, this slide is showing the estimated surface energy prevalence in general population in mainland China was around 6.89%. So this translated into the estimated number of people who live with hepatitis B was 84 million in general population in 2018. Another important issue is we can see over 90% of the persons who are positive for surface energy actually are older than 20 years old. In other words, in the younger generation, as I mentioned earlier, those less younger than 20 years old, especially those than 50 years old, the prevalence of surface energy positivity was already very low. So the total number of the persons account only 10% of the total number of surface energy positivity in the whole China. Now, we can see another very good example in Taiwan. Actually, this is the only area that start the universal vaccination of hepatitis B for all newborn as early as in 1984. So after that, of course, the prevalence of surface energy declined dramatically. But even more importantly, it's a declining of the disease burden. We can see the left panel, the chronic liver disease and mortality dramatically declined after the adoption of universal vaccination, both in males and in females. In the mid panel, we can see the incidence of HCC also declined after the adoption of universal vaccination program, both in males and females. And lastly, we can see the mortality of HCC also dramatically declined after the universal vaccination program, both in males and females. So actually, that's the role model for the people to be prevented by the universal vaccination, not only by the prevalence, but also by the disease burden. So almost last we can see, actually by 2017, the West Pacific region goal of surface energy less than 1% among children five years old already achieved. So that means the new infection rate and the number of new infection is already very low in this region. However, we can see if we want to reduce the mortality of HIV related disease, we still need a large scale test and treatment strategy in our region. We can see the right panel, if we only treat only those who come to the hospital, the disease, the number of deaths still very high. For the blue line, we can see if we treat test and treat all patients, then we can see the death number will decline very rapidly. So only by doing this kind of test and treat strategy, we can achieve the goal set by WHO that by year 2030, the mortality should be reduced by 65% by 2030. So this is still a huge task. We still need to do a lot of things to test and treat those who are infected with chronic hepatitis B. So lastly, I would like to thank Dr. Pauline from WHO West April for kindly providing some of the updated slides. Thank you for your attention. I'm grateful to the ASLB and the organizers for inviting me to this very important program. I bring greetings from the Institute of Liver and Biliary Science. I have nothing to disclose. I would cover several brief topics. The first being what is the status of HPV in the world versus in Asia. As you would notice that the number of deaths due to hepatitis B have probably increased and not decreased over the period of last two decades. In Asia also, liver diseases are a major cause of death. And these areas show the red ones and the yellow ones that at least three to 6% or more deaths are due to liver disease. Why focus on Asia? Of the total deaths, 4.6% of the deaths in Asia are due to liver diseases. And if you look globally, Asia accounts for nearly two thirds of the deaths due to liver diseases. Let's look at the individual cirrhosis related deaths in Asian countries. Now this is to show you hepatitis B and you can see most countries including the one in South Asia, South Asian countries like India, Pakistan and Nepal and others, 40% of the deaths are due to hepatitis B. Similarly, liver cancer, hepatitis B accounts for 40% of the deaths. The good news is that it is decreasing. Let's look at India, Pakistan and many other countries. There is a decline in the trend of HBV infection and deaths. However, still it remains 2.5 to 5% in many parts of the world. When we look at acute hepatitis, hepatitis B still remains amongst the major causes. However, I have some concern on this. The concern is what we diagnose as acute hepatitis actually is probably reactivation of a chronic HBV infection detected in adulthood. How do you differentiate? In acute hepatitis B most of us know that there is cell death and there is cell-mediated immune injury and death. So viral loads are much lower and several studies including the first one from our group showed if it is reactivation viral DNA is more than 10 raised to power 4 international units. Of course, in addition you have IgM anti-core positive and e-antigen is negative or positive with zero reversion. The message here is if you have reactivation and high DNA, don't wait. You start treating and evaluate for underlying chronic liver disease. This will help in reduction in deaths. In India before 1989 4.6% of the population was HBACG positive but 2018 it's about 2.5%. Predominantly it is E- genotype D and cirrhosis and HCC account for about one third of all the deaths. This diagram was conceptualized to show the gaps, challenges, actions and priorities. If everybody today gets the vaccine, this was for 2014 and we thought 66 years would be the life of a common Indian at that time. Everyone, every newborn gets a vaccine and every adult is treated. So nobody knew will be getting the virus. So we had to identify, screen and treat all those people and then if you start today 65 years there will be elimination of hepatitis B from the country. So based on that India launched the largest and the biggest program for viral hepatitis control which covers diagnosis, screening and free drugs for hepatitis B and C for 45 million B and nearly 10 million hepatitis C and it is on the roll now. We have shown and others that hepatitis B in India is mainly mother and baby. This first study showed when we took 116 HBV positive children, 18% of their mothers were surface antigen positive but remaining about 60% had other markers of hepatitis B. In total three fourths of the mothers had a telltale evidence of presence of hepatitis B during their pregnancy or in subsequent years. The relevance of this is if a person, if a patient comes to you when he is about 30 years old we age the virus and 30 years of his age means the virus is 30 years and that is what determines the outcome of the patient. In this study we wanted to investigate what inactive carrier is truly inactive. Persistently normal for 12 months of ALT and E-. When we looked into these patients in this study in gastro two series of studies about 14% of the patients had F2 or more fibrosis. When we took up intermittently normal in one year there were fluctuations even one or twice nearly 63% of the patients had F2 or more fibrosis. So what we call as inactive is actually not inactive and may have significant fibrosis. These flares come every 4.3 to 6 months time. Slight rise and it comes down and the injury continues. We therefore had proposed way back in 99 that inactive HPV carrier is not an appropriate term and it should be replaced by chronic hepatitis B virus infection. Lo and behold after nearly two decades several societies including easel have suggested that E- chronic infection is a better term than inactive carrier. Why I'm stressing on this is because currently no treatment is recommended because you consider it's inactive but these people are much worse than those who get treated. The last part of my presentation is whether changing a terminology will help us and whether vaccination strategy should be improved. As I showed you earlier chronic HPV carrier should be replaced by chronic hepatitis B virus infection. The biggest advantage is like for HIV and HCV we will be able to eliminate hepatitis B once this term of inactive carrier is put to rest. Then we can open up to treat all. I know it is contentious but I want to promote so that we can achieve virus negative world. HPV negative. Now here is a trial where vaccine plus HB was compared with vaccine alone and all these were mothers who hepatitis B positive. Their children would be born either negative or positive in a large study. What we wanted to study important is from the positive mother the babies who are born do they have good immune response with or without DNA positivity or have poor. 106 babies born to HPV positive mothers received vaccine plus HB and 116 vaccine alone. As you would notice that a fair proportion of them had occult HPV means DNA was positive and the important part is that they had an end point of no infection and good immune response only in 41 or 39 percent. 60 had inadequate response. When we looked at the anti-HBs level 18 weeks because in the beginning you have given HB so we had to wait 18 weeks or even 6 months to 18 months. The virus the antibody response inadequate was seen in one fourth. It only shows that if the babies born to positive mothers are not in good shape. Our current policy of immunoprophylaxis is we give it perinatal period at delivery and within 12 hours. We propose that the viral transmission in utero occurs during the nine months and it becomes chronic. It is much better to intervene in the early stage. My carry home message is hepatitis B in South Asia current and future. The current scenario is hepatitis B remains a major health problem and in fact is the commonest cause of cirrhosis and HCC even today. Though it is decreasing alcohol and fatty liver disease are catching up. Majority of acute HPV is indeed reactivation should be treated to prevent deaths. Major route is mother-baby transmission. We should avoid and stop using the term inactive carrier it's a misnomer and use chronic HPV infection. This will open us the window opportunity and enable the society to treat all so that there is nobody with hepatitis B who is living with a positive virus. We have drugs we have the capability we just need to move forward to have a brighter future. Thank you for your attention. Dear colleagues, dear friends it's my pleasure to participate in this webinar and to have the opportunity to present you some key data on the current and future disease burden of HPV in Europe. These are my disclosures but I have nothing specifically to disclose for this presentation. The current and future disease burden of HPV in Europe as in any other part of the world depends on the changing epidemiology of that area. Changing HPV epidemiology in Europe depends on the changing incidence and prevalence. There are different changes among different countries and areas and different roles of factors affecting the epidemiological changes. However we have to admit that we don't have good epidemiological data because they're often old and weak. There is wide variability among different areas and no recent data from several parts of Europe. Europe is not a region with high numbers of chronic HPV infected patients. In fact it's the second last area in the world after the regions of America. Looking at this map we realize that countries in the North and Western Europe have low HPV prevalence, while countries in the South, and particularly Southeast or Eastern Europe, have high HPV prevalence, while there are several countries, those appearing in dark blue, with no recent data about HPV prevalence. In this systematic review, published by WHO, and including data from 1965 to 2013, the prevalence was estimated to be something above 2%, with a total number of HPS antigen-positive patients close to 18.5 million. According to a more recent report from WHO Europe, the prevalence of HPS antigen, estimated in 2015, was around 1.6%, with approximately 15 million persons living with HPV, and according to a more recent publication, based on data but also modeling, the modeled HPS antigen prevalence was 1.5%, while in 2016, something below 14 million persons were living with HPV infection in Europe. In any case, the decrease of chronic HPV prevalence in Europe was confirmed, and this is particularly true for areas of Europe in which the chronic HPV prevalence was relatively high, like the Central East areas, or the South countries of Europe, but in the West, in areas in which the chronic HPV prevalence was considered to be low, below 2%, there may be an increase in the recent years due to migration. Let's see some factors which affect the HPV epidemiology, and therefore the burden of disease in Europe. These include the vaccination, the other prevention strategies which we are not going to discuss, the migration, the changes in high-risk groups, which also we are not going to discuss due to limited time, and the treatment coverage. Looking at this graph, which shows the rates of HPV vaccination coverage in infancy in different parts of the world, we realize that in Europe, as in the other parts of the world, the rates start to increase steadily from early and mid-90s, and reached a plateau at high levels in late 2000. Infant vaccination is recommended by WHO, and it has been implemented in all but 10 countries, and as you see, 3 of those 10 countries are in Europe, and in fact, 3 additional European countries implemented infant vaccination only very recently. Vaccination coverage is usually high, but not in all European countries. In countries in which infant vaccination has been implemented early, since at least mid-90s, there is an effect, and in fact, the effect of infant vaccination has been clearly shown in the change in incidence of acute hepatitis B, and also delta, in countries like Italy, which had, in the previous decade, a medium-moderate HPV prevalence. Let's see some data about migration. Here you see a graph showing the estimated numbers of HPS antigen-positive individuals in the largest migrant groups by country, with the dark green color are the HPS antigen-positive cases, and we see that Germany has the highest number of HPS antigen-positive immigrants, then it is Spain, then France, Italy, Turkey, UK, Portugal, and Greece comes after Portugal. Another way of looking at the impact of immigration on the HPV prevalence is to look at the proportion of the HPV prevalence which is attributable to migration, and we see that this can range from 20-22%, but up to 90%, particularly in the northern European countries, in which I already told you that the HPV prevalence in the native population was really low. Let's see some data about treatment cover. Looking at this graph with the estimated treatment cascade of chronic HPV in WHO Europe, we realize that only 17% of the total estimated infected patient population have been diagnosed, and of the patients who are considered to be eligible for therapy, 27% of the total group, only 7% are actually treated. The main reasons for the high rates of HPV under diagnosis in European countries are associated with the screening recommendations. As you see in this table, screening for HPV is not recommended in most European countries for most of the groups that are high risk for HPV infection, and only Germany recommends screening for almost any high risk group for HPV. Of course, screening in the general population is not recommended in any European country. And from a systematic review we published a few years ago for four European countries for which data were available, you see that the treatment rates among the diagnosed patients who have treatment indications start from 66% in the UK and go down to below 40%, 37% in France. Let's now see some data on HPV mortality in Europe. According to WHO, the estimated number of deaths in 2015 were 56,000 in WHO Europe, and obviously the causes of HPV-related deaths are fulminant acute hepatitis, cirrhosis, and hepatocellular carcinoma. Looking at the European Liver Transplant Registry, we see that obviously the number of patients undergoing liver transplantation for HPV-related cirrhosis, including hepatitis delta, has steadily decreased over the last decades, while the transplantation for hepatocellular carcinoma, regardless of the cause, has steadily increased. In a recent study, we showed that in Caucasian European chronic hepatitis B patients treated with oral antivirals, the overall standardized mortality is similar to that of the general population. In fact, patients without cirrhosis or those who do not develop ACC, the mortality is significantly better to that of the general population and substantially increases only in patients who develop hepatocellular carcinoma. Looking at this slide, we realize that ACV is the predominant cause of ACC in several European countries, but still in southeastern European countries like Turkey, Greece, or in countries in which HPV is usually found in immigrants, HPV has the predominant role for ACC development. In conclusion, HBs antigen prevalence and incidence of acute hepatitis B are decreasing in Europe, where we have two groups of chronic HPV patients. Caucasians who are older, mostly genotype D or A, e-antigen negative, in active carriers or with advanced disease, therapy is provided for most diagnosed cases. Or non-Caucasian immigrants who are younger, mostly infected with other genotypes, they have high proportion of the antigen positivity, non-advanced disease, and they are highly infectious. Morbidity and mortality are improving, but still exist at substantial rates due to ACC in treated cases, particularly if therapy starts at advanced stage, ACC or decompensation in undiagnosed and or untreated chronic cases, which is decreasing, and fulminant acute hepatitis B, which is also decreasing. Thank you very much for your attention. I would like to thank the organizers for the opportunity to present in this webinar. I'm Carla Coffin, and I'm from the University of Calgary, and my talk will be focusing on the burden of hepatitis B in North America, specifically within Canada and the U.S. As highlighted by my colleagues in this webinar, hepatitis B has significant global burden, and 80% of persons affected live in Africa, the Western Pacific region, and in Southeast Asia. Although Canada and the United States are considered low endemic regions, the disease still has significant impact when considering global immigration patterns. Both Canada and the U.S. have very high rates of immigration. Data from the Canadian census, as well as from the International Migration Policy Institute, have shown that one in seven Americans and one in five Canadians are foreign born, meaning that they did not have either Canadian or U.S. citizenship at birth. The top 10 countries of origin in both Canada and the U.S. include mainly Asian countries. However, in the U.S., over 25% of individuals originate from Latin America, especially Mexico. In Canada, the most recent census has shown a changing trend in that most of the recent immigrants also originate from Asia, but Africa has replaced Europe as the second highest source continent. Now, either Canada or the U.S. has official data on the percentage of people diagnosed with hepatitis B or those on treatment, but immigration data has been used to estimate the burden of disease using so-called imputation methods. So based on the yearly number of immigrants, the prevalence of hepatitis B within the country of origin suggests up to two million residents are living with hepatitis B in the U.S. The CDC, or the U.S. Center for Disease Control, has a reporting system for hepatitis B, but it's also limited by missing data from some states as well as detailed demographic data. The U.S. National Health and Nutrition Examination Survey, or NHANES, has a population-based database with serial surveys of U.S. civilians and has a much lower estimated prevalence. However, the NHANES data may be more limited due to language and cultural barriers as well as limited survey participation for certain high-risk groups, including immigrants or foreign-born individuals. Both the CDC and the NHANES do show a high prevalence in persons of Asian descent. Recently a review commissioned by the Chronic Liver Disease Foundation by an expert hepatology panel looked at all of the evidence, including these imputation research studies and NHANES survey, and estimate that based on this available evidence, conservatively, hepatitis B affects up to two and a half million people in the U.S. There is also limited data on the true prevalence of hepatitis B in Canada, with studies only being conducted in smaller regions or selected subpopulations. A survey that was conducted several years ago showed an overall low prevalence of hepatitis B. The Public Health Agency of Canada, or PHAC, does have a notifiable disease surveillance system and in 2017 reported over 4,000 cases. However, the data was limited in that some provinces did not specify whether it was acute versus chronic infection. There was also limited demographic data or data on risk factors. Moreover, certain regions of the country, especially British Columbia or Western Canada, has much higher rates of hepatitis B infection compared to the national average, especially affecting East Asians and tended to be older population. A report from the Canadian Liver Foundation in 2013 stated that the estimated prevalence of hepatitis B is much likely to be significantly higher, and this is based on modeling data as well as immigration statistics, and the report suggested that anywhere from 240,000 up to 460,000 individuals will be living with hepatitis B in Canada by the year 2020. Hepatitis B Research Network is a consortium of 21 clinical centers in the U.S. as well as one center in Canada. They have conducted important studies to address the data gap on epidemiology of hepatitis B in North America. In one study in which over 1,600 adults were enrolled, they showed that the majority of patients were of Asian descent and that the major genotypes present were hepatitis B genotype B and C, consistent with what is published on hepatitis B genotypes within Asian countries. Clearly, the Canadian Hepatitis B Network has conducted real-world nationwide studies on hepatitis B epidemiology, looking at eight provincial jurisdictions. Our retrospective study showed there was a very diverse ethnic and racial background of persons living with hepatitis B in Canada. However, over 70% of those enrolled were Asian. Over 50% had genotypes B or C in those that were tested. Most of the persons living with hepatitis B in Canada reported being born outside of Canada. The expert hepatology panel for the Chronic Liver Disease Foundation also conducted a review of hepatitis B prevalence in other high-risk groups that would be excluded by N.A.I.N. studies, and they did find a variant disease burden. In Canada, it's noteworthy that Northern Indigenous communities that were historically hyper-endemic for hepatitis B now have rates similar to the rest of Canada due to the success of universal birth dose vaccination programs. Hepatitis B perinatal transmission is essential in order to achieve the World Health Organization elimination targets. In Canada, although there's been a national childhood vaccination program since the mid-1990s, the timing of the vaccine administration greatly varies across the country, with only two territories and one province recommending birth dose vaccine. The U.S. CDC does recommend universal birth dose vaccination. They also recommend monitoring and treatment of hepatitis B in pregnancy if needed to reduce the risk of mother-to-child transmission. In Canada, there's no formal public health authority recommendations, although certainly the guidelines are followed by most clinical care providers. Recent studies show high rates of hepatitis B vaccination and immunity in early childhood in both countries, although there's still up to 1,000 annual mother-to-child infections reported in the U.S. This data is not tracked in Canada. Over a third of all Canadian children under the age of 15 years were foreign-born or had at least one foreign-born parent, based on the most recent Canadian census data, and this highlights the importance of universal birth dose vaccination for all babies. Like hepatitis B, it's the most common cause of liver cancer globally. The global obesity epidemic and associated rise in non-alcoholic fatty liver disease and the metabolic syndrome is also an important cause of morbidity and mortality in individuals living with hepatitis B. Real-world studies in the U.S. using insurance claim database have reported increasing age as well as increasing non-liver related comorbidities, especially cardiovascular disease and healthcare utilization over the last decade. Similarly, the hepatitis B research network has also reported increasing incidence of diabetes, prediabetes, and metabolic syndrome in hepatitis B carriers, especially those that were Black or immigrated over 20 years ago. In Canada, the Ontario Burden of Infectious Disease study has reported that chronic hepatitis B is a fifth leading cause of death secondary to infectious diseases, and overall this highlights that broader outreach efforts are needed to improve linkage to appropriate care and follow up of persons living with hepatitis B. A number of studies have shown that there are gaps in the cascade of care for persons living with hepatitis B in North America. Less than one-third of hepatitis B infected patients are actually aware of their infection in the U.S. A Canadian survey showed that 50% were unaware of infection. A recent real-world study of almost 200 million patients based on a private claims database and an NAIDS survey showed that less than 20% were diagnosed, only a small percentage were treated, and in fact, even those with very advanced liver disease were not treated for hepatitis B. Overall, there's been a study shown significant gaps in care, monitoring, and delayed diagnosis of advanced disease, and there's a number of reasons why this could be happening, and certainly there's future research needed to address, including efforts to reduce feelings of stigma and shame and barriers to care for foreign-born people, although this place will place increasing demands and pressures on social support and healthcare budget. In summary, results show that even in high-income countries such as Canada and the U.S., improvements are still needed to achieve the WHO elimination targets. Although there are basic systems in place for prevention, we still need to implement universal birth dose vaccination in both countries. Hepatitis B antiviral therapy is known to reduce liver disease progression and risk of liver cancer, and thus we need additional research to improve linkage to care, to understand the barriers to care, and develop and implement interventions in order to overcome these challenges and to meet the needs of a diverse population. I would like to acknowledge Dr. Carla Oshawa from the Public Health Agency of Canada for providing some of the data used in this presentation, to Professor Mindy Nguyen for her feedback, and also to the Canadian Hepatitis B Network for some of the data used. Thank you. Hello to everybody. I'm Dr. Adrián Galano, head of the liver unit at Hospital Italiano in Buenos Aires, Argentina. First of all, I would like to thank ASLD for inviting me to participate in this webinar in which I will talk about current and future disease burden of HBV in South America and Central America. I have no disclosures concerning this topic. In Latin America, the impact of hepatitis B is significant and there's an estimated 6 million people infected. The prevalence has increased in recent years, mostly as a consequence of global migration and sexual transmission in non-vaccinated adult population. Vaccination has not yet proven its global impact and constitutes an unmet need and the scenario is heterogeneous in prevalence and access to diagnostic methods and treatment. In 2015, when the global prevalence of HBV infection in the world was about 3.5%, in Latin America, unfortunately, there were limited studies, but showing a huge differences between region and region. In some areas with very high prevalence, as you can see in red, coexisting with others with intermediate or low prevalence. There was, for instance, a relatively low prevalence around 1% in Argentina, my country, very low in Chile, intermediate in Peru, again low in Colombia, and intermediate in Brazil, and high in some countries of Central America as, for instance, Dominica and Republic. But where the problem is very important and the prevalence is very high is in the Amazonian basin, as I will tell in the next slide. This region, the Amazon, is home of many indigenous groups, totaling approximately 35 million people in nine countries that share this region, the center of South America. And as you can see, there's a very high incidence in all these populations, ranging from about 5% HBS antigen in Chaparra, Bolivia, to, for instance, 25, also a quarter of the population in Sierra de Santa Marta in Colombia, and 15% in Brazil. Look in Colombia, for instance, from the infected people, 60% of them are co-infected with Delta virus. And even more important in this population in Central South America, in the Amazonia, many of those people are infected and have a relatively advanced disease. As you can see here, about half of the patients have F2 in red or F3 or F4 fibrosis, and this is a very important point. HPV is also responsible for about 15% of cases of hepatocellular carcinoma in Latin America and more than 40% of hepatocellular carcinoma in Amazonia, where, of course, it is the first etiology of liver cancer. Regarding genotypes, an interesting distribution is observed with an important representation of genotype F and genotype H in the region. Some of the genotypes are imported from other continents, but most of the population has been infected with aufactinous genotypes as genotype F for hepatitis B and genotype 3 for Delta, and this may be related with clinical implications. Hepatitis B is also one of the major responsibles for acute liver failure cases in the region, as shown in this multicenter recent study in Argentina, in which around 20% of the cases of ALF were secondary to HPV infection. In addition, another recent trial from our unit, including 200 patients with acute hepatitis B in Argentina, has shown that genotype F is the main responsible for these infections, accounting for more than 75% of the cases, as you can see in blue. And this is relevant because we have demonstrated, as you can see here, that there are specific pre-core and core mutations in subtype 1B of genotype F that may lead to more severe forms of acute hepatitis and even acute liver failure. So, considering this complex scenario, which would be the most important recommendations or challenges for a better management of hepatitis B regarding prevention, diagnosis, and treatment? What about prevention? Despite HPV immunization, around 10% of the infants born to HPE antigen-positive mothers still become chronically infected. This is a high number. So, HPV detection in pregnant women is essential. Pregnant women at high risk of transmission should have access to treatment, and universal vaccination of the newborn must be guaranteed. What about diagnosis? Only a minority of the infected people with HPV have been tested and know their status. And we estimate that this proportion is only about 9% of people living with HPV. So, the systematic detection of HPV must be requested and be available to all people at risk in all appropriate health and community settings. National public health authorities should ensure that sufficient resources are allocated for the detection of HPV, and this should include not only big cities, but also countryside and, of course, rainforests. Access to affordable, quality-assured diagnostics remains a barrier. The tests needed for treatment decisions are still expensive, and the cost of tests that quantify, for instance, the nucleic acids of HPV ranges from $60 to $200, and this is impossible to pay for in most of the countries. And finally, what about treatment? Despite those diagnosed with HPV infection, the proportion of patients on treatment with WHO-recommended antivirals does not exceed 10%. While the prices have decreased rapidly in some countries, they remain still unaffordable in others. And as you can observe in the cascade among the diagnosed, treatment has reached only a small fraction. We consider that that is less than 10%. So, less than 10% diagnosed and less than 10% of those people treated. So, as part of the global strategy started by the World Health Assembly in 2016, we work from the Latin American Association for the Study of the Liver in order to achieve first a strategic information system based on surveillance and data is needed to direct policies implementation. We need universal immunization against hepatitis B, including all adults, prevention of mother-to-child transmission, blood and injection safety, coverage of testing and treatment. Hepatitis services need to be delivered through a public health approach and benefit all the population, and of course, sustainable financing. So, we are convinced that to achieve this, we can only success if we work together. This should be shared among scientific societies, key opinion leaders, patient advocacy groups, healthcare authorities, and pharma, among others. And with this, I finish this presentation and I want to thank you deeply for your attention.

ASLD-HBV-Sick webinar

Hepatitis B

disease burden

global perspective

regional perspective

treatment strategies

prevention

vaccination

diagnosis

collaboration