Medical Director, Hepatology Department, Hospices Civils de Lyon
Head of the Viral Hepatitis Laboratory, Cancer Research Center of Lyon, INSERM U1052
Professor of Medicine, Lyon I University, Lyon, France.
Professor Fabien Zoulim obtained his MD in gastroenterology and hepatology from 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 has been a professor of medicine at Lyon I University since 1997. He is currently the medical director of the hepatology department at the Hospices Civils de Lyon, and scientific director of the department of immunology and virology at INSERM Unit 1052 where he is leading the team on antiviral therapy of viral hepatitis. Professor Zoulim has served as an associate editor for the 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 ANRS, and in different national and international committees. He has also been a governing board member of the European Association for the Study of the Liver (EASL). He is coordinating the national HBV cure program at ANRS.
Professor Zoulim received the William Prusoff award of the International Society for Antiviral Research in recognition of his work in the field of HBV molecular biology and anti-HBV therapy. 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 involved in several European projects. Fabien Zoulim is a recognised expert in the field of viral hepatitis and antiviral therapy. He has published more than 350 articles (H-index 59, Web of Science).
Despite the availability of an efficient vaccine, chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide with 250 million chronic carriers of the virus. Chronic HBV infections are the first cause of hepatocellular carcinoma (HCC) worldwide. Currently, there are two main classes of antivirals to treat chronic hepatitis B. Interferon (IFN) alpha can induce a sustained viral suppression in approximately 20% of patients. Administration of new generation Nucleos(t)ide analogues (NUCs) can achieve viral suppression in the majority of patients, but life-long therapy is needed to prevent relapse of viral replication. The issue of antiviral drug resistance remains relevant in high endemic areas because of the use of less expensive drugs with a low barrier to resistance.
A functional cure of the infection, defined by the loss of serum HBsAg, is achieved in only 10% of patients treated with IFN or NUCs. To make significant progress in the management of this deadly infection, it is critical to develop new antiviral strategies with the aim of doing better than viral suppression and achieve at least a “functional” cure of the infection or a complete cure of infection in a large proportion of patients.
HBV is a non-cytopathic DNA virus which belongs to the Hepadnaviridae family. Its persistence within infected hepatocytes is maintained by a covalently closed circular DNA (cccDNA). It is associated to histones and represents a viral minichromosome which is the template for the transcription of all viral mRNAs and the viral pregenomic RNA. The pathobiology of the infection also involves the host immune response which is required to control viral replication. HBV has evolved mechanisms to evade both the innate and the adaptive immunity to establish persistent infections.
Major progress has been made in the last few years in the understanding of several key steps of the viral cycle including the identification of cellular receptor for viral entry, the identification of key nuclear enzymes involved in cccDNA formation, the discovery that induction of cellular signaling pathways may degrade at least partially cccDNA, as well as a better understanding of the mechanism involved in the exhaustion of HBV-specific T cells. Improved experimental models for the study of HBV replication and pathobiology in more relevant hepatocyte culture systems and animal models have been established.
This knowledge and new tools represent the basis to explore novel concepts of antiviral therapy to defeat chronic HBV infections. These includes the pre-clinical or early clinical evaluation of direct antivirals: i) entry inhibitors, ii) drugs targeting cccDNA formation, degradation or epigenome, iii) RNA interference to suppress viral genome expression, iv) nucleocapsid assembly modulators, iv) inhibitors of viral morphogenesis and egress; and of immunotherapeutic approaches: i) TLR agonists to boost innate immune responses, ii) check-point inhibitors such as PD-1 blockade to restore exhausted T cell activity, iii) engineering of re-directed specific T cells (HBV specific T cell receptors, chimeric antigen receptors), iv) therapeutic vaccines.
This knowledge has paved the way of the development of novel treatment concepts and new combination therapies which are being evaluated in clinical trials with the aim of curing the infection.
Chronic HBV infections are a major public health concern!
Despite the availability of an efficient vaccine, chronic hepatitis B virus (HBV) infections remain a major public health problem worldwide with 250 million chronic carriers of the virus. Chronic HBV infections are the first cause of hepatocellular carcinoma (HCC) worldwide and HCC ranks 3rd in terms of cancer mortality.
Current treatments options
Interferon alpha administration provides a remission of the infection in only 20% of patients. Nucleos(t)ide analogues administration achieves viral suppression in the majority of patients but life-long therapy is needed to prevent relapses. A functional cure (loss of HBsAg with the persistence of cccDNA) is achieved in only 10% of the treated patients in the long-term.
Its mechanism is linked to the persistence of cccDNA, the viral minichromosome, in the liver, and to defective host immune responses.
Dr. Karin was born in Tel Aviv, Israel and received the Bachelor of Science degree in 1975 from Tel Aviv University, with a major in Biology. In 1975 he arrived in the US and in 1979 received a Ph.D. degree in Molecular Biology from the University of California, Los Angeles. Dr. Karin followed his graduate studies with postdoctoral fellowships at the Fox Chase Institute for Cancer Research, working in the laboratory of Dr. Beatrice Mintz, and the laboratory of Dr. John Baxter at the University of California, San Francisco. Dr. Karin joined the faculty at the University of California, San Diego in 1986, where currently he is a Distinguished Professor of Pharmacology.
Dr. Karin has received numerous awards including the Oppenheimer Award for Excellence in Research from the Endocrine Society in 1990, an American Cancer Society Research Professorship in 1999, the C.E.R.I.E.S. Research Award for Physiology or Biology of the Skin in 2000, the Harvey Prize in Human Health in 2011, the Brupbacher Prize in Cancer Research in 2013 and the William B. Coley Award for Distinguished Research in Basic and Tumor Immunology in 2013. Dr. Karin was elected to the National Academy of Sciences in 2005, as a Foreign Associate of EMBO in 2007, and to the Institute of Medicine in 2011. Dr. Karin also serves on several advisory boards and was cofounder of Signal Pharmaceuticals (currently Celgene).
Dr. Karin has spent his entire academic career investigating stress and inflammation signaling covering the entire gamut of research approaches from basic biochemistry through molecular cell biology to animal pathophysiology. After discovering how environmental stress caused by either infection, inflammation or exposure to toxic substances leads to activation of AP-1, NF-κB and other transcription factors, his lab began to examine the role of the key signaling pathways controlling these transcription factors in the pathogenesis of cancer, degenerative and metabolic diseases. The Karin group has identified some of the fundamental mechanisms through which inflammation and obesity promote tumor development and progression and contribute to type II diabetes. They had established the mechanisms through which members of the IL-6 cytokine family contribute to the development of colorectal and liver cancer through activation of STAT3 and other transcription factors. They had also established the complex and cell type specific mechanisms through which NF-κB activation via IκB kinases (IKK) controls development and progression of colon, liver and prostate cancers. They were amongst the first to demonstrate that not onlyinnate immune cells, such as macrophages, but also adaptive immune cells, including T regulatory cells and B lymphocytes, also contribute to tumorigenesis and its progression. Through this work, Dr. Karin has contributed to the founding of the Inflammation and Cancer field.
How chronically damaged liver tissues undergo malignant conversion and give rise to hepatocellular carcinoma.