HBV Serum Biomarkers Workshop

ICE-HBV virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting was held in October 2020. The event was aimed at scientists, clinicians, pharmaceutical and diagnostic industry representatives.  The workshop, chaired by Anna Kramvis and Peter Revill, was put together by the ICE-HBV serum biomarkers working group. Both classic and future biomarkers were. The workshop will lead to a consensus statement on promising serum biomarkers. Links to recordings & slides can be find on the programme below. 

Background & Objectives:

Functional cure, the loss of HBV surface antigen is the major goal of many HBV cure strategies, using direct acting antivirals and anti-HBV immune-stimulating responses. On the other hand, complete cure involves the elimination or inactivation of the covalently closed circular DNA (cccDNA) reservoir.  As new therapies are developed and tested, there is an urgent need for serum biomarkers that can:

  • accurately correlate with cccDNA expression in the liver,
  • predict HBsAg loss,
  • measure stimulation of host antiviral immune responses
  • screen HBV carriers in order to identify those at high risk of developing hepatocellular carcinoma

Although a number of alternative HBV serum biomarkers have been proposed, including HBV RNA and core related antigen, their clinical relevance, in all settings of chronic HBV infection, has yet to be resolved.

In this workshop, a range of experts will discuss the latest advances and identify knowledge gaps in our understanding of serum biomarkers.  They will discuss challenges that need to be overcome to ensure the utility of various biomarkers in the clinic and for screening new antiviral therapies. Presentations will be complemented by two in-depth discussion panels that will debate these challenges and propose a way forward.

Program

October 5th – 

Session Co-Chairs: Timothy M. Block and Veronica Miller

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Timothy Block, Ph.D. is President and (with his wife, Joan and Paul and Jan Witte) co-founder of the Hepatitis B Foundation (HBF). He also founded its Baruch S. Blumberg (Research) Institute (BSBI) and Pennsylvania Biotechnology Center (PABC). He is Adjunct Professor, U. of Pennsylvania, formerly (1983-2006) Professor, Jefferson and Drexel Medical Schools. He and colleagues (Blumberg, Mehta, Dwek, Su) pioneered the use of glycoproteomics and “micro DNA” in the urine for detection of biomarkers of liver cancer risk, (with Guo) identified inhibitors of hepatitis B virus, which are in clinical phase testing. He has published >250 papers. Honors include (Hon. M.D.), election to Bulgarian National Academy, Fellow, American Association for the Advancement of Science, Glycobiology Institute (University of Oxford), US National Academy of Inventors. Named a “Visionary in Hepatitis” by the World Hepatitis Alliance.

Dr. Miller is an Adjunct Professor at the UC Berkeley School of Public Health. She developed and teaches a course on FDA and Drug Development based on case studies from the Forum’s rich history in facilitating drug development to Berkeley and Bay Area graduate students and post-docs. She mentors interns and fellows pursuing regulatory, biotech and translational medicine careers. Dr. Miller serves on numerous industry and government advisory boards, publishing over 100 peer-reviewed publications on HIV treatment strategies and regulatory strategies for HIV and HCV throughout her career. She joined the Forum in 2001 after directing the interdisciplinary HIV Research Group at the HIV Outpatient Clinic of the JW Goethe University in Frankfurt, Germany. Together with Joep Lange, she co-founded and chaired the Euro-Guidelines Group on HIV Drug Resistance, the first pan-European group established for the purpose of assuring a common standard-of-care for patients in all European states. Dr. Miller obtained a Bachelor of Science in Microbiology from the University of Manitoba, and a Doctor of Philosophy in Immunology from the University of Manitoba.

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Noon  Housekeeping Rules Capucine Penicaud
12:00-12:05pm 

Welcome and aims of the workshop. Introduction to Session Chairs Timothy M. Block  and Veronica Miller

See Welcome Video.

Anna Kramvis
12:05-12:25pm  Summary of the Viral Serum Biomarker Landscape + Q&As

See Abstract

Title: Summary of the Viral Serum Biomarker Landscape 

Date of presentation: October, 5th 2020 

Authors: Dr. Barbara TESTONI 

Affiliation: Cancer Research Center of Lyon (CRCL) – INSERM U1052 

Abstract Body: 

Chronic hepatitis B infection develops in severe liver disease and liver cancer. Viral persistence is due to the lack of therapies that can effectively target the hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in hepatocytes and by the presence of viral sequences integrated in the human genome. HBV integration does not sustain viral replication, but can transcribe for viral antigens and is associated to pathogenesis. As the unique viral genomic repository and matrix for full viral replication, cccDNA remains the utmost target for curing chronic HBV infections. Routine circulating biomarkers used for clinical monitoring of patients do not accurately reflect HBV intrahepatic activity. New emerging non-invasive biomarkers are therefore under evaluation for their relevance in reflecting liver viral activity, in improving the classification of patients with regards to their natural history and in the evaluation of novel compounds to assess target engagement and to define new virological endpoints.

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See Presentation Video.

Barbara Testoni

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Barbara Testoni obtained her PhD in Genetics and Molecular Biology at the University of Milan, working on eukaryotic transcriptional regulation in the setting of skin development. Then, she moved to the University of Rome “La Sapienza”, where she began working on liver disease and type-I interferon signalling. At present, she is a PI in the “Viral Hepatitis” team at CRCL – INSERM U1052 in Lyon. Her research interests mainly include the investigation of the epigenetic mechanisms at the basis of host and viral gene regulation during HBV infection, with particular focus on the transcriptional regulation of the HBV minichromosome.

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12:25-12:45pm  Summary of Immunological Serum Biomarkers Landscape + Q&As

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Title: Summary of Immunological Serum Biomarkers Landscape 

Date of presentation:  October 5, 2020 

Authors:  Kyong-Mi Chang 

Affiliation:  University of Pennsylvania and Crescenz VA Medical Center 

Abstract Body: Liver disease in HBV infection is largely immune-mediated. Antiviral CD8 T-cells mediate both cytolytic and non-cytolytic virus control upon MHC class I-mediated recognition of virus-infected hepatocytes, with a key regulatory role for CD4 T-cells. However, in chronic hepatitis B, virus persists with dynamic variations in hepatocellular injury with inflammation versus disease and/or virus control, with the participation of multiple immune effector and regulatory pathways. Lacking safe and convenient access to the liver compartment, there is an interest to examine the peripheral compartment for immune markers to gain mechanistic as well as clinical and prognostic insights. This presentation will highlight aspects of HBV immune pathogenesis and summarize available literature on immunologically-based serum biomarkers with potential relevance to clinical outcomes of HBV infection and therapy.

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Kyong-Mi Chang

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Dr. Kyong-Mi Chang is a translational investigator with expertise in immune pathogenesis of human liver disease, including hepatitis B and C with progression to cirrhosis and cancer. Currently, she is Professor of Medicine in the Division of Gastroenterology at the University of Pennsylvania with an administrative leadership role as the Associate Chief of Staff and Associate Dean for Research at the Corporal Michael J. Crescenz VA Medical Center in Phliadelphia. Dr. Chang is also examining the genetic underpinnings of cardiometabolic disorders including liver disease among US Veteran participants in the Million Veteran Program.

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12:45-1pm  What is serum HBV RNA? + Q&As

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Title: What is serum HBV RNA?

Date of presentation: 5 October 2020

Authors: Florian van Bömmel

Affiliation: Leipzig University Medical Center, Department of Hepatology, Leipzig, Germany

Abstract Body: Serum HBV RNA is believed to be derived from cccDNA and there is a growing body of evidence that the circulating HBV RNA may serve as a new serum biomarker for cccDNA activity. Accordingly, HBV RNA in serum shows some correlation to other HBV markers as HBV DNA, HBeAg and HBcrAg. However, methods that were presented for quantification of HBV RNA are difficult to compare, and species and existence form of serum HBV RNA have not been thoroughly been characterized.  In recent studies, HBV RNA was found to be associated with HBV infection stages, treatment response and disease prognosis. Also, HBV RNA was found to be a marker for relapse of HBV replication after treatment cessation. Although to date it remains unclear whether serum HBV RNA is better than current biomarkers, HBV RNA possess potentials to be a new marker for chronic hepatitis B virus infection.

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Florian Van Bömmel

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Florian van Bömmel (MD) is Hepatologist and Gastroenterologist deputy head of the Department of Hepatology at the University of Leipzig, Germany. He has been involved in clinical and translational research in many studies in Hepatitis B. A special focus of his research is the development of novel serum markers of HBV replications.

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1-1:15pm  What is core related antigen? + Q&As

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Title: What is core related antigen? (Characterization of Hepatitis B core-related Antigens and Their Applications in HBV-infected Patients and Animal Models)  

Date of presentation: October 5, 2020 

Authors: Xupeng Hong1, Laurie Luckenbaugh1, Megan Mendenhall1, Stefan Wieland2, Renae Walsh3, Liza Cabuang3, Sally Soppe3, Peter Revill3, Dara Burdette4, Becket Feierbach4, William Delaney4, Stephan Menne5, Jianming Hu1 

Affiliation: 1. Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA. 2. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. 3. Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Melbourne, Australia. 4. Gilead Sciences, Inc., Foster City, California, USA. 5. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, USA. 

Abstract Body: 

Current therapies rarely cure chronic hepatitis B virus (HBV) infection due to the persistence of the viral episome, covalently closed circular DNA (cccDNA), in hepatocytes. The so-called hepatitis B core-related antigen (HBcrAg), a composite antigen found in the blood of infected patients, has emerged as one potential marker to monitor the intrahepatic cccDNA and define new meaningful treatment endpoints. In this study, we aimed to comprehensively characterize the compositions of HBcrAg and its equivalents in the woodchuck hepatitis virus (WHV) and investigate their kinetics during the natural infection and antiviral treatments. We have found that components of HBcrAg included the classical hepatitis B core antigen (HBcAg or HBc) and hepatitis B e antigen (HBeAg), and additionally, the PreCore-related antigen (PreC) that retain the N-terminal signal peptide sequence. Both HBeAg and PreC antigens displayed heterogeneous proteolytic processing at their C-terminus resulting in multiple species. HBeAg was the predominant form of HBcrAg in HBeAg-positive patients. HBc, but not HBeAg or PreC proteins, were found as the main component of capsids in DNA-containing or empty virions. The woodchuck hepatitis virus (WHV) core related antigen also included the WHcAg, WHeAg, and WHV PreC proteins analogous to HBV PreC proteins. WHeAg and PreC proteins, but not HBeAg or PreC, were N-glycosylated. A positive correlation was found between the serum WHeAg and intrahepatic cccDNA. Analysis of the kinetics of each HBcrAg component (HBeAg, HBc, and PreC) in HBV-infected chimpanzees and analogous WHV antigens in WHV-infected woodchucks revealed multiple distinct phases of decline during the natural resolution of HBV and WHV infection and in response to different antiviral treatments. Careful monitoring of each component of HBcrAg, i.e., HBc, HBeAg, and PreC proteins, along with other classical markers such as viral DNA and HBV surface antigen will help understand intrahepatic HBV gene expression and replication, including cccDNA levels and activity, so as to elucidate natural resolution mechanisms as well as guide antiviral development.

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Slides and video for this presentation will not be published as it contains unpublished information. 

Jianming Hu

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MD: Wuhan University School of Medicine 

PhD: Penn State University College of Medicine 

Currently: Professor, Department of Microbiology and Immunology, Penn State University College of Medicine 

Research interest: HBV replication and persistence, virus-host interactions, antivirals, biomarkers 

Co-Chair, ICE-HBV Working Group – Innovative Tools 

Member, ICE-HBV Working Group – Virology

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1:15-1:35pm  Utility of serum biomarkers to follow natural history and treatment of chronic hepatitis B + Q&As

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Title: Utility of serum biomarkers to follow clinical phases and treatment of chronic hepatitis B 

Date of presentation: October 5, 2020 

Authors: Harry L.A. Janssen and Hannah Choi 

Affiliation: Toronto Centre for Liver Disease, University of Toronto 

Abstract Body: 

The management of chronic HBV infection is challenging, owing to the varying natural course of infection and persistence of cccDNA. Thus, it is essential to monitor HBV biomarkers for diagnosis and effective management of the disease. Although serum HBVDNA and HBsAg remain the most well-characterized, clinically relevant biomarkers in chronic hepatitis B, supplemental, or even superior, biomarkers may be needed for disease monitoring, especially with HBV genome integration. Moreover, in the current era of effective NA therapy leading to complete HBV DNA suppression and to explore new treatment modalities which bring functional cure, HBV RNA and HBcrAg may serve as important additional markers of viral activity and immune control. Combinations of these biomarkers will likely be required to evaluate treatment efficacy, determine prognosis, and define true, (sterilizing) cure. In my lecture, the clinical utility of both established and emerging biomarkers will be appraised regarding the course of infection, disease progression, and response to established and new treatment.

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Harry Janssen

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Harry Janssen is Professor of Medicine at the University of Toronto, Ontario, Canada, where he holds the Francis Family Chair in Hepatology. He currently works at Toronto General Hospital as Chief of Hepatology and Director of the Toronto Centre for Liver Disease. 

Dr. Janssen has coordinated numerous clinical and translational studies on treatment for chronic viral hepatitis and other liver diseases. His main research interest is cure of chronic hepatitis B. He has published more than 500 original peer-reviewed papers and many book chapters. His H-index is over 100 and he has been cited 45,000 times (Google Scholar). He has received several prestigious international awards and has mentored over 50 PhD students, of whom many have taken leadership positions in the field of Hepatology or Virology.

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Panel Co-Chairs: Adam Gehring and Ulrike Protzer

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Adam Gehring received his Ph.D. at Case Western Reserve University in Cleveland, Ohio.  His training included a Postdoctoral Fellowship in the Institute of Hepatology at University College London and a position of Senior Research Fellow, and subsequently Assistant Principal Investigator, at the Singapore Institute for Clinical Sciences with Antonio Bertoletti. During his postdoctoral training Dr. Gehring was instrumental in developing TCR gene therapy for chronic HBV. His foundational work resulted in human application of engineered T cells for HBV-related HCC tumors expressing viral antigen. Dr. Gehring moved to Saint Louis University as an Assistant Professor in the Molecular Microbiology and Immunology department in March 2013 before joining the Toronto Center for Liver Disease as Biology Lead in February 2016.  

Dr. Gehring is currently Co-Chair for the Immune Monitoring Workgroup of the HBV Forum. He is Co-Chair for the International HBV Meeting being organized in Toronto in September, 2021. 

Dr. Gehring runs a translational HBV immunology research lab focused on liver pathogenesis and sex-based differences in disease progression. His primary interest lies in defining the mechanisms driving liver inflammation during HBV-related flares using functional and transcriptomic approaches in liver biopsies. He has established an internal immune monitoring core within his lab to process and analyze immune responses in Phase 2 clinical studies for HBV. 

Ulrike Protzer is an expert clinical virologist with many years of research in molecular virology, virus-host interaction and immunology mostly focusing on hepatitis B virus (HBV). Ulrike studied medicine in Germany, South Africa and Switzerland. She did a clinical training in infectious diseases, gastroenterology and hepatology before she went into virology, and has passed board exams in Internal Medicine as well as in Microbiology and Virology. 

Her scientific efforts focus on understanding the interaction between viruses and their hosts and on translating this knowledge into novel therapeutic approaches. She developed cell culture and mouse models of HBV infection to understand how HBV persists and how the nuclear HBV persistence form, the so called cccDNA, can be attacked. Her scientific work indicates that immune stimulation is required to keep cccDNA in check. Her group is exploiting therapeutic vaccines, adoptive T cell therapies and antibodies to reconstitute HBV-specific immunity and finally cure HBV. More recently, she also focusses on SARS-coronavirus. 

Since 2007, Ulrike Protzer holds the Chair of Virology at the Technical University of Munich (TUM)and is director of the Institutes of Virology at TUM and at Helmholtz Zentrum Muenchen. She serves in numerous advisory and supervisory boards and is vice dean of the School of Medicine. She leads two national and an international research consortium, was member of the executive board of the German Center for Infection Research and now is the speaker of its Thematic Translational Unit “Viral Hepatitis”.

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1:35-2:20pm

Industry Panel Discussion – What are the virological and immunological gaps that need to be addressed? What biomarkers are most needed to meet HBV cure endpoints? 

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Gavin Cloherty, Jenny Yang, Bill Delaney, Oliver Lenz, Harry Janssen and MF Yuen

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Gavin A. Cloherty, Ph.D., is head of Infectious Disease Research for Abbott’s diagnostics business. He provides scientific leadership in the area of infectious disease diagnostics by conducting groundbreaking clinical studies on hepatitis and HIV and developing new tests. As one of the top experts in the field, his innovative research is changing the way infectious diseases are being diagnosed to help improve patient outcomes.

Gavin has more than 20 years of experience with Abbott and leads a team of scientists in the study of  the viral diversity of HIV and hepatitis. His expertise is sought after globally through his established partnerships with commercial organizations, ministries of health, government agencies and academic institutions, such as the Centers for Disease Control and Prevention (CDC) and National Institutes of Health’s AIDS Clinical Trial Group (ACTG) and Hepatitis B Research Network (HBRN). He has worked with the Republic of Georgia to help eradicate hepatitis C in the country, and is looking to expand these efforts to other regions of the world severely impacted by this disease.

Jenny Yang, PharmD is a Senior Director of Clinical Research at Gilead Sciences.  After working on the global development and registration of Gilead’s HCV marketed products including Sovaldi®, Harvoni®, and Vosevi®, she now leads the HBV Cure clinical development program at Gilead.  Prior to her 13-year experience in drug development at Gilead and Novartis, she completed her PharmD at the University at Buffalo, School of Pharmacy and Pharmaceutical Sciences. 

William Delaney, PhD joined Assembly Biosciences as Chief Scientific Officer, Virology in May 2020. Prior to joining Assembly, he most served as Executive Director, Biology at Gilead. During his 20-year career at the Gilead, he headed the Viral Hepatitis & Herpes Discovery Biology Groups and served as the Research Therapeutic Area Head for HBV. He began his career as a Research Scientist, Clinical Virology at Gilead and later transitioned into Drug Discovery where he held positions of increasing responsibility. Over the course of his career, he has contributed to the development of several marketed products, including Hepsera®, Viread®, and Vemlidy® for HBV and Sovaldi®, Harvoni®, Epclusa®, and Vosevi® for HCV. He earned a BS in Biotechnology from the University of Delaware and a PhD in Cell and Molecular Biology from the Penn State College of Medicine. In addition, he was a Postdoctoral Fellow at the Victorian Infectious Diseases Reference Laboratory (VIDRL), Department of Research & Molecular Development. 

Oliver Lenz, PhD is Scientific Director Clinical Microbiology and Immunology at Janssen Infectious Diseases, part of the Janssen Pharmaceutical Companies of Johnson & Johnson. He is the global virology lead for the development of HBV therapeutics from pre-clinical through clinical development. Prior to his work in HBV he was involved in the discovery of the HCV protease inhibitor simeprevir which he supported subsequently through clinical development until registration. Oliver Lenz completed his PhD at the University of Marburg, Germany, mainly working on hemorrhagic fever viruses and did a postdoctoral fellowship at the European Molecular Biology Laboratory (EMBL) at Grenoble, France, on HIV GP41 structural biology. He is author of 70 peer reviewed papers and co-chair of the HBV Forum surrogate endpoints working group.   

Harry Janssen is Professor of Medicine at the University of Toronto, Ontario, Canada, where he holds the Francis Family Chair in Hepatology. He currently works at Toronto General Hospital as Chief of Hepatology and Director of the Toronto Centre for Liver Disease. 

Dr. Janssen has coordinated numerous clinical and translational studies on treatment for chronic viral hepatitis and other liver diseases. His main research interest is cure of chronic hepatitis B. He has published more than 500 original peer-reviewed papers and many book chapters. His H-index is over 100 and he has been cited 45,000 times (Google Scholar). He has received several prestigious international awards and has mentored over 50 PhD students, of whom many have taken leadership positions in the field of Hepatology or Virology. 

Professor Yuen obtained his first bachelor degree of medicine in 1992. He further pursued his academic excellence through the achievement of obtaining 3 doctoral degrees including Doctor of Medicine with Sir Patrick Manson Gold Medal in 2001, Doctor of Philosophy in 2005 and Doctor of Science in 2017.  

Professor Yuen’s research interests include prevention, natural history, molecular virology and treatment of chronic hepatitis B and C, and hepatocellular carcinoma. He is one of the top internationally renowned researchers in the field of hepatitis B disease. He has now published more than 440 papers in world renowned medical journals.  

At present, he is the pioneering clinical researcher leading numerous studies on novel antiviral and immunomodulatory agents for the treatment of chronic hepatitis B. He is also actively performing cutting edge research on novel markers for hepatitis B infection and occult hepatitis B infection.  

As a specialist of Gastroenterology and Hepatology, Professor Yuen have been providing clinical care and services for patients in Queen Mary Hospital, The University of Hong Kong for more than 20 years. He is also serving as medical advisor and consultant for different health related units of the Government of Hong Kong, many academic centres and commercial enterprises for different aspects related to the diseases of Gastroenterology and Hepatology.  

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October 12th – 

Session Co-Chairs: Christian Bréchot & Ourania M. Andrisani 

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Christian Bréchot, MD, PhD joined the USF Health Morsani College of Medicine part time as Senior Associate Dean for Research in Global Affairs, Associate Vice President for International Partnerships and Innovation, and Professor in the Division of Infectious Disease, Department of Internal Medicine   Since 2017, Dr. Brechot has served as President of the Global Virus Network, a network of 48 research centers worldwide, headquartered in Baltimore.

Before serving as president of the Pasteur Institute from 2013 to 2017, Dr. Bréchot was vice president of medical and scientific affairs at Institut-Merieux, a company that develops new approaches to fight infectious diseases and cancers.  He also served as the general director of Inserm, the French national agency for biomedical research from 2002 to 2007. As professor of hepatology and cell biology at Necker School of Medicine, Paris Descartes University, he led the clinical department of liver diseases at Necker-Enfants Maldes Hospital from 1997 to 2001.

Authoring more than 400 articles in medical and scientific journals, Dr. Bréchot was ranked by the Institute for Scientific Information as the 4th most cited author on the topic of hepatitis C. He has been recognized as an inventor on 18 patents, and helped create three biotechnology companies: Rarecells, ALFACT Innovation, and The Healthy Aging Company.

Dr. Bréchot’s research activities have focused on viral hepatitis: hepatitis B (HBV) and C (HCV), particularly with regard to their role in liver cancer (Hepatocellular carcinoma: HCC) and to the molecular mechanisms that drive liver regeneration and cancer (in particular, cell cycle deregulation and the impact of oxidative stress). He has been the member of numerous scientific committees and societies and has received prestigious awards.

Ourania Andrisani, Ph.D.,
Distinguished Professor of Basic Medical Sciences, Purdue University,
Program Leader, Purdue Center for Cancer Research.
Ourania Andrisani is a molecular biologist with research interests and expertise on molecular mechanisms of transcriptional regulation, epigenetics, and signal transduction involved in cell growth control, cellular differentiation and cancer pathogenesis. Her laboratory studies epigenetic mechanisms involved both in Hepatitis B virus (HBV) biosynthesis and virus-mediated hepatocarcinogenesis. Her laboratory aims to identify essential mechanisms that can be targeted to suppress both HBV infection and HBV-mediated liver cancer.
She is Program Leader for the Purdue Center of Cancer Research (2018-present), co-organizer of the International Conference on the Molecular Biology of Hepatitis B viruses for 2020/21, and has been actively involved in graduate education and training. She has served as permanent member of the Endocrinology (NIDDK) and the Molecular Oncogenesis (NCI) study sections, and continues to serve as reviewer of other NIH study sections, international funding agencies, and high impact journals.

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Noon   Housekeeping Rules Capucine Penicaud
12:00-12:10pm 

Welcome by Peter Revill & Fabien Zoulim – ICE-HBV Chairmanship Handover.

Introduction of Session Chairs Christian Bréchot and Ouriana M. Andrisani. 

See Welcome Video.

 
12:10-12:25pm  Biomarkers of HBV cccDNA expression + Q&As

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Title: Biomarkers of HBV cccDNA expression 

Date of presentation: October 12th, 2020 

Authors: Maura Dandri 

Affiliation: Research Group Viral Hepatitis, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany 

Abstract Body: 

Chronic hepatitis B virus infection cannot be completed eliminated due to the persistence of the covalently closed circular (cccDNA), the template of HBV transcription in infected hepatocytes. Since assessment of cccDNA amounts and activity requires an invasive procedure, there is an urgent need for serum biomarkers that can accurately correlate with cccDNA expression in the liver. Different types of HBV serum biomarkers have been proposed, which include classical markers, such as HBsAg, and newer markers such as HBV RNA and core related antigen. However, their function, events that may affect their production and clinical relevance in chronic HBV infection is not fully understood. This presentation will focus on the cccDNA as producer of HBV serological biomarkers, giving emphasis on how distinct therapeutic approaches may affect the levels of virological markers, in particularly HBV RNA in serum, and to which extent such changes can provide information about the amounts and activity of intrahepatic cccDNA. Current gaps of knowledge, caveats and open questions will be discussed.

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Maura Dandri

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Maura Dandri is full Professor at the University Medical Center Hamburg-Eppendorf, where she leads the research group Viral Hepatitis. She received her B.S. in Natural Science and PhD in Microbiology and Immunology at the University of Trieste, Italy; was Post-doctoral Fellow at Albert Einstein College of Medicine, New York, and at Heinrich-Pette-Institute, Hamburg, Germany (EMBO Fellowship). The German Research Foundation awarded her with a Heisenberg Professorship. Her research focuses on developing infection models to study interactions between hepatitis viruses, human hepatocytes and immune cells. She also investigates the potential of HBV/HDV therapeutic strategies using humanized mice and patient sample analyses.

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12:25-12:40pm  Biomarkers of Occult HBV infection  + Q&As

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Title: Biomarkers of Occult HBV infection 

Date of presentation: Oct 12, 2020 

Authors: Teresa Pollicino 

Affiliation: University Hospital of Messina, Italy 

Abstract Body: 

Occult HBV infection (OBI) is defined as the presence of replication-competent HBV DNA (cccDNA) in the liver and/or HBV DNA in the blood of people who test negative for HBsAg. Intrahepatic HBV DNA is the gold standard diagnostic biomarker for OBI. However, liver tissue is not always available, and there is no standardized assay. A more common (but less sensitive) approach to diagnose OBI is the detection of HBV DNA in the blood. Because serum HBV DNA is usually present in low concentrations and may only be intermittently detected in OBI, analyzing serially collected blood samples, and testing DNA extracts from no less than 1 ml of serum/plasma is recommended for OBI diagnosis. Anti-HBc may be used as a surrogate marker to identify OBI in blood/organ donors and people who will receive immunosuppressive therapies.  However, the absence of anti-HBc does not rule out OBI.

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Theresa Pollicino

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Teresa Pollicino MD is a Professor of Molecular Medicine and Pathophysiology and Head of the Molecular Hepatology Laboratory of the Division of Clinical and Molecular Hepatology, University Hospital of Messina, Italy.  

In 1990, she received her MD in Medicine and Surgery at the of Messina, where she completed her residency in Hematology and Internal Medicine.  

Dr. Pollicino has worked in numerous international research centers including: 

1996-1998, “Unité de Recombinaison et Expression Génétique”, Institut Pasteur, Paris, France 

2002-2003, Laboratory of Gene Expression, Regina Elena Institute, Rome 

2015-2016, Hepatic Pathogenesis section, Laboratory of Infectious Diseases, NIH, Bethesda, MA, US.

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12:40-12:55pm  Biomarkers of liver cancer  +Q&As 

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Title: Biomarkers of Liver Cancer

Date of presentation: October 12, 2020

Author: Patrizia Farci, MD

Affiliation: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, NIAID, NIH

Abstract Body:

HCC is the seventh most common human cancer and the second leading cause of cancer-related death globally. HBV is the leading cause of HCC worldwide. The prognosis of HCC is poor and, as a result, the incidence and mortality rates are roughly equivalent. The complexity of HCC is rarely seen in other cancers, and the lack of early diagnostics and effective treatments has made this cancer one of the most challenging. Patients with cirrhosis are at highest risk for developing HCC. The current surveillance strategies in high-risk populations using ultrasound imaging with or without serum alpha-fetoprotein (AFP) are suboptimal for the early detection of HCC, which is critical for a better prognosis. Although a series of HCC biomarkers are under clinical evaluation, including novel biomarkers derived from Omic technologies, their clinical validation is still in the early phases. Only AFP has completed the 5 phases required for routine clinical use, but there are limitations with its sensitivity and specificity. In my presentation, I will discuss the current state of HCC surveillance, the present challenges, and the areas of future research. 

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Patrizia Farci 

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Patrizia Farci, M.D.

Chief Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, NIAID, NIH

Patrizia Farci earned her M.D. at the University of Cagliari Medical School, Italy, and then became a board-certified specialist in Infectious Diseases and in Gastroenterology at the same University. She did her postdoctoral training at the Molinette Hospital in Turin under Dr. Mario Rizzetto and at the Royal Free Hospital School of Medicine in London under Prof. Sheila Sherlock. In 1989, she joined the laboratory of Dr. Robert H. Purcell at the NIH as a Visiting Scientist. In 1992, she became Associate Professor of Medicine and, in 2000, Full Professor of Medicine and Director of the Liver Unit at the University of Cagliari, Italy.  In 2007, she returned to the NIH, where in 2010 she become the Chief of Hepatic Pathogenesis Section in the LID, NIAID.

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12:55-1:10pm  Point of Care Testing – an unmet and urgent need + Q&As

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Title: Point of Care Testing- an unmet and urgent need

Date of presentation: October 12, 2020

Authors: Daryl Lau, MD, MPH

Affiliation: Harvard Medical School

Abstract Body:

Current access to HBV care is suboptimal in the resources limited settings. The inaccessibility of diagnostic tests poses an obstacle for effective HBV screening and treatment programs. There is an urgent need for reliable and affordable point-of-care (POC) tests that can be applied to provide the best quality of care within available resources.  A comprehensive and practical HBV management guidance applying such POC tests to meet the acceptable health standards and prepare the health systems to adapt to the evolving hepatitis B treatment advances is essential in the resources limited settings. 

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Daryl Lau

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Daryl Lau, MD, MPH is an associate professor of medicine in Harvard Medical School. Her major research interest has been the clinical and translational investigation of liver disease and in particularly viral hepatitis. She has conducted studies on the natural history, therapeutic trials and new diagnostic assays on hepatitis B, hepatitis C and delta hepatitis. Currently, she serves as the program director of the NIH sponsored Harvard hepatitis B Consortium to advance the diagnosis, understanding of the pathogenesis and treatment of chronic hepatitis B and its complications.

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1:10-1:30pm 

Bench to Bed: Relevance of biomarkers used in in vitro and in vivo model systems to the clinic + QAs

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Dieter Glebe

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Institute of Medical Virology, Justus Liebig University Giessen, National Reference Centre for Hepatitis B Viruses and Hepatitis D viruses Head: Prof. Dieter Glebe, PhD.

Major Research Interest: The overall aim of his research is focused on understanding the evolutionary background and molecular mechanism involved in infectivity, persistence and neutralization of hepatitis B and D viruses. In the past, he discovered and characterized a new species of hepatitis delta-like viruses and various hepadnaviruses from mammals, including hepadnaviruses from primates, bats and shrews that could serve as animal models for HBV and HDV. He is also interested in HBV vaccines and analysed efficiency of neutralising antibodies against HBV surface proteins. During the last years, D. Glebe has devoted substantial parts of his research to the understanding of processes that constitute current genetic diversity, infectivity and pathogenicity of hepatitis B viruses, hepatitis D viruses and related animal viruses.

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Panel Co-Chairs: Fabien Zoulim and Mala Maini

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Fabien Zoulim obtained his M.D. in Gastroenterology and Hepatology in Lyon Medical School in 1991. He has also obtained a PhD in Molecular and Cellular Biology and was trained as a post-doctoral researcher at Fox Chase Cancer Center in Philadelphia. He is Professor of Medicine at Lyon I University since 1997. He is currently Medical Director of the Hepatology Department at the Hospices Civils de Lyon, and Scientific Director of the Department of Immunology and Virology of INSERM Unit 1052 where he is leading the team on ‘Antiviral therapy of viral hepatitis’. Dr Zoulim has served as an Associate Editor for Journal of Hepatology and is currently Associate Editor for Gut. He also served as an expert in the microbiology study section of the INSERM and is currently head of the clinical viral hepatitis study section at ANRS. He served as a Governing Board member of the European Association for the Study of the Liver (EASL). Dr Zoulim received the William Prusoff award of the International Society for Antiviral Research. Furthermore, he has been the scientific coordinator of a European community-funded Network of Excellence on the management of antiviral drug resistance, and is currently head of the ANRS “HBV cure” program in France. Fabien Zoulim is a recognised expert in the field of viral hepatitis and antiviral therapy. He has published more than 350 articles (H index 63, Web of Science). 

Mala Maini is a Professor of Viral Immunology in the Division of Infection and Immunity at UCL, London and also works as a Consultant Physician in the viral hepatitis clinic. Her lab researches liver immunity and immunopathology, focusing on cellular interactions and metabolic constraints. By dissecting the immune correlates of viral persistence and liver damage, the Maini lab aims to contribute to the development of novel immunotherapeutic strategies for hepatitis B and hepatocellular carcinoma. Their work is funded by the Wellcome Trust, Cancer Research UK, Medical Research Foundation, NIHR, EU, UKRI, British Infection Association.  

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1:30-2:20pm

Industry Panel Discussion: What are the most clinically relevant biomarkers?

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Participants: Gavin Cloherty, Jenny Yang, Oliver Lenz, Anna-Maria Geretti, Bill Delaney, Henry Chan and Maria Beumont.

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Gavin A. Cloherty, Ph.D., is head of Infectious Disease Research for Abbott’s diagnostics business. He provides scientific leadership in the area of infectious disease diagnostics by conducting groundbreaking clinical studies on hepatitis and HIV and developing new tests. As one of the top experts in the field, his innovative research is changing the way infectious diseases are being diagnosed to help improve patient outcomes.

Gavin has more than 20 years of experience with Abbott and leads a team of scientists in the study of  the viral diversity of HIV and hepatitis. His expertise is sought after globally through his established partnerships with commercial organizations, ministries of health, government agencies and academic institutions, such as the Centers for Disease Control and Prevention (CDC) and National Institutes of Health’s AIDS Clinical Trial Group (ACTG) and Hepatitis B Research Network (HBRN). He has worked with the Republic of Georgia to help eradicate hepatitis C in the country, and is looking to expand these efforts to other regions of the world severely impacted by this disease.

Jenny Yang, PharmD is a Senior Director of Clinical Research at Gilead Sciences.  After working on the global development and registration of Gilead’s HCV marketed products including Sovaldi®, Harvoni®, and Vosevi®, she now leads the HBV Cure clinical development program at Gilead.  Prior to her 13-year experience in drug development at Gilead and Novartis, she completed her PharmD at the University at Buffalo, School of Pharmacy and Pharmaceutical Sciences. 

Oliver Lenz, PhD is Scientific Director Clinical Microbiology and Immunology at Janssen Infectious Diseases, part of the Janssen Pharmaceutical Companies of Johnson & Johnson. He is the global virology lead for the development of HBV therapeutics from pre-clinical through clinical development. Prior to his work in HBV he was involved in the discovery of the HCV protease inhibitor simeprevir which he supported subsequently through clinical development until registration. Oliver Lenz completed his PhD at the University of Marburg, Germany, mainly working on hemorrhagic fever viruses and did a postdoctoral fellowship at the European Molecular Biology Laboratory (EMBL) at Grenoble, France, on HIV GP41 structural biology. He is author of 70 peer reviewed papers and co-chair of the HBV Forum surrogate endpoints working group.   

Anna Maria Geretti – MD, PhD – has a dual appointment as Expert Scientist at Roche Pharma Research & Early Development in Switzerland and as Professor of Virology & Infectious Diseases and Consultant in Infectious Diseases at the University of Liverpool in the United Kingdom. Anna Maria’s current research focuses on novel curative treatments for chronic HBV infection and includes a specific interest in the identification and validation of biomarkers for patient stratification and monitoring. Anna Maria’ s ambition is to work collaboratively across academia and industry to promote progress of medicine and science and globally benefit public health and patient care.

William Delaney, PhD joined Assembly Biosciences as Chief Scientific Officer, Virology in May 2020. Prior to joining Assembly, he most served as Executive Director, Biology at Gilead. During his 20-year career at the Gilead, he headed the Viral Hepatitis & Herpes Discovery Biology Groups and served as the Research Therapeutic Area Head for HBV. He began his career as a Research Scientist, Clinical Virology at Gilead and later transitioned into Drug Discovery where he held positions of increasing responsibility. Over the course of his career, he has contributed to the development of several marketed products, including Hepsera®, Viread®, and Vemlidy® for HBV and Sovaldi®, Harvoni®, Epclusa®, and Vosevi® for HCV. He earned a BS in Biotechnology from the University of Delaware and a PhD in Cell and Molecular Biology from the Penn State College of Medicine. In addition, he was a Postdoctoral Fellow at the Victorian Infectious Diseases Reference Laboratory (VIDRL), Department of Research & Molecular Development. 

Professor Henry Lik Yuen Chan is Professor of Medicine and Associate Dean (External Affairs) of Faculty of Medicine, The Chinese University of Hong Kong. He is a world-renowned expert in viral hepatitis B, and is chairman of the Strategic Technical Advisory Committee on Viral Hepatitis for the Western Pacific Regional Office of World Health Organization. He has published over 450 papers in peer-reviewed journals, and is awarded Highly Cited Researcher by Clarivate Analytics in 2018 and 2019 for producing multiple top 1% cited papers under Web of Science. 

Maria Beumont is a Senior Medical Director at Janssen in the role of Hepatitis Franchise Medical Lead. She received her MD degree from the University of Buenos Aires Argentina, and moved to the United States where she completed a Fellowship in Infectious Diseases at the University of Pennsylvania. Prior to joining the Pharmaceutical Industry, she served as the Director of HIV Services for the City of Philadelphia at the Philadelphia Department of Public Health and subsequently she became Assistant Professor, responsible for out-patient HIV care, at Thomas Jefferson University. 

 

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2:20-2:30pm 

Concluding remarks and next steps

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Anna Kramvis

 

This event is endorsed by the HBV International Meeting.