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He Z, Wang C, Tian H. Letter to the Editor: Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort. Hepatology 2025; 81:E166-E167. [PMID: 39527090 DOI: 10.1097/hep.0000000000001159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Affiliation(s)
- Ziyi He
- Department of Oncology, The Second Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, China
| | - Chenxi Wang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
| | - Huichuan Tian
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China
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John BV, Bastaich D, Amoli MM, Wong RJ, Evon DM, Rogal SS, Ross DB, Morgan TR, Spector SA, Villada G, Chao HH, Dahman B. Association of HDV infection and HCC, hepatic decompensation, and all-cause and liver-related death in a national cohort. Hepatology 2025; 81:1822-1835. [PMID: 39255517 DOI: 10.1097/hep.0000000000001092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 08/23/2024] [Indexed: 09/12/2024]
Abstract
BACKGROUND AND AIMS HDV infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a US-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with HBV infection. APPROACH AND RESULTS In a national cohort of 4817 veterans infected with HBV tested for HDV (99.6% US-born, 3.3% HDV-positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of HCC, decompensation, and liver-related mortality, and all-cause mortality of patients with HDV compared to HBV mono-infection. HDV coinfection (vs. HBV mono-infection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p < 0.001) and 10 years (19.14 vs. 10.18, p < 0.001), respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by nonhepatic malignancies (15.6% vs. 14.8%), cardiac (11.7% vs. 15.2%), and lung disease (5.2% vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (adjusted hazard ratio: 2.57, 95% CI: 1.87-3.52, p < 0.001) and all-cause mortality (adjusted hazard ratio: 1.52, 95% CI: 1.20-1.93, p < 0.001). CONCLUSIONS In a predominantly US-born cohort of veterans, HDV coinfection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.
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Affiliation(s)
- Binu V John
- Division of Gastroenterology and Hepatology, Department of Medicine, Miami VA Medical System, Miami, Florida, USA
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dustin Bastaich
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Robert J Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, Palo Alto VA Health System, Palo Alto, California, USA
- Division of Gastroenterology, Department of Medicine, Stanford University, Palo Alto, California, USA
| | - Donna M Evon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Shari S Rogal
- Center for Health Equity Research and Promotion, Pittsburgh VA Health System, Pittsburgh, Pennsylvania, USA
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - David B Ross
- Division of Infectious Diseases, Department of Medicine, VA Washington DC Health Care, Washington, Columbia, USA
- Department of Medicine, George Washington University School of Medicine, Washington, Columbia, USA
| | - Timothy R Morgan
- Division of Gastroenterology and Hepatology, Department of Medicine, Long Beach VA Health System, Irvine, California, USA
- Division of Gastroenterology, Department of Medicine, University of California, Irvine, California, USA
| | - Seth A Spector
- Department of Surgery, Miami VA Health System, and University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Gabriel Villada
- Department of Pathology, Miami VA Medical System, Miami, Florida, USA
| | - Hann-Hsiang Chao
- Department of Radiation Oncology, Richmond VA Medical Center and Virginia Commonwealth University, Richmond, Virginia
| | - Bassam Dahman
- Department of Health Policy, Virginia Commonwealth University, Richmond, Virginia
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Cardoso MF, Machado MV. The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3723. [PMID: 39594679 PMCID: PMC11591730 DOI: 10.3390/cancers16223723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/22/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatitis delta virus (HDV) infection requires the presence of hepatitis B virus (HBV), and chronic HBV-HDV coinfection is considered the most severe form of viral hepatitis. When compared with HBV mono-infection, HBV-HDV coinfection is associated with higher rates of liver cirrhosis and hepatocellular carcinoma (HCC). In this review, we aim to elucidate the complex relationship between HDV infection and the development of HCC. The exact mechanisms underlying the carcinogenic potential of HDV remain to be fully elucidated. Evidence suggests that HDV has both indirect and direct oncogenic effects. Indirect effects promote accelerated progression to liver cirrhosis, which results in a different tumor microenvironment. Direct oncogenic effects are suggested by a distinct molecular signature. The recent epidemiological data regarding HBV-HDV coinfection should make us reconsider the HCC screening strategy, with special focus in younger non-cirrhotic patients. Finally, treating HCC in patients with chronic HDV poses unique challenges due to the complex interplay between HBV and HDV and the severity of liver disease. An in-depth understanding of the epidemiology and pathophysiology of HDV infection and carcinogenesis is essential to improve disease management in this high-risk population.
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Affiliation(s)
- Mariana Ferreira Cardoso
- Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal;
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Mariana Verdelho Machado
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
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Wranke A, Lobato C, Ceausu E, Dalekos GN, Rizzetto M, Turcanu A, Niro GA, Keskin O, Gherlan G, Abbas M, Ingiliz P, Muche M, Buti M, Jachs M, Vanwolleghem T, Cornberg M, Abbas Z, Yurdaydin C, Dörge P, Wedemeyer H. Long-term outcome of hepatitis delta in different regions world-wide: Results of the Hepatitis Delta International Network. Liver Int 2024; 44:2442-2457. [PMID: 38888267 DOI: 10.1111/liv.16006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/23/2024] [Accepted: 05/23/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND AND AIMS Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. METHODS The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long-term follow-up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver-related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver-related death. RESULTS Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow-up was 6.4 (.6-28) years. During follow-up, 195 patients (32%) developed a liver-related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow-up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa-based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. CONCLUSIONS The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection.
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
| | - Cirley Lobato
- Centro de Ciências de Saúde e do Desporto, Universidade Federal do Acre, Rio Branco, Brazil
| | - Emanoil Ceausu
- Infectious Diseases, Dr. Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest, Romania
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - Mario Rizzetto
- Department of Internal Medicine-Gastroenterology, University of Torino, Torino, Italy
| | - Adela Turcanu
- Department of Gastroenterology, State University of Medicine "Nicolae Testemitanu", Chisinau, Republic of Moldova
| | - Grazia A Niro
- Division of Gastroenterology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Onur Keskin
- Medical Faculty, Ankara University, Ankara, Turkey
| | - George Gherlan
- Infectious Diseases, Dr. Victor Babes Clinical Hospital for Infectious and Tropical Diseases, Bucharest, Romania
| | - Minaam Abbas
- Department of Hepatogastroenterology and Liver Transplantation, Ziauddin University Hospital Karachi, Karachi, Pakistan
| | | | - Marion Muche
- Department of Gastroenterology, Infectious Diseases and Rheumatology (including Clinical Nutrition), Charité, Berlin, Germany
| | - Maria Buti
- Liver Unit, Valle d'Hebron University Hospital and Ciberhed del Instituto CarlosIII, Barcelona, Spain
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Vanwolleghem
- Faculty of Medicine and Health Sciences, Laboratory of Experimental Medicine and Pediatrics, Viral Hepatitis Research group, University of Antwerp, Antwerp, Belgium
- European Reference Network RARE-LIVER
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- D-SOLVE: EU-Funded Network on Individualized Management of Hepatitis D
- Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany
| | - Zaigham Abbas
- Department of Hepatogastroenterology and Liver Transplantation, Ziauddin University Hospital Karachi, Karachi, Pakistan
| | - Cihan Yurdaydin
- Medical Faculty, Ankara University, Ankara, Turkey
- Department of Gastroenterology & Hepatology, Koc University Medical School, Istanbul, Turkey
| | - Petra Dörge
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- D-SOLVE: EU-Funded Network on Individualized Management of Hepatitis D
- Centre for Individualized Infection Medicine (CiiM), c/o CRC, Hannover, Germany
- Hannover Medical School, Excellence Cluster RESIST, Hannover, Germany
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Schinas G, Antonopoulou N, Vamvakopoulou S, Tsachouridou O, Protopapas K, Petrakis V, Petrakis EC, Papageorgiou D, Metallidis S, Papadopoulos A, Barbounakis E, Kofteridis D, Panagopoulos P, Lekkou A, Paliogianni F, Akinosoglou K. Prevalence of Hepatitis D in People Living with HIV: A National Cross-Sectional Pilot Study. Viruses 2024; 16:1044. [PMID: 39066206 PMCID: PMC11281684 DOI: 10.3390/v16071044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/24/2024] [Accepted: 06/26/2024] [Indexed: 07/28/2024] Open
Abstract
This study assesses the prevalence of hepatitis D virus (HDV) in people living with HIV (PLWHIV) in Greece. Given the compounding effects of HDV and hepatitis B (HBV) on liver disease progression, as well as the emergence of new therapeutic options such as bulevirtide, understanding regional disparities and the epidemiological impact of such co-infections is vital. A cross-sectional analysis was conducted utilizing 696 serum samples from PLWHIV attending five major university hospitals. The methodology included HDV antibody detection by ELISA and HDV RNA confirmation. Of the 30 HBsAg-positive samples analyzed, the study population was primarily male (93%), with a median age of 54 years. Participants had been on antiretroviral therapy for a median of 10 years, and the median CD4 count was 738 (539-1006) copies/mL. Additional serological findings revealed a 7% prevalence of hepatitis C virus (HCV) IgG antibodies and a 55% prevalence of hepatitis A virus (HAV) IgG antibodies. Seroreactivity for syphilis (RPR/VDRL/TPHA positive) was identified in 33% of the participants. The results indicated a low HDV prevalence, with only one individual (3%) testing positive for anti-HDV IgG antibodies and none for HDV RNA. This indicates a lower prevalence of HDV among PLWHIV with chronic HBV in Greece compared to global data.
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Affiliation(s)
- Georgios Schinas
- School of Medicine, University of Patras, 26504 Patras, Greece; (G.S.); (N.A.); (D.P.)
| | - Nikolina Antonopoulou
- School of Medicine, University of Patras, 26504 Patras, Greece; (G.S.); (N.A.); (D.P.)
| | - Sofia Vamvakopoulou
- Department of Microbiology, University General Hospital of Patras, 26504 Patras, Greece (F.P.)
| | - Olga Tsachouridou
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Thessaloniki “AHEPA”, 54636 Thessaloniki, Greece; (O.T.); (S.M.)
| | - Konstantinos Protopapas
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University General Hospital, 12462 Athens, Greece; (K.P.); (A.P.)
| | - Vasileios Petrakis
- Departments of Internal Medicine and Infectious Diseases, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (V.P.); (P.P.)
| | - Emmanouil C. Petrakis
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (E.C.P.); (E.B.); (D.K.)
| | - Despoina Papageorgiou
- School of Medicine, University of Patras, 26504 Patras, Greece; (G.S.); (N.A.); (D.P.)
| | - Simeon Metallidis
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Thessaloniki “AHEPA”, 54636 Thessaloniki, Greece; (O.T.); (S.M.)
| | - Antonios Papadopoulos
- 4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Attikon University General Hospital, 12462 Athens, Greece; (K.P.); (A.P.)
| | - Emmanouil Barbounakis
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (E.C.P.); (E.B.); (D.K.)
| | - Diamantis Kofteridis
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Heraklion, 71500 Heraklion, Greece; (E.C.P.); (E.B.); (D.K.)
| | - Periklis Panagopoulos
- Departments of Internal Medicine and Infectious Diseases, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (V.P.); (P.P.)
| | - Alexandra Lekkou
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Patras, 26504 Patras, Greece;
| | - Fotini Paliogianni
- Department of Microbiology, University General Hospital of Patras, 26504 Patras, Greece (F.P.)
| | - Karolina Akinosoglou
- School of Medicine, University of Patras, 26504 Patras, Greece; (G.S.); (N.A.); (D.P.)
- Departments of Internal Medicine and Infectious Diseases, University General Hospital of Patras, 26504 Patras, Greece;
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Iacob S, Gheorghe L, Onica M, Huiban L, Pop CS, Brisc C, Sirli R, Ester C, Brisc CM, Diaconu S, Rogoveanu I, Sandulescu L, Vuletici D, Trifan A. Prospective study of hepatitis B and D epidemiology and risk factors in Romania: A 10-year update. World J Hepatol 2024; 16:640-649. [PMID: 38689751 PMCID: PMC11056896 DOI: 10.4254/wjh.v16.i4.640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/19/2024] [Accepted: 03/22/2024] [Indexed: 04/24/2024] Open
Abstract
BACKGROUND The global burden of hepatitis D virus (HDV) infection represents a major medical challenge and a public health crisis worldwide. However, there is a lack of accurate data on the epidemiology and risk factors for HDV. Hepatitis B virus (HBV) and HDV coinfection causes the most severe form of viral hepatitis, leading to a higher cumulative incidence of liver-related events compared with HBV monoinfection, including the need for liver transplantation and death. AIM To investigate the epidemiology, natural history, risk factors and clinical management of HBV and HDV coinfection in Romanian patients. METHODS This prospective study was conducted between January and July 2022 in six tertiary gastroenterology and hepatology referral centres in Romania. All consecutive adults admitted for any gastroenterology diagnosis who were HBV-positive were enrolled. Patients with acute hepatitis or incomplete data were excluded. Of the 25390 individuals who presented with any type of gastroenterology diagnosis during the study period, 963 met the inclusion criteria. Testing for anti-HDV antibodies and HDV RNA was performed for all participants. Demographic and risk factor data were collected by investigators using medical charts and patient questionnaires. All data were stored in an anonymized online database during the study. RESULTS The prevalence of HBV was 3.8%; among these patients, the prevalence of HBV/HDV coinfection was 33.1%. The median age of the study population was 54.0 years, and it consisted of 55.1% men. A higher prevalence of HBV/HDV coinfection was observed in patients 50-69 years old. Patients with HBV/HDV coinfection were significantly older than those with HBV monoinfection (P = 0.03). Multivariate multiple regression analysis identified female gender (P = 0.0006), imprisonment (P < 0.0001), older age at diagnosis (P = 0.01) and sexual contact with persons with known viral hepatitis (P = 0.0003) as significant risk factors for HDV. CONCLUSION This study shows that HDV infection among those with HBV remains endemic in Romania and updates our understanding of HDV epidemiology and associated risk factors. It emphasizes the need for systematic screening for HDV infection and collaborative initiatives for controlling and preventing HBV and HDV infection.
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Affiliation(s)
- Speranta Iacob
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest 022328, Romania
| | - Liana Gheorghe
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest 022328, Romania.
| | - Mirela Onica
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest 022328, Romania
| | - Laura Huiban
- Department of Gastroenterology, Grigore T Popa University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, Saint Spiridon County Hospital, Iasi 700111, Romania
| | - Corina Silvia Pop
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology and Medical Oncology, University Emergency Clinical Hospital, Bucharest 050098, Romania
| | - Ciprian Brisc
- Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410087, Romania
- Department of Gastroenterology, Emergency County Hospital, Oradea 410169, Romania
| | - Roxana Sirli
- Center for Advanced Research in Gastroenterology and Hepatology, Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, Timisoara 300041, Romania
- Department of Gastroenterology and Hepatology, Timiş County Emergency Clinical Hospital "Pius Branzeu", Timisoara 300723, Romania
| | - Carmen Ester
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest 022328, Romania
| | - Cristina Mihaela Brisc
- Faculty of Medicine and Pharmacy, University of Oradea, Oradea 410087, Romania
- Department of Gastroenterology, Emergency County Hospital, Oradea 410169, Romania
| | - Sorina Diaconu
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Internal Medicine II and Gastroenterology, University Emergency Clinical Hospital, Bucharest 050098, Romania
| | - Ion Rogoveanu
- Department of Gastroenterology, University of Medicine and Pharmacy, Craiova 200349, Romania
- Department of Cardiology, Emergency County Hospital, Craiova 200642, Romania
| | - Larisa Sandulescu
- Department of Gastroenterology, Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy, Craiova 200349, Romania
- Department of Gastroenterology, Emergency County Hospital, Craiova 200642, Romania
| | - Deiana Vuletici
- Center for Advanced Research in Gastroenterology and Hepatology, Department of Gastroenterology and Hepatology, "Victor Babeş" University of Medicine and Pharmacy, Timisoara 300041, Romania
- Department of Gastroenterology and Hepatology, Timiş County Emergency Clinical Hospital "Pius Branzeu", Timisoara 300723, Romania
| | - Anca Trifan
- Institute of Gastroenterology and Hepatology, Saint Spiridon County Hospital, Iasi 700111, Romania
- Department of Gastroenterology, Faculty of Medicine, Grigore T Popa University of Medicine and Pharmacy, Iasi 700115, Romania
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7
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Lombardo D, Franzè MS, Caminiti G, Pollicino T. Hepatitis Delta Virus and Hepatocellular Carcinoma. Pathogens 2024; 13:362. [PMID: 38787214 PMCID: PMC11124437 DOI: 10.3390/pathogens13050362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/25/2024] Open
Abstract
The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.
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Affiliation(s)
| | | | | | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University Hospital of Messina, 98124 Messina, Italy; (D.L.); (M.S.F.); (G.C.)
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8
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Demirel A, Uraz S, Deniz Z, Daglilar E, Basar O, Tahan V, Ozaras R. Epidemiology of hepatitis D virus infection in Europe: Is it vanishing? J Viral Hepat 2024; 31:120-128. [PMID: 37964693 DOI: 10.1111/jvh.13899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/13/2023] [Accepted: 11/04/2023] [Indexed: 11/16/2023]
Abstract
Co-infection with hepatitis delta virus (HDV) is a challenging health care problem worldwide, estimated to occur in approximately 5%-10% of patients with chronic hepatitis B virus (HBV) infection. While HBV prevalence is decreasing globally, the prevalence of HDV infection is rising in some parts mainly due to injection drug use, sexual transmission and immigration from high endemicity areas. Eastern Europe and the Mediterranean are among the regions with high rates of endemicity for HDV and the immigration from high endemicity areas to Central and Western Europe has changed the HDV epidemiology. We aimed to review the prevalence of HDV infection in Europe. A paucity of publication appears in many European countries. Prevalence studies from some countries are old dated and some other countries did not report any prevalence studies. The studies are accumulated in few countries. Anti-HDV prevalence is high in Greenland, Norway, Romania, Sweden and Italy. Belgium, France, Germany, Spain, Switzerland, Turkey and United Kingdom reported decreasing prevalences. Among cirrhotic HBV patients, Germany, Italy and Turkey reported higher rates of HDV. The studies including centres across the Europe reported that HIV-HBV coinfected individuals have higher prevalence of HDV infection. The immigrants contribute the HDV infection burden in Greece, Italy, and Spain in an increasing rate. Previous studies revealed extremely high rates of HDV infection in Germany, Greece, Italy and Sweden. The studies report a remarkably high prevalence of hepatitis delta among HIV/HBV-coinfected individuals, individuals who inject drugs, immigrants and severe HBV infected patients across Europe. The HDV infection burden still appears to be significant. In the lack of an effective HDV therapy, prevention strategies and active screening of HBV/HDV appear as the most critical interventions for reducing the burden of liver disease related to HDV infection in Europe.
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Affiliation(s)
- Aslıhan Demirel
- Department of Infectious Diseases, School of Medicine, Demiroglu Bilim University, Istanbul, Turkey
| | - Suleyman Uraz
- Department of Gastroenterology, School of Medicine, Demiroglu Bilim University, Istanbul, Turkey
| | - Zeynep Deniz
- School of Medicine, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey
| | - Ebubekir Daglilar
- Department of Gastroenterology, West Virginia University-Charleston Area Medical Center, Charleston, West Virginia, USA
| | - Omer Basar
- Division of Gastroenterology, Summa Health System, Akron, Ohio, USA
| | - Veysel Tahan
- Division of Gastroenterology, Summa Health System, Akron, Ohio, USA
- Division of Gastroenterology, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Resat Ozaras
- Department of Infectious Diseases, Medilife Hospital, Istanbul, Turkey
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9
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Kamal H, Lindahl K, Ingre M, Gahrton C, Karkkonen K, Nowak P, Vesterbacka J, Stål P, Wedemeyer H, Duberg AS, Aleman S. The cascade of care for patients with chronic hepatitis delta in Southern Stockholm, Sweden for the past 30 years. Liver Int 2024; 44:228-240. [PMID: 37904316 DOI: 10.1111/liv.15770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/02/2023] [Accepted: 10/12/2023] [Indexed: 11/01/2023]
Abstract
BACKGROUND AND AIMS Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. METHODS HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression. RESULTS Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6). CONCLUSION Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis.
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Affiliation(s)
- Habiba Kamal
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Karin Lindahl
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Michael Ingre
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Centre for Bioinformatics and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Caroline Gahrton
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Kerstin Karkkonen
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Piotr Nowak
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Jan Vesterbacka
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
| | - Per Stål
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University of Hannover, Hannover, Germany
| | - Ann-Sofi Duberg
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Soo Aleman
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
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10
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Anastasiou OE, Caruntu FA, Curescu MG, Yalcin K, Akarca US, Gürel S, Zeuzem S, Erhardt A, Lüth S, Papatheodoridis GV, Keskin O, Port K, Radu M, Celen MK, Idilman R, Heidrich B, Mederacke I, von der Leyen H, Kahlhöfer J, von Karpowitz M, Hardtke S, Cornberg M, Yurdaydin C, Wedemeyer H. Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D. Liver Int 2024; 44:139-147. [PMID: 37787009 DOI: 10.1111/liv.15745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 08/09/2023] [Accepted: 09/11/2023] [Indexed: 10/04/2023]
Abstract
BACKGROUND & AIMS Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. METHODS In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 μg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). RESULTS Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p = .179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p = .04) and hepatic decompensation (p = .009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p > .999) but was associated with a higher chance of HDV-RNA suppression (p = .024, odds ratio 3.9 [1.3-12]). CONCLUSIONS Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. CLINICAL TRIAL REGISTRATION NCT00932971.
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Affiliation(s)
- Olympia E Anastasiou
- Institute for Virology, Medical Faculty of the University of Duisburg-Essen, Essen, Germany
| | | | | | - Kendal Yalcin
- Dicle University Medical Faculty, Diyarbakir, Turkey
| | | | - Selim Gürel
- Uludağ University Medical Faculty, Bursa, Turkey
| | - Stefan Zeuzem
- Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany
| | - Andreas Erhardt
- Heinrich Heine University, Dusseldorf, Germany
- Petrus Hospital, Wuppertal, Germany
| | - Stefan Lüth
- Department of Gastroenterology, Diabetology and Hepatology, University Hospital Brandenburg, Brandenburg Medical School (Theodor Fontane), Brandenburg, Germany
- Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Germany
| | | | - Onur Keskin
- Ankara University Medical School, Ankara, Turkey
| | | | - Monica Radu
- Institutul de Boli Infectioase, Bucharest, Romania
| | | | | | | | | | - Heiko von der Leyen
- Hannover Medical School, Hannover, Germany
- Orgenesis, Inc, Germantown, Maryland, USA
| | - Julia Kahlhöfer
- Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- D-SOLVE Consortium an EU Horizon Europe funded project (No 101057917), Hannover, Germany
| | | | - Svenja Hardtke
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Cornberg
- Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- D-SOLVE Consortium an EU Horizon Europe funded project (No 101057917), Hannover, Germany
- German Center for Infection Research, Partner Site Hannover-Braunschweig, Hannover, Germany
| | - Cihan Yurdaydin
- Department of Gastroenterology & Hepatology, Koc University Medical School, Istanbul, Turkey
| | - Heiner Wedemeyer
- Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), HepNet Study-House/German Liver Foundation, Hannover, Germany
- D-SOLVE Consortium an EU Horizon Europe funded project (No 101057917), Hannover, Germany
- German Center for Infection Research, Partner Site Hannover-Braunschweig, Hannover, Germany
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11
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Sandmann L, Berg T, Deterding K, Fischer N, Hinrichsen H, Petersen J, Tacke F, Cornberg M. Addendum „Antivirale Therapie der chronischen Hepatitis-D-Virusinfektion“ zur S3-Leitlinie „Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virusinfektion“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:1635-1653. [PMID: 38081179 DOI: 10.1055/a-2181-3046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Affiliation(s)
- Lisa Sandmann
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
- D-SOLVE Consortium, Horizon Europe Project, partner-site Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Thomas Berg
- Bereich Hepatologie, Medizinische Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Katja Deterding
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Nadine Fischer
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | | | - Jörg Petersen
- IFI Institut für Interdisziplinäre Medizin an der Asklepios Klinik St Georg, Hamburg, Deutschland
| | - Frank Tacke
- Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin, Berlin, Deutschland
| | - Markus Cornberg
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
- Centre for individualised infection Medicine (CiiM), Hannover, Deutschland
- Deutsches Zentrum für Infektionsforschung (DZIF), partner-site Hannover-Braunschweig, Deutschland
- D-SOLVE Consortium, Horizon Europe Project, partner-site Medizinische Hochschule Hannover, Hannover, Deutschland
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12
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Sandmann L, Berg T, Deterding K, Fischer N, Hinrichsen H, Petersen J, Tacke F, Cornberg M. Antiviral Therapy of Chronic Hepatitis D Virus Infection - Addendum to the S3 Guideline "Prophylaxis, Diagnosis and Therapy of Hepatitis B Virus Infection" of the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2023; 61:e715-e732. [PMID: 38081178 DOI: 10.1055/a-2181-3345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, Horizon Europe Project, partner-site Hannover Medical School, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nadine Fischer
- German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS), Berlin, Germany
| | | | - Jörg Petersen
- IFI Institute for Interdisciplinary Medicine at Asklepios Klinik St Georg, Hamburg, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Centre for individualised infection Medicine (CiiM), Hannover, Germany
- German Center for Infection Research (DZIF), partner-site Hannover-Braunschweig, Germany
- D-SOLVE Consortium, Horizon Europe Project, partner-site Hannover Medical School, Germany
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13
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Ferrante ND, Kallan MJ, Sukkestad S, Kodani M, Kitahata MM, Cachay ER, Bhattacharya D, Heath S, Napravnik S, Moore RD, Yendewa G, Mayer KH, Reddy KR, Hayden T, Kamili S, Martin JN, Kim HN, Lo Re V. Prevalence and determinants of hepatitis delta virus infection among HIV/hepatitis B-coinfected adults in care in the United States. J Viral Hepat 2023; 30:879-888. [PMID: 37488783 PMCID: PMC10592429 DOI: 10.1111/jvh.13874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023]
Abstract
Hepatitis delta virus (HDV) infection increases the risk of liver complications compared to hepatitis B virus (HBV) alone, particularly among persons with human immunodeficiency virus (HIV). However, no studies have evaluated the prevalence or determinants of HDV infection among people with HIV/HBV in the US. We performed a cross-sectional study among adults with HIV/HBV coinfection receiving care at eight sites within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) between 1996 and 2019. Among patients with available serum/plasma specimens, we selected the first specimen on or after their initial HBV qualifying test. All samples were tested for HDV IgG antibody and HDV RNA. Multivariable log-binomial generalized linear models were used to estimate prevalence ratios (PRs) with 95% CIs of HDV IgG antibody-positivity associated with determinants of interest (age, injection drug use [IDU], high-risk sexual behaviour). Among 597 adults with HIV/HBV coinfection in CNICS and available serum/plasma samples (median age, 43 years; 89.9% male; 52.8% Black; 42.4% White), 24/597 (4.0%; 95% CI, 2.4%-5.6%) were HDV IgG antibody-positive, and 10/596 (1.7%; 95% CI, 0.6%-2.7%) had detectable HDV RNA. In multivariable analysis, IDU was associated with exposure to HDV infection (adjusted PR = 2.50; 95% CI, 1.09-5.74). In conclusion, among a sample of adults with HIV/HBV coinfection in care in the US, 4.0% were HDV IgG antibody-positive, among whom 41.7% had detectable HDV RNA. History of IDU was associated with exposure to HDV infection. These findings emphasize the importance of HDV testing among persons with HIV/HBV coinfection, especially those with a history of IDU.
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Affiliation(s)
- Nicole D. Ferrante
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Michael J. Kallan
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Sophia Sukkestad
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Maja Kodani
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Mari M. Kitahata
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - Edward R. Cachay
- Department of Medicine, Division of Infectious Diseases and Global Public Health University of California, San Diego, CA
| | - Debika Bhattacharya
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Sonya Heath
- Division of Infectious Disease, Department of Medicine, University of Alabama, Birmingham, AL
| | - Sonia Napravnik
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Richard D. Moore
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD
| | - George Yendewa
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Kenneth H. Mayer
- The Fenway Institute, Fenway Health, Boston, MA; Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
| | - K. Rajender Reddy
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Tonya Hayden
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Jeffrey N. Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - H. Nina Kim
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - Vincent Lo Re
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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14
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Post Z, Reau N. What Is the Real Epidemiology of Hepatitis D Virus and Why so Many Mixed Messages? Clin Liver Dis 2023; 27:973-984. [PMID: 37778780 DOI: 10.1016/j.cld.2023.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
The disease burden of HDV is poorly understood. Our review identified multiple reasons: (1) HDV infection rates are overestimated in the general population due to limited sample sizes, sampling high-risk populations, and significant regional variations, (2) estimates are based on chronic HBV populations, but HBV burden itself is uncertain, (3) there is a lack of testing in at-risk populations, (4) prevalence testing is based on HDV antibody testing and not HDV RNA, which distinguishes between active infection versus prior exposure, (5) older studies used less reliable testing and (6) HBV vaccination programs have affected HDV prevalence, but is often not accounted for.
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Affiliation(s)
- Zoë Post
- Department of Digestive Diseases, Rush University Medical Center, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA
| | - Nancy Reau
- Section of Hepatology, Solid Organ Transplantation, Rush University Medical Center, 1725 West Harrison Street, Suite 319, Chicago, IL 60612, USA.
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15
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Abdul Majeed N, Zehnder B, Koh C, Heller T, Urban S. Hepatitis delta: Epidemiology to recent advances in therapeutic agents. Hepatology 2023; 78:1306-1321. [PMID: 36738087 DOI: 10.1097/hep.0000000000000331] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/19/2022] [Indexed: 02/05/2023]
Abstract
Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.
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Affiliation(s)
- Nehna Abdul Majeed
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Benno Zehnder
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF) - Heidelberg Partner Site, Heidelberg, Germany
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16
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Papatheodoridis G, Mimidis K, Manolakopoulos S, Triantos C, Vlachogiannakos I, Veretanos C, Deutsch M, Karatapanis S, Goulis I, Elefsiniotis I, Cholongitas E, Sevastianos V, Christodoulou D, Samonakis D, Manesis E, Kapatais A, Papadopoulos N, Ioannidou P, Germanidis G, Giannoulis G, Lakiotaki D, Kogias D, Kranidioti Η, Zisimopoulos K, Mela M, Kontos G, Fytili P, Manolaka C, Agorastou P, Pantzios SI, Papatheodoridi M, Karagiannakis D, Geladari E, Psychos N, Zachou K, Chalkidou A, Spanoudaki A, Thomopoulos K, Dalekos G. HERACLIS-HDV cohort for the factors of underdiagnosis and prevalence of hepatitis D virus infection in HBsAg-positive patients. Liver Int 2023; 43:1879-1889. [PMID: 37288712 DOI: 10.1111/liv.15638] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/07/2023] [Accepted: 05/26/2023] [Indexed: 06/09/2023]
Abstract
BACKGROUND AND AIMS Hepatitis D virus (HDV) underdiagnosis remains common. We assessed the HDV screening and prevalence rates in HBsAg-positive patients seen at tertiary liver centres throughout Greece as well as factors affecting HDV diagnosis. METHODS All adult HBsAg-positive patients seen within the last 5 years were included. Non-screened patients who visited or could be recalled to the clinics over a 6-month period were prospectively tested for anti-HDV. RESULTS Of 5079 HBsAg-positive patients, 53% had anti-HDV screening (41% before and 12% after study initiation). Pre-study (8%-88%) and total screening rates (14%-100%) varied widely among centres. Screening rates were associated with older age, known risk group, elevated ALT, centre location and size and period of first visit. Anti-HDV prevalence was 5.8% without significant difference in patients screened before (6.1%) or after study initiation (4.7%, p = 0.240). Anti-HDV positivity was associated with younger age, parenteral drug use, born abroad, advanced liver disease and centre location. Overall, HDV RNA detectability rate was 71.6% being more frequent in anti-HDV-positive patients with elevated ALT, advanced liver disease and hepatitis B therapy. CONCLUSIONS Anti-HDV screening rates and recall capabilities vary widely among Greek liver clinics being higher in HBsAg-positive patients of known risk group with active/advanced liver disease seen at smaller centres, while non-medical factors are also important. Anti-HDV prevalence varies throughout Greece being higher in patients born abroad with younger age, parenteral drug use and advanced liver disease. Viremia is more frequently but not exclusively detected in anti-HDV-positive patients with elevated ALT and advanced liver disease.
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Affiliation(s)
- George Papatheodoridis
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Mimidis
- First Department of Internal Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Spilios Manolakopoulos
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Triantos
- Gastroenterology Clinic, University General Hospital of Patras, Patras, Greece
| | - Ioannis Vlachogiannakos
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Christos Veretanos
- Fourth Internal Medicine and Gastroenterology Department, General Hospital of Athens "Evangelismos", Athens, Greece
| | - Melanie Deutsch
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Ioannis Goulis
- Fourth Department of Internal Medicine, General Hospital of Thessaloniki "Hippokratio", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Elefsiniotis
- Department of Internal Medicine, General and Oncology Hospital of Kifisia "Agioi Anargyroi", Athens, Greece
| | - Evangelos Cholongitas
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Vassilios Sevastianos
- Fourth Internal Medicine and Gastroenterology Department, General Hospital of Athens "Evangelismos", Athens, Greece
| | | | - Dimitrios Samonakis
- Department of Gastroenterology, University General Hospital of Heraklion Crete, Heraclion, Greece
| | | | - Andreas Kapatais
- Department of Internal Medicine, General Hospital Nikaia-Piraeus "Agios Panteleimon" & General Hospital of Western Attica "Agia Varvara", Piraeus, Greece
| | - Nikolaos Papadopoulos
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiota Ioannidou
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Georgios Germanidis
- First Department of Internal Medicine, University General Hospital of Thessaloniki "AHEPA", Thessaloniki, Greece
| | - George Giannoulis
- Department of Internal Medicine, General University Hospital of Larissa, Larissa, Greece
| | - Dimitra Lakiotaki
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Dionysios Kogias
- First Department of Internal Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Ηarikleia Kranidioti
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Maria Mela
- Fourth Internal Medicine and Gastroenterology Department, General Hospital of Athens "Evangelismos", Athens, Greece
| | - George Kontos
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Paraskevi Fytili
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | | | - Polyxeni Agorastou
- Fourth Department of Internal Medicine, General Hospital of Thessaloniki "Hippokratio", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Spyridon I Pantzios
- Department of Internal Medicine, General and Oncology Hospital of Kifisia "Agioi Anargyroi", Athens, Greece
| | - Margarita Papatheodoridi
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Karagiannakis
- Department of Gastroenterology, General Hospital of Athens "Laiko", Medical School of National & Kapodistrian University of Athens, Athens, Greece
| | - Eleni Geladari
- Fourth Internal Medicine and Gastroenterology Department, General Hospital of Athens "Evangelismos", Athens, Greece
| | - Nikolaos Psychos
- Department of Gastroenterology, University General Hospital of Ioannina, Ioannina, Greece
| | - Kalliopi Zachou
- Department of Internal Medicine, General University Hospital of Larissa, Larissa, Greece
| | - Anna Chalkidou
- First Department of Internal Medicine, University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Anastasia Spanoudaki
- Second Department of Internal Medicine, General Hospital of Athens "Hippokratio", Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - George Dalekos
- Department of Internal Medicine, General University Hospital of Larissa, Larissa, Greece
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17
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Brunetto MR, Ricco G, Negro F, Wedemeyer H, Yurdaydin C, Asselah T, Papatheodoridis G, Gheorghe L, Agarwal K, Farci P, Buti M. EASL Clinical Practice Guidelines on hepatitis delta virus. J Hepatol 2023; 79:433-460. [PMID: 37364791 DOI: 10.1016/j.jhep.2023.05.001] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/01/2023] [Indexed: 06/28/2023]
Abstract
Hepatitis D virus (HDV) is a defective virus that requires the hepatitis B virus to complete its life cycle and cause liver damage in humans. HDV is responsible for rare acute and chronic liver diseases and is considered the most aggressive hepatitis virus. Acute infection can cause acute liver failure, while persistent infection typically causes a severe form of chronic hepatitis which is associated with rapid and frequent progression to cirrhosis and its end-stage complications, hepatic decompensation and hepatocellular carcinoma. Major diagnostic and therapeutic innovations prompted the EASL Governing Board to commission specific Clinical Practice Guidelines on the identification, virologic and clinical characterisation, prognostic assessment, and appropriate clinical and therapeutic management of HDV-infected individuals.
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18
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Papatheodoridi A, Papatheodoridis G. Hepatocellular carcinoma: The virus or the liver? Liver Int 2023; 43 Suppl 1:22-30. [PMID: 35319167 DOI: 10.1111/liv.15253] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/28/2022] [Accepted: 03/19/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) represents a major public health problem being one of the most common causes of cancer-related deaths worldwide. Hepatitis B (HBV) and C viruses have been classified as oncoviruses and are responsible for the majority of HCC cases, while the role of hepatitis D virus (HDV) in liver carcinogenesis has not been elucidated. HDV/HBV coinfection is related to more severe liver damage than HBV mono-infection and recent studies suggest that HDV/HBV patients are at increased risk of developing HCC compared to HBV mono-infected patients. HBV is known to promote hepatocarcinogenesis via DNA integration into host DNA, disruption of molecular pathways by regulatory HBV x (HBx) protein and excessive oxidative stress. Recently, several molecular mechanisms have been proposed to clarify the pathogenesis of HDV-related HCC including activation of signalling pathways by specific HDV antigens, epigenetic dysregulation and altered gene expression. Alongside, ongoing chronic inflammation and impaired immune responses have also been suggested to facilitate carcinogenesis. Finally, cellular senescence seems to play an important role in chronic viral infection and inflammation leading to hepatocarcinogenesis. In this review, we summarize the current literature on the impact of HDV in HCC development and discuss the potential interplay between HBV, HDV and neighbouring liver tissue in liver carcinogenesis.
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Affiliation(s)
- Alkistis Papatheodoridi
- Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, "Alexandra" General Hospital of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
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19
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Kamal H, Aleman S. Natural history of untreated HDV patients: Always a progressive disease? Liver Int 2023; 43 Suppl 1:5-21. [PMID: 36308026 DOI: 10.1111/liv.15467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 10/20/2022] [Accepted: 10/25/2022] [Indexed: 02/13/2023]
Abstract
A severe course has been described in early studies on chronic hepatitis D (CHD), with faster pace towards liver cirrhosis with subsequent high liver-related morbidity and mortality in the majority of patients. Earlier studies have included risk groups as people using intravenous drugs (PWID) or those with multiple co-morbidities. During the last decade, the epidemiological landscape of CHD has changed with domestic cases decreasing while increasing cases of CHD consisting of younger persons immigrating from endemic regions to low-endemic regions. Recently, further insights into the spectrum of the disease with an indolent disease course in a substantial proportion of persons with CHD have been gained. At diagnosis, ≥30%-50% had already established liver cirrhosis. Older age, liver cirrhosis, co-infection with HIV and lack of interferon (IFN) therapy are the main predictors of worse clinical outcome. The newly introduced and upcoming antivirals against CHD are highly anticipated, considering the historically low virological response rates to antiviral therapy. Further knowledge is needed to fully comprehend the natural course and the spectrum of this severe form of viral hepatitis. This is also to be able to evaluate the long-term effects of the new antivirals on disease progression.
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Affiliation(s)
- Habiba Kamal
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Infectious Diseases, Karolinska Institute, Stockholm, Sweden
| | - Soo Aleman
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Infectious Diseases, Karolinska Institute, Stockholm, Sweden
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20
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Glynn M, Cohen C, Gish RG, Andrews R, Trang A, Zovich B, Hall W, Clary R, Joseph B, Scott L, Scott R, Jackson T, Ntiri-Reid B, Southworth A, Dieterich D, Sepe T. Advancing research, awareness, screening, and linkage to care to eliminate HDV in the U.S. Hepatol Commun 2023; 7:e00168. [PMID: 37347227 PMCID: PMC10289781 DOI: 10.1097/hc9.0000000000000168] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 03/30/2023] [Indexed: 06/23/2023] Open
Abstract
HDV, which coinfects individuals living with HBV, is the most aggressive form of viral hepatitis. Compared with hepatitis B monoinfection, hepatitis delta is associated with more rapid progression to cirrhosis and an increased risk of liver cancer and death. Despite being a major contributor to hepatitis B-associated liver disease, hepatitis delta remains largely unknown to the general public, health care providers, and at-risk communities. Given the widespread lack of awareness and underdiagnosis of hepatitis delta in the US, the American Liver Foundation (ALF) and the Hepatitis B Foundation (HBF) convened a virtual Hepatitis Delta Roundtable Meeting on April 21 and 22, 2022. The Roundtable Panel included persons living with hepatitis delta, caregivers, liver disease specialists, primary care providers, state and federal public health professionals, and community-based organizations. The Panel identified several major challenges surrounding hepatitis delta, including a lack of awareness of hepatitis delta among the public and health care providers; complex risk-based testing protocols; a lack of accurate prevalence data; limited data on linkage to care; and inadequate communications among stakeholders. Potential strategies to address these challenges include improving and expanding education for different audiences; advocating for simplified protocols for hepatitis B screening with hepatitis delta reflex testing; expanding surveillance for hepatitis delta; requiring automated reporting and national notification; improving data sharing for research; and enhancing communications around hepatitis delta. The recent CDC recommendations for universal adult screening and vaccination against hepatitis B and the anticipated availability of new therapies for hepatitis delta present a unique opportunity to focus attention on this dangerous virus. The Roundtable Panel calls for urgent action to make significant progress in addressing hepatitis delta among individuals living with hepatitis B.
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Affiliation(s)
- Megan Glynn
- American Liver Foundation, Programs, Toledo, Ohio
| | | | | | | | - Amy Trang
- Hepatitis B Initiative of Washington DC, Washington, DC
| | | | | | | | | | | | | | | | | | | | | | - Thomas Sepe
- Clinical Professor of Medicine, University Gastroenterology
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21
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Tsaneva-Damyanova DT, Georgieva LH. Epidemiology Pattern, Prevalent Genotype Distribution, Fighting Stigma and Control Options for Hepatitis D in Bulgaria and Other European Countries. Life (Basel) 2023; 13:1115. [PMID: 37240760 PMCID: PMC10222293 DOI: 10.3390/life13051115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis D virus (HDV) is a satellite virus that causes the most aggressive form of all viral hepatitis in individuals already infected with HBV (hepatitis B virus). In recent years, there has been a negative trend towards an increase in the prevalence of chronic hepatitis D in Europe, especially among immigrant populations coming from regions endemic for the virus. The aim of this review is to analyse the current epidemiology of chronic HDV, routes of transmission, prevalent genotype, its management, prevention, fighting stigma and options for viral control in European countries, such as Bulgaria.
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Affiliation(s)
| | - Lora Hristova Georgieva
- Department of Social Medicine and Healthcare Organization, Medical University, 9000 Varna, Bulgaria
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22
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Brancaccio G, Shanyinde M, Puoti M, Gaeta GB, Monforte AD, Vergori A, Rusconi S, Mazzarelli A, Castagna A, Antinori A, Cozzi-Lepri A. Hepatitis delta coinfection in persons with HIV: misdiagnosis and disease burden in Italy. Pathog Glob Health 2023; 117:181-189. [PMID: 35249472 PMCID: PMC9970224 DOI: 10.1080/20477724.2022.2047551] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Hepatitis Delta virus (HDV) causes severe liver disease. Due to similarities in transmission routes, persons living with HIV (PLWH) are at risk of HDV infection. This analysis investigates the prevalence and the long-term clinical outcome of people with HDV in a large cohort of PLWH. We retrieved HBsAg ± anti-HDV positive PLWH enrolled from 1997 to 2015 in the multicentre, prospective ICONA study. The primary endpoint was a composite clinical outcome (CCO = having experienced ≥1 of the following: Fib4 score >3.25; diagnosis of cirrhosis; decompensation; hepatocellular carcinoma or liver-related death). Kaplan-Meier curves and unweighted and weighted Cox regression models were used for data analysis. Less than half of HBsAg positive patients had been tested for anti-HDV in clinical practice. After testing stored sera, among 617 HBV/HIV cases, 115 (19%) were anti-HDV positive; 405 (65%) HBV monoinfected; 99 (16%) undeterminate. The prevalence declined over the observation period. HDV patients were more often males, intravenous drug users, HCV coinfected. After a median of 26 months, 55/115 (48%) developed CCO among HDV+; 98/403 (24%) among HBV monoinfected; 18/99 (18%) in HDV unknown (p < 0.001). After controlling for geographical region, alcohol consumption, CD4 count, anti-HCV status and IFN-based therapies, the association with HDV retained statistical significance [HR = 1.67 (1.15, 2.95; p = 0.025)]. HDV infection among PLWH is underdiagnosed, although HDV entails an high risk of liver disease progression. Because effective drugs to treat HDV are now available, it is even more crucial to identify PLWH at an early stage of liver disease.
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Affiliation(s)
| | - Milensu Shanyinde
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Massimo Puoti
- Infectious Diseases, Hospital Niguarda, Milan, Italy
| | - Giovanni B Gaeta
- Department of Mental and Physical Health and Preventive Medicine, University L. Vanvitelli, Naples, Italy
| | | | - Alessandra Vergori
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
| | - Stefano Rusconi
- UOC Malattie Infettive, Ospedale Civile di Legnano, ASST Ovest Milanese, Legnano, Italy
| | - Antonio Mazzarelli
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
| | | | - Andrea Antinori
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
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23
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Pisaturo M, Alessio L, Starace M, Macera M, Occhiello L, Cordua E, Capuano S, Onorato L, Scotto G, Di Caprio G, Calò F, Monari C, Sagnelli C, Coppola N. Characterization of hepatitis virus co-infections in a cohort of immigrants living in southern Italy. J Med Virol 2023; 95:e28665. [PMID: 36905118 DOI: 10.1002/jmv.28665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/22/2023] [Accepted: 03/08/2023] [Indexed: 03/12/2023]
Abstract
To characterize viral hepatitis co-infections in a cohort of immigrants living in southern Italy. In a prospective multicenter study, all undocumented immigrants and low-income refugees consecutively evaluated for a clinical consultation at one of the five first-level clinical centers in southern Italy from January 2012 to February 2020 were enrolled. All subjects included in the study were screened for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and anti-HIV; the HBsAg-positive were screened also for anti-delta. Of the 2923 subjects enrolled, 257 (8%) were HBsAg-positive alone (Control group B), 85 (2.9%) only anti-HCV-positive (Control group C), 16 (0.5%) HBsAg/anti-HCV-positive (Case group BC), and 8 (0.2%) HBsAg/anti-HDV-positive (Case group BD). Moreover, 57 (1.9%) subjects were anti-HIV-positive. HBV-DNA positivity was found less frequently in the 16 subjects in Case group BC (43%) and in the 8 in Case group BD (12.5%) than in the 257 in Control group B (76%; p = 0.03 and 0.0000, respectively). Similarly, HCV-RNA positivity was more frequent in Case group BC than in Control group C (75% vs. 44.7% p = 0.02). The subjects in Group BC had a lower prevalence of asymptomatic liver disease (12.5%) than Control group B (62.2%, p = 0.0001) and Control group C (62.3%, p = 0.0002). Conversely, liver cirrhosis was more frequently identified in Case group BC (25%) than in Control groups B and C (3.11% and 2.35%, p = 0.0000 and 0.0004, respectively). The present study contributes to the characterization of hepatitis virus co-infections in the immigrant population.
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Affiliation(s)
- Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro Sociale ex Canapificio, Caserta, Italy
| | - Loredana Alessio
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro di Accoglienza "La tenda di Abramo", Caserta, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
| | - Margherita Macera
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro per la Tutela della Salute degli Immigrati, Naples, Italy
| | - Laura Occhiello
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
| | - Emanuele Cordua
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
| | - Salvatore Capuano
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro Suore Missionarie della Carità, Naples, Italy
| | - Gaetano Scotto
- Medical Center, Centro Borgoroma, Foggia, Italy
- Infectious Diseases Unit, Foggia, Italy
| | - Giovanni Di Caprio
- Medical Center, Centro Sociale ex Canapificio, Caserta, Italy
- Infectious Diseases Unit, AORN Sant'Anna e San Sebastiano, Caserta, Italy
| | - Federica Calò
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro per la Tutela della Salute degli Immigrati, Naples, Italy
| | - Caterina Monari
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
- Medical Center, Centro Suore Missionarie della Carità, Naples, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Università degli studi della Campania Luigi Vanvitelli, Caserta, Italy
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24
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Kushner T. Delta hepatitis epidemiology and the global burden of disease. J Viral Hepat 2023; 30 Suppl 1:4-10. [PMID: 36625781 DOI: 10.1111/jvh.13797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 11/25/2022] [Indexed: 01/11/2023]
Abstract
Delta Hepatitis is considered the most severe form of hepatitis, with varied prevalence, genotype distribution and risk factors worldwide. Current knowledge of global epidemiology is limited due to variable screening practices for HDV. Here, we summarize what is currently known about the prevalence of testing and prevalence of HDV positivity globally.
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Affiliation(s)
- Tatyana Kushner
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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25
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Costante F, Stella L, Santopaolo F, Gasbarrini A, Pompili M, Asselah T, Ponziani FR. Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection. J Hepatocell Carcinoma 2023; 10:713-724. [PMID: 37128594 PMCID: PMC10148646 DOI: 10.2147/jhc.s384751] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/06/2023] [Indexed: 05/03/2023] Open
Abstract
Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.
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Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Leonardo Stella
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Tarik Asselah
- Service d’Hépatologie, Hôpital Beaujon UMR 1149 Inserm - Université de Paris, Clichy, France
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
- Correspondence: Francesca Romana Ponziani; Federico Costante, Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, Rome, 00168, Italy, Tel +390630156264, Email ;
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26
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Pisaturo M, Alessio L, Di Fraia A, Macera M, Minichini C, Cordua E, Onorato L, Scotto G, Di Caprio G, Calò F, Sagnelli C, Coppola N. Hepatitis D virus infection in a large cohort of immigrants in southern Italy: a multicenter, prospective study. Infection 2022; 50:1565-1572. [PMID: 36222979 PMCID: PMC9554856 DOI: 10.1007/s15010-022-01938-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/30/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Since few data are available in the literature on the prevalence of anti-Delta-positive subjects in immigrant populations, the aim of the present study was to evaluate the demographic and virological characteristics of HDV infection in a large cohort of immigrants living in southern Italy. METHODS Between January 2012 and February 2020 all immigrants attending one of the 5 first- level centers were enrolled and screened for HBsAg, the HBsAg-positive for anti-Delta and if positive, for HDV-RNA and HDV genotype. RESULTS Of the 3521 immigrants observed in the study period, 3417 (97.0%) agreed to be screened; they were mainly males (61%), with a median age of 27 years (IQR 8-74) and came prevalently (58%) from sub-Saharan Africa. Of the 3417 patients enrolled, 319 (9%) subjects were HBsAg-positive, and of those, 8 (2.5%) were anti-Delta-positive. No difference in the demographic and epidemiological characteristics was observed between the anti-Delta-negative vs -positive. Of the 8 anti-Delta-positive subjects, only one was HDV-RNA-positive (viral load: 7050 IU/mL), genotype 1, with clinical signs of cirrhosis. CONCLUSIONS the present study showed a prevalence of HDV of 2.5% in a large cohort of asymptomatic immigrants, suggesting the need for screening campaigns for viral infections including delta hepatitis in this population.
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Affiliation(s)
- Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro Sociale ex Canapificio, Caserta, Italy
| | - Loredana Alessio
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro di Accoglienza "La Tenda di Abramo", Caserta, Italy
| | - Alessandra Di Fraia
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Margherita Macera
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro per la Tutela Della Salute Degli Immigrati, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Emanuele Cordua
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro Suore Missionarie Della Carità, Naples, Italy
| | - Gaetano Scotto
- Medical Center, Centro Borgoroma, Foggia, Italy
- Infectious Diseases Unit, Foggia, Italy
| | - Giovanni Di Caprio
- Medical Center, Centro Sociale ex Canapificio, Caserta, Italy
- Infectious Diseases Unit, AORN Sant'Anna e San Sebastiano, Caserta, Italy
| | - Federica Calò
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro per la Tutela Della Salute Degli Immigrati, Naples, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
- Medical Center, Centro Suore Missionarie Della Carità, Naples, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy.
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27
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Abstract
Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward.
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28
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Stroffolini T, Morisco F, Ferrigno L, Pontillo G, Iantosca G, Cossiga V, Crateri S, Tosti ME. Acute Delta Hepatitis in Italy spanning three decades (1991-2019): Evidence for the effectiveness of the hepatitis B vaccination campaign. J Viral Hepat 2022; 29:78-86. [PMID: 34585819 DOI: 10.1111/jvh.13620] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/01/2021] [Accepted: 09/06/2021] [Indexed: 01/04/2023]
Abstract
Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come.
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Affiliation(s)
- Tommaso Stroffolini
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, Rome, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples Federico II, Naples, Italy
| | - Luigina Ferrigno
- National Center for Global Health, National Institute of Health (Istituto Superiore di Sanità ISS), Rome, Italy
| | - Giuseppina Pontillo
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples Federico II, Naples, Italy
| | - Giuseppina Iantosca
- National Center for Global Health, National Institute of Health (Istituto Superiore di Sanità ISS), Rome, Italy
| | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Gastroenterology and Hepatology Unit, University of Naples Federico II, Naples, Italy
| | - Simonetta Crateri
- National Center for Global Health, National Institute of Health (Istituto Superiore di Sanità ISS), Rome, Italy
| | - Maria Elena Tosti
- National Center for Global Health, National Institute of Health (Istituto Superiore di Sanità ISS), Rome, Italy
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29
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Lempp FA, Roggenbach I, Nkongolo S, Sakin V, Schlund F, Schnitzler P, Wedemeyer H, Le Gal F, Gordien E, Yurdaydin C, Urban S. A Rapid Point-of-Care Test for the Serodiagnosis of Hepatitis Delta Virus Infection. Viruses 2021; 13:2371. [PMID: 34960640 PMCID: PMC8703323 DOI: 10.3390/v13122371] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis Delta virus (HDV) is a satellite of the Hepatitis B virus (HBV) and causes severe liver disease. The estimated prevalence of 15-20 million infected people worldwide may be underestimated as international diagnostic guidelines are not routinely followed. Possible reasons for this include the limited awareness among healthcare providers, the requirement for costly equipment and specialized training, and a lack of access to reliable tests in regions with poor medical infrastructure. In this study, we developed an HDV rapid test for the detection of antibodies against the hepatitis delta antigen (anti-HDV) in serum and plasma. The test is based on a novel recombinant large hepatitis delta antigen that can detect anti-HDV in a concentration-dependent manner with pan-genotypic activity across all known HDV genotypes. We evaluated the performance of this test on a cohort of 474 patient samples and found that it has a sensitivity of 94.6% (314/332) and a specificity of 100% (142/142) when compared to a diagnostic gold-standard ELISA. It also works robustly for a broad range of anti-HDV titers. We anticipate this novel HDV rapid test to be an important tool for epidemiological studies and clinical diagnostics, especially in regions that currently lack access to reliable HDV testing.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- German Centre for Infection Research (DZIF), 69120 Heidelberg, Germany
| | - Imme Roggenbach
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Shirin Nkongolo
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- German Centre for Infection Research (DZIF), 69120 Heidelberg, Germany
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Volkan Sakin
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Franziska Schlund
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Paul Schnitzler
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Heiner Wedemeyer
- Clinic for Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany
| | - Frédéric Le Gal
- Laboratoire de Microbiologie Clinique, Hôpital Avicenne, APHP, 93000 Bobigny, France
| | - Emmanuel Gordien
- Laboratoire de Microbiologie Clinique, Hôpital Avicenne, APHP, 93000 Bobigny, France
| | - Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara, Ankara 06560, Turkey
- Department of Gastroenterology and Hepatology, Koç University Medical School, Istanbul 34450, Turkey
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany
- German Centre for Infection Research (DZIF), 69120 Heidelberg, Germany
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30
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Sagnelli C, Pisaturo M, Curatolo C, Codella AV, Coppola N, Sagnelli E. Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic. World J Gastroenterol 2021; 27:7271-7284. [PMID: 34876788 PMCID: PMC8611207 DOI: 10.3748/wjg.v27.i42.7271] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/20/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.
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Affiliation(s)
- Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80131, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, University of Campania, Naples 80135, Italy
| | - Caterina Curatolo
- Department of Mental Health and Public Medicine, University of Campania, Naples 80135, Italy
| | - Alessio Vinicio Codella
- Department of Mental Health and Public Medicine, University of Campania, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, University of Campania, Naples 80135, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80131, Italy
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31
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Can Interferon therapy change natural course of Hepatitis Delta infection, A clinical and pathological study. Antimicrob Agents Chemother 2021; 66:e0158621. [PMID: 34694876 DOI: 10.1128/aac.01586-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Introduction: Chronic delta hepatitis (CDH) has a worser outcome than other viral hepatitis. High dose, long-term Interferon-α (IFNα) is the approved treatment and may ameliorate course. We evaluated long-term histological outcomes of CDH patients treated with IFNα. Method: Histologically proved non-cirrhotic CDH patients treated with high dose IFNα for at least 1 year were grouped as cirrhotic and non-cirrhotic at the end of treatment. Non-cirrhotic patients had also post-treatment liver biopsies. Patients were grouped as histologically responsive and non-responsive regarding fibrosis status. Histological, virological and biochemical courses were analyzed. Results: 48 patients were treated with IFNα (conventional and/or pegylated) for median 24 months with a post-treatment follow-up of 5 years. During the follow-up, cirrhosis developed in 24 patients, 5 of whom were decompensated. There was no difference between pre- and post-treatment fibrosis scores of 24 non-cirrhotic patients at the end of follow-up. Among patients; 13% (n:6) had decreased, 21%(n:10) had steady and 16% (n:8) had increased fibrosis scores. Persistent viral response (PVR) was achieved in 16 patients (33%). 20% of entire group was histologically responsive (decreasing or steady fibrosis scores with improved necro-inflammatory score) while near 80% had histological progression/cirrhosis. PVR was significantly associated with histological response. Conclusions: Long-term natural course of patients who were treated with high dose IFNα for at least one year was evaluated clinically and histologically. Despite the association of PVR with histological response, IFNα treatment didn't change the natural course of CDH, clinical and histological progression continued in two-thirds of the cases despite treatment.
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Hayashi T, Takeshita Y, Hutin YJF, Harmanci H, Easterbrook P, Hess S, van Holten J, Oru EO, Kaneko S, Yurdaydin C, Bulterys M. The global hepatitis delta virus (HDV) epidemic: what gaps to address in order to mount a public health response? Arch Public Health 2021; 79:180. [PMID: 34663473 PMCID: PMC8525025 DOI: 10.1186/s13690-021-00693-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 09/13/2021] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Co-infection between hepatitis B virus (HBV) and hepatitis delta virus (HDV) causes the severest chronic hepatitis and is associated with a high risk of cirrhosis and hepatocellular carcinoma (HCC). The Global Health Sector Strategy on Viral Hepatitis called for the elimination of hepatitis (- 65% mortality and - 90% incidence) by 2030. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV. METHODS We performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment. RESULTS Prevalence of infection and genotypes are heterogeneous distributed, with highest prevalence in foci around the Mediterranean, in the Middle East, and in Central, Northern Asia and Eastern Asia. Persons who inject drugs (PWID) and migrants from highly endemic areas are highly affected. While antibody detection tests are available, HDV RNA tests of current infection are not standardized nor widely available. The few therapeutic options, including lofartinib, are not widely available; however several new and promising agents have entered clinical trials. CONCLUSION HDV infection is an poorly known cause of chronic liver disease. To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options.
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Affiliation(s)
- Tomoyuki Hayashi
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland.
- Department of Gastroenterology, Kanazawa University and WHO Collaborating Center for Chronic Hepatitis and Liver Cancer, Kanazawa, Ishikawa, Japan.
| | - Yumie Takeshita
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
- Department of Gastroenterology, Kanazawa University and WHO Collaborating Center for Chronic Hepatitis and Liver Cancer, Kanazawa, Ishikawa, Japan
| | - Yvan J-F Hutin
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | - Hande Harmanci
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | | | - Sarah Hess
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | - Judith van Holten
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | - Ena Oghenekaro Oru
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University and WHO Collaborating Center for Chronic Hepatitis and Liver Cancer, Kanazawa, Ishikawa, Japan
| | - Cihan Yurdaydin
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
- Hepatology Institute, University of Ankara, Ankara, Turkey
| | - Marc Bulterys
- Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
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33
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Kamal H, Fornes R, Simin J, Stål P, Duberg AS, Brusselaers N, Aleman S. Risk of hepatocellular carcinoma in hepatitis B and D virus co-infected patients: A systematic review and meta-analysis of longitudinal studies. J Viral Hepat 2021; 28:1431-1442. [PMID: 34291520 DOI: 10.1111/jvh.13577] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/02/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta-analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co-infected, compared to HBV mono-infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross-sectional studies. Random-effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta-regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co-infected and 57,620 chronic HBV mono-infected patients were analysed. The overall pooled ES showed that HBV/HDV co-infected patients were at 2-fold increased risk of HCC compared to HBV mono-infected patients (ES = 2.12, 95% CI 1.14-3.95, I2 = 72%, N = 12). A six-fold significant increased risk of HCC was noted among HIV/HBV/HDV triple-infected, compared to HIV/HBV co-infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow-up duration in univariable meta-regression analysis. This systematic review and meta-analysis shows that infection with HDV is associated with a 2-fold higher risk of HCC development compared to HBV mono-infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted.
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Affiliation(s)
- Habiba Kamal
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Romina Fornes
- Centre for Translational Microbiome Research (CTMR), Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Johanna Simin
- Centre for Translational Microbiome Research (CTMR), Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Per Stål
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
| | - Ann-Sofi Duberg
- Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Nele Brusselaers
- Centre for Translational Microbiome Research (CTMR), Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, Stockholm, Sweden
| | - Soo Aleman
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.,Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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34
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Scheller L, Hilgard G, Anastasiou O, Dittmer U, Kahraman A, Wedemeyer H, Deterding K. Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients. Medicine (Baltimore) 2021; 100:e26571. [PMID: 34260535 PMCID: PMC8284709 DOI: 10.1097/md.0000000000026571] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/08/2021] [Indexed: 01/04/2023] Open
Abstract
Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2-14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51-16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80-2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89-0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8-8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7-8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6-13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3-7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.
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Affiliation(s)
- Laura Scheller
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
| | - Gudrun Hilgard
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
| | | | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Max Grundig Clinic, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Katja Deterding
- Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
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35
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Niro GA, Ferro A, Cicerchia F, Brascugli I, Durazzo M. Hepatitis delta virus: From infection to new therapeutic strategies. World J Gastroenterol 2021; 27:3530-3542. [PMID: 34239267 PMCID: PMC8240063 DOI: 10.3748/wjg.v27.i24.3530] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/07/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis delta virus (HDV) is a small RNA virus that encodes a single protein and which requires the hepatitis B virus (HBV)-encoded hepatitis B surface antigen (HBsAg) for its assembly and transmission. HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations, specifically intravenous drug users, practitioners of high-risk sexual behaviours, and patients with cirrhosis and hepatocellular carcinoma. The chronic form of HDV-related hepatitis is usually severe and rapidly progressive. Patterns of the viral infection itself, including the status of co-infection or super-infection, virus genotypes (both for HBV and HDV), and persistence of the virus’ replication, influence the outcome of the accompanying and manifested liver disease. Unfortunately, disease severity is burdened by the lack of an effective cure for either virus type. For decades, the main treatment option has been interferon, administered as mono-therapy or in combination with nucleos(t)ide analogues. While its efficacy has been reported for different doses, durations and courses, only a minority of patients achieve a sustained response, which is the foundation of eventual improvement in related liver fibrosis. The need for an efficient therapeutic alternative remains. Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle; the most promising among these are myrcludex B, which inhibits virus entry into hepatocytes, lonafarnib, which inhibits farnesylation of the viral-encoded L-HDAg large hepatitis D antigen, and REP-2139, which interferes with HBsAg release and assembly.
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Affiliation(s)
- Grazia A Niro
- Department of Gastroenterology, IRCCS Casa Sollievo della Sofferenza Hospital Foundation, San Giovanni Rotondo 71013, Italy
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
| | | | | | - Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin 10126, Italy
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36
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Papatheodoridi M, Papatheodoridis GV. Is hepatitis delta underestimated? Liver Int 2021; 41 Suppl 1:38-44. [PMID: 34155795 DOI: 10.1111/liv.14833] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 02/22/2021] [Indexed: 01/08/2023]
Abstract
Hepatitis D virus may be underestimated because it is a significant problem in HBsAg-positive patients, especially those who inject drugs, have HIV or HCV co-infections and/or live in certain endemic regions. In the past few decades, the prevalence of HDV was expected to have decreased as a result of improvements in public healthcare policies and universal HBV vaccination programs. However, HDV has continued to spread in low-income countries, with local outbreaks and migration to less endemic areas, so that its prevalence has remained stable or even increased in certain regions. As a result, research has been focused on the epidemiology of HDV. Contradicting data from three large recent meta-analyses have reported that the prevalence of HDV may be between 0.16% and 1.00% in the global general population, and 4.5% and 14.6% in HBsAg-positive patients, with an estimated 12 to 70 million HDV patients worldwide. The exact prevalence and estimated number of HDV patients is still a subject of debate for several reasons, including the unreliable assessment of the infection and a lack of real-world screening. HDV infection is associated with an increased risk of progression to cirrhosis and the development of HCC compared to patients with HBV mono-infection, a risk which is even higher in patients with HIV co-infection. Morbidity and mortality from HDV-related cirrhosis should not be overlooked. In conclusion, hepatitis D virus is probably underestimated and certainly underdiagnosed, and screening for HDV should be performed in all HBsAg-positive patients in clinical practice.
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Affiliation(s)
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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37
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Abstract
Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.
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38
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Rizzetto M, Hamid S, Negro F. The changing context of hepatitis D. J Hepatol 2021; 74:1200-1211. [PMID: 33484770 DOI: 10.1016/j.jhep.2021.01.014] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 01/04/2021] [Accepted: 01/09/2021] [Indexed: 12/18/2022]
Abstract
The global epidemiology of hepatitis D is changing with the widespread implementation of vaccination against hepatitis B. In high-income countries that achieved optimal control of HBV, the epidemiology of hepatitis D is dual, consisting of an ageing cohort of domestic patients with advanced liver fibrosis who represent the end stage of the natural history of HDV, and of a younger generation of immigrants from endemic countries who account for the majority of new infections. As observed in Europe in the 1980s, the distinctive clinical characteristic of chronic hepatitis D in endemic countries is the accelerated progression to cirrhosis and hepatocellular carcinoma. Despite some recent progress, the therapeutic management of HDV remains unsatisfactory, as most patients are not cured of HDV with currently available medicines. This review article describes the current epidemiology and clinical features of chronic hepatitis D, based on the literature published in the last 10 years.
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Affiliation(s)
- Mario Rizzetto
- Department of Medical Sciences, University of Turin, Turin, Italy.
| | - Saeed Hamid
- Department of Medicine, The Aga Khan University, Karachi, Pakistan
| | - Franco Negro
- Division of Gastroenterology and Hepatology, Geneva University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland
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Vieira Barbosa J, Sahli R, Aubert V, Chaouch A, Moradpour D, Fraga M. Demographics and outcomes of hepatitis B and D: A 10-year retrospective analysis in a Swiss tertiary referral center. PLoS One 2021; 16:e0250347. [PMID: 33905426 PMCID: PMC8078781 DOI: 10.1371/journal.pone.0250347] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 04/05/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is a major global health challenge with approximately 250-350 million chronically infected individuals. An improved understanding of the demographic features and outcomes of chronic HBV infection and hepatitis D virus (HDV) infection in low-endemic areas may improve prevention, early identification and management both at individual and community levels. Here, we retrospectively analyzed the demographic and clinical characteristics, treatment rates and outcomes of adult patients with chronic HBV infection with or without HDV coinfection examined at Lausanne University Hospital, Switzerland over a 10-year period. METHODS We analyzed the medical records of all adult patients with chronic HBV and HDV infection examined in our center between 2007 and 2016. Liver-related outcome was defined as the occurrence of cirrhosis, hepatocellular carcinoma, liver transplantation or liver-related death. Analyses were performed using logistic regression and results were reported as odds ratio (OR) and 95% confidence interval (CI). RESULTS Of 672 consecutive patients, 421 (62.6%) were male, median age was 36 years (interquartile range, 28-46 years), and 233 (34.7%) were of African origin. The prevalence of HDV coinfection was 7.1% and the proportion of anti-HDV-positive patients with detectable HDV RNA was 70.0%. In multivariate analysis, HDV coinfection was the strongest predictor for liver-related outcome (OR 6.06, 95% CI 2.93-12.54, p<0.001), followed by HBeAg positivity (OR 2.47, 95% CI 1.30-4.69, p = 0.006), age (OR per 10-year increase 2.03, 95% CI 1.63-2.52, p<0.001) and sex (OR for female 0.39, 95% CI 0.22-0.71, p = 0.002). The predictive accuracy of the multivariate model was high (receiver operator characteristic area under the curve 0.81). CONCLUSION This retrospective study underscores the importance of migration in the epidemiology of chronic hepatitis B in low-endemic areas. HDV coinfection, HBeAg positivity and age predicted liver-related outcomes while female sex had a protective effect.
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Affiliation(s)
- Joana Vieira Barbosa
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America
| | - Roland Sahli
- Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Vincent Aubert
- Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Aziz Chaouch
- Division of Biostatistics, Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Montserrat Fraga
- Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- * E-mail:
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Transaminase Elevations during Treatment of Chronic Hepatitis B Infection: Safety Considerations and Role in Achieving Functional Cure. Viruses 2021; 13:v13050745. [PMID: 33922828 PMCID: PMC8146791 DOI: 10.3390/v13050745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 11/17/2022] Open
Abstract
While current therapies for chronic HBV infection work well to control viremia and stop the progression of liver disease, the preferred outcome of therapy is the restoration of immune control of HBV infection, allowing therapy to be removed while maintaining effective suppression of infection and reversal of liver damage. This “functional cure” of chronic HBV infection is characterized by the absence of detectable viremia (HBV DNA) and antigenemia (HBsAg) and normal liver function and is the goal of new therapies in development. Functional cure requires removal of the ability of infected cells in the liver to produce the hepatitis B surface antigen. The increased observation of transaminase elevations with new therapies makes understanding the safety and therapeutic impact of these flares an increasingly important issue. This review examines the factors driving the appearance of transaminase elevations during therapy of chronic HBV infection and the interplay of these factors in assessing the safety and beneficial nature of these flares.
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Gao E, Hercun J, Heller T, Vilarinho S. Undiagnosed liver diseases. Transl Gastroenterol Hepatol 2021; 6:28. [PMID: 33824932 DOI: 10.21037/tgh.2020.04.04] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 03/19/2020] [Indexed: 02/06/2023] Open
Abstract
The landscape of chronic liver disease has drastically changed over the past 20 years, largely due to advances in antiviral therapy and the rise of metabolic syndrome and associated non-alcoholic fatty liver disease (NAFLD). Despite advances in the diagnosis and treatment of a variety of liver diseases, the burden of chronic liver disease is increasing worldwide. The first step to addressing any disease is accurate diagnosis. Here, we discuss liver diseases that remain undiagnosed, either because they are difficult to diagnose or due to hepatic manifestations of an unrecognized systemic disease. Additionally, their underlying etiology may remain unknown or they represent previously uncharacterized and therefore novel liver diseases. Our goal is to provide a framework for approaching undiagnosed liver diseases which elude standard hepatic diagnostic work-up and whose patterns of disease are often overlooked.
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Affiliation(s)
- Emily Gao
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Julian Hercun
- Translational Hepatology Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Bethesda, MD, USA
| | - Theo Heller
- Translational Hepatology Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institute of Health, Bethesda, MD, USA
| | - Sílvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA.,Department of Pathology, Yale School of Medicine, New Haven, CT, USA
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Gençdal G, Yurdaydin C. Developing New Therapies for Delta Hepatitis: The Race Is On. Hepatol Commun 2021; 5:556-558. [PMID: 33860114 PMCID: PMC8034575 DOI: 10.1002/hep4.1685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 11/25/2022] Open
Affiliation(s)
- Genco Gençdal
- Department of Gastroenterology and HepatologyKoç University Medical SchoolIstanbulTurkey
| | - Cihan Yurdaydin
- Department of Gastroenterology and HepatologyKoç University Medical SchoolIstanbulTurkey
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43
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Rizzetto M, Stroffolini T. Forty-Five Years after the Discovery of the Hepatitis D Virus: Where Do We Stand? Viruses 2021; 13:555. [PMID: 33810224 PMCID: PMC8066537 DOI: 10.3390/v13040555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 12/16/2022] Open
Abstract
The discovery of the Australia Antigen in the mid-1960s led, in a few years, to the identification of the virus of Hepatitis B [...].
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Affiliation(s)
- Mario Rizzetto
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Tommaso Stroffolini
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome, 00161 Rome, Italy;
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44
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Isaeva OV, Il'chenko LY, Saryglar AA, Karlsen AA, Kyuregyan KK, Mikhailov MI. [Clinical course and outcomes of chronic viral hepatitis D in patients from Republic of Tuva as endemic region]. Vopr Virusol 2021; 66:74-83. [PMID: 33683068 DOI: 10.36233/0507-4088-29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/07/2021] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Hepatitis D (delta, 5) is caused by an RNA virus (hepatitis D virus, HDV) from genus Deltavirus, and is the most severe and difficult to treat disease among both viral hepatitis and infectious diseases in general. The development of HDV infection in the host organism is possible only in the presence of hepatitis B virus (HBV). Coinfection with HBV and HDV is associated with a more rapid progression of chronic viral hepatitis (CVH) to liver cirrhosis (LC) and an unfavorable outcome in comparison with HBV monoinfection. Data on the influence of clinical, biochemical and virological factors on the infectious process in patients with hepatitis D are limited due to the insufficient amount of research on this theme.The study aimed to determine demographic, clinical, biochemical, and virological factors influencing the course and progression of CVH D in patients followed during 10 years, residing in the territory of the Tuva Republic, one of the endemic regions of the Russian Federation. MATERIAL AND METHODS Changes in clinical and laboratory parameters were analyzed in dynamics in 121 HDV infected patients with a different course of the disease, who were under observation from 2009 to 2019. Three groups of patients were identified: group 1 - 61 patients with disease progression of chronic hepatitis to LC (Child-Pugh class B-C), group 2 - 49 patients with non-progressive chronic hepatitis, and group 3 - 11 patients with slowly progressive LC (class A). Demographic data, the presence of detectable HBV DNA, indicators of the functional state of the liver: alanine aminotransferase (ALT/GPT), aspartate aminotransferase (AST/GOT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), and total bilirubin content were analyzed. The severity of hepatic encephalopathy was assessed by the duration of the numbers connection test (NCT). RESULTS All patients belonged to the same ethnic group (Tuvinians), were infected with HDV genotype 1 and were positive for HDV RNA throughout the entire follow-up period. There were no significant differences in sex ratio and mean age at the time of inclusion in the study between the groups. In group 1, the average number of years from inclusion in the study to the formation of LC was 3.65 ± 2.3 years, years to the lethal outcome: 4.5 ± 3 years. Significantly higher levels of AST/GOT, ALP, GGT, total bilirubin (TB) and NCT grade were found in group 1 compared to group 2. ALT/GPT levels did not differ significantly in these groups. When comparing groups with disease progression and slowly progressive LC (groups 1 and 3), no significant differences were found in any of the clinical and biochemical parameters. ALT/GPT, GGT, TB and NCT values were significantly higher in patients with slowly progressive LC (group 3) compared to group 2. No differences in AST/GOT and ALP levels were found between these groups. Detectable HBV DNA was significantly more frequent in patients with progressive disease and with chronic viral hepatitis than in patients with slowly progressive LC. There were no significant differences in the frequency of HBV DNA detection in patients from groups 1 and 2. CONCLUSION The results obtained on a relatively homogeneous cohort demonstrated that age and gender are not the factors influencing the progression of chronic viral hepatitis D to cirrhosis. The lack of detectable HBV DNA is associated with the slow progression of LC. The revealed differences in clinical and biochemical parameters reflect the degree of functional liver damage in chronic viral hepatitis D and HDV-associated cirrhosis.
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Affiliation(s)
- O V Isaeva
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - L Yu Il'chenko
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBSI M.P. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences; FSAEI HE N.I. Pirogov Russian Research Medical University of the Ministry of Health of Russia
| | | | - A A Karlsen
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - K K Kyuregyan
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - M I Mikhailov
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
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Sagnelli C, Sagnelli E, Russo A, Pisaturo M, Occhiello L, Coppola N. HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges. Life (Basel) 2021; 11:169. [PMID: 33671730 PMCID: PMC7926847 DOI: 10.3390/life11020169] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/18/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Several investigations have been published on Hepatitis Delta Virus (HDV) infection in recent years, from which we have drawn the salient data to provide readers with useful information to improve their knowledge on the subject. HDV genotypes 5-8 have been recently imported to Western countries from central Africa, whose clinical relevance deserves further investigation. Ongoing HDV replication has been identified as an independent predictor of progression to cirrhosis and HCC for patients with HDV chronic hepatitis (HDV-CH). Long-term treatments of HDV-CH with standard or pegylated interferon alfa (peg-IFN-α) have all been unsatisfactory, leading to a sustained virological response (SVR) only in 20-30% of patients treated, faced with a poor tolerability and frequent serious adverse reactions; the addition of HBV nucleo(s)tide analogues to peg-IFN- α did not improve the rate of SVR. The improved knowledge of the HDV life cycle has allowed the development of direct acting agents towards key-points of the HDV life cycle, namely bulevirtide, lonafarnib and nucleic acid polymers. Preliminary data have shown that these drugs are more effective than interferon-based therapies, but adverse reactions are also common, which however seem toned down in combination therapy with other antivirals.
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Affiliation(s)
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (C.S.); (A.R.); (M.P.); (L.O.); (N.C.)
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Risk Factors for Delta Hepatitis in a North American Cohort: Who Should Be Screened? Am J Gastroenterol 2021; 116:206-209. [PMID: 33027083 PMCID: PMC9205618 DOI: 10.14309/ajg.0000000000000954] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 08/28/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The American Association for the Study of Liver Diseases recommends hepatitis D virus (HDV) screening in certain high-risk groups; however, the effectiveness is unknown. METHODS A study of North American patients with hepatitis B (HBV) referred to the NIH was performed to identify risk factors associated with HDV infection. Active HDV was "confirmed" by serum HDV RNA or histologic HDV antigen staining. RESULTS Six hundred fifty-two were studied, of which 91 were HDV "confirmed." Independent risk factors for HDV included: intravenous drug users, HBV-DNA <2,000 IU/mL, alanine aminotransferase >40 U/L, and HDV endemic country of origin. DISUSSION North American patients with HBV and significant risk factors should be screened for HDV.
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47
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Wranke A, Hardtke S, Heidrich B, Dalekos G, Yalçin K, Tabak F, Gürel S, Çakaloğlu Y, Akarca US, Lammert F, Häussinger D, Müller T, Wöbse M, Manns MP, Idilman R, Cornberg M, Wedemeyer H, Yurdaydin C. Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta. J Viral Hepat 2020; 27:1359-1368. [PMID: 32707605 DOI: 10.1111/jvh.13366] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/05/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022]
Abstract
Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFNα-2a) is the only effective treatment but its long-term clinical impact is unclear. The aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFNα-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFNα-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFNα-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFNα-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFNα-2a treatment leads to improved clinical long-term outcome.
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Svenja Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site HepNet Study-House, Hannover, Germany
| | - Benjamin Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site HepNet Study-House, Hannover, Germany
| | - George Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Kendal Yalçin
- Dicle University Medical Faculty, Diyarbakir, Turkey
| | - Fehmi Tabak
- Department of Infectious Diseases Cerrahpaşa School of Medicine, Istanbul University, Istanbul, Turkey
| | - Selim Gürel
- Uludağ University Medical School, Bursa, Turkey
| | | | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany
| | | | - Michael Wöbse
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site HepNet Study-House, Hannover, Germany
| | - Ramazan Idilman
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner Site HepNet Study-House, Hannover, Germany
| | - Heiner Wedemeyer
- German Center for Infection Research (DZIF), Partner Site HepNet Study-House, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Medical Faculty of the University Duisburg-Essen, Essen, Germany
| | - Cihan Yurdaydin
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.,Department of Gastroenterology and Hepatology, Koç University Medical School, Istanbul, Turkey
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Ferrante ND, Lo Re V. Epidemiology, Natural History, and Treatment of Hepatitis Delta Virus Infection in HIV/Hepatitis B Virus Coinfection. Curr HIV/AIDS Rep 2020; 17:405-414. [PMID: 32607773 DOI: 10.1007/s11904-020-00508-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs. RECENT FINDINGS Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.
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Affiliation(s)
- Nicole D Ferrante
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA
| | - Vincent Lo Re
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA.
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
- Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Tan M, Bhadoria AS, Cui F, Tan A, Van Holten J, Easterbrook P, Ford N, Han Q, Lu Y, Bulterys M, Hutin Y. Estimating the proportion of people with chronic hepatitis B virus infection eligible for hepatitis B antiviral treatment worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020; 6:106-119. [PMID: 33197397 PMCID: PMC7801814 DOI: 10.1016/s2468-1253(20)30307-1] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/08/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND In 2016, of the estimated 257 million people living with chronic hepatitis B virus (HBV) infection worldwide, only a small proportion was diagnosed and treated. The insufficiency of information on the proportion of people infected with HBV who are eligible for treatment limits the interpretation of global treatment coverage. We aimed to estimate the proportion of people with chronic HBV infection who were eligible for antiviral treatment worldwide, based on the WHO 2015 guidelines. METHODS In this systematic review and meta-analysis, we searched Medline, EMBASE, and the Cochrane databases from Jan 1, 2007, to Jan 31, 2018, for studies describing HBsAg-positive people in the population or health-care facilities. We extracted information from published studies using a standardised form to estimate the frequency of cirrhosis, abnormal alanine aminotransferase (ALT), HBV DNA exceeding 2000 IU/mL or 20 000 IU/mL, presence of HBeAg, and eligibility for treatment as per WHO and other guidelines as reported in the studies. We pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020132345. FINDINGS Of the 13 497 studies, 162 were eligible and included in our analysis. These studies included 145 789 participants. The pooled estimate of the proportion of cirrhosis was 9% (95% CI 8-10), ranging from 6% (4-8) in community settings to 10% (9-11) in clinic settings. Examining the proportion of participants who had characteristics used to determine eligibility in the WHO guidelines, 1750 (10·1%) of 17 394 had HBV DNA exceeding 20 000 IU/mL, and 20 425 (30·8%) of 66 235 had ALT above the upper limit of normal. 32 studies reported eligibility for treatment according to WHO or any other guidelines, with a pooled estimate of eligibility at 19% (95% CI 18-20), ranging from 12% (6-18) for studies in community settings to 25% (19-30) in clinic settings. INTERPRETATION Many studies described people with HBV infection, but few reported information in a way that allowed assessment of eligibility for treatment. Although about one in ten of the 257 million people with HBV infection (26 million) might be in urgent need of treatment because of cirrhosis, a larger proportion (12-25%) is eligible for treatment in accordance with different guidelines. Future studies describing people with HBV infection should report on treatment eligibility, according to broadly agreed definitions. FUNDING WHO and US Centers for Disease Control and Prevention.
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Affiliation(s)
- Mingjuan Tan
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland; Department of Medicine, National University Health System, Singapore
| | - Ajeet S Bhadoria
- All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Fuqiang Cui
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | | | - Judith Van Holten
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | | | - Nathan Ford
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | - Qin Han
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | - Ying Lu
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | - Marc Bulterys
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland
| | - Yvan Hutin
- Department of HIV/AIDS and Global Hepatitis Programme, WHO, Geneva, Switzerland.
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50
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Roulot D, Brichler S, Layese R, BenAbdesselam Z, Zoulim F, Thibault V, Scholtes C, Roche B, Castelnau C, Poynard T, Chazouillères O, Ganne N, Fontaine H, Gournay J, Guyader D, Le Gal F, Nahon P, Roudot-Thoraval F, Gordien E, Landman R, Hezode C, Riachi G, Lascoux-Combe C, Loustaud-Ratti V, Rosa I, Mathurin P, Nguyen-Khac E, Causse X, Naveau S, Habersetzer F, Metivier S, Labadie H, Sellier P, Bottero J, de Ledinghen V, Alric L, Calès P, Goujard C, Cadranel JF, Salmon D, Hillaire S. Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta. J Hepatol 2020; 73:1046-1062. [PMID: 32634548 DOI: 10.1016/j.jhep.2020.06.038] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 06/04/2020] [Accepted: 06/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS HDV infection causes severe chronic liver disease in individuals infected with HBV. However, the factors associated with poor prognosis are largely unknown. Thus, we aimed to identify prognostic factors in patients with HDV infection. METHODS The French National Reference Centre for HDV performed a nationwide retrospective study on 1,112 HDV-infected patients, collecting epidemiological, clinical, virological and histological data from the initial referral to the last recorded follow-up. RESULTS The median age of our cohort was 36.5 (29.9-43.2) years and 68.6% of our cohort were male. Most patients whose birthplace was known were immigrants from sub-Saharan Africa (52.5%), southern and eastern Europe (21.3%), northern Africa and the Middle East (6.2%), Asia (5.9%) and South America (0.3%). Only 150 patients (13.8%) were French native. HDV load was positive in 659 of 748 tested patients (88.1%). HDV-1 was predominant (75.9%), followed by sub-Saharan genotypes: HDV-5 (17.6%), HDV-7 (2.9%), HDV-6 (1.8%) and HDV-8 (1.6%). At referral, 312 patients (28.2%) had cirrhosis, half having experienced at least 1 episode of hepatic decompensation. Cirrhosis was significantly less frequent in African than in European patients regardless of HDV genotype. At the end of follow-up (median 3.0 [0.8-7.2] years), 48.8% of the patients had developed cirrhosis, 24.2% had ≥1 episode(s) of decompensation and 9.2% had hepatocellular carcinoma. European HDV-1 and African HDV-5 patients were more at risk of developing cirrhosis. Persistent replicative HDV infection was associated with decompensation, hepatocellular carcinoma and death. African patients displayed better response to interferon therapy than non-African patients (46.4% vs. 29.1%, p <0.001). HDV viral load at baseline was significantly lower in responders than in non-responders. CONCLUSION Place of birth, HDV genotype and persistent viremia constitute the main determinants of liver involvement and response to treatment in chronic HDV-infected patients. LAY SUMMARY Chronic liver infection by hepatitis delta virus (HDV) is the most severe form of chronic viral hepatitis. Despite the fact that at least 15-20 million people are chronically infected by HDV worldwide, factors determining the severity of liver involvement are largely unknown. By investigating a large cohort of 1,112 HDV-infected patients followed-up in France, but coming from different areas of the world, we were able to determine that HDV genotype, place of birth (reflecting both viral and host-related factors) and persistent viremia constitute the main determinants of liver involvement and response to treatment.
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Affiliation(s)
- Dominique Roulot
- AP-HP, Hôpital Avicenne, Unité d'hépatologie, Université Paris 13, Bobigny; Inserm U955, équipe 18, Université Paris-Est, Créteil.
| | - Ségolène Brichler
- AP-HP, Hôpital Avicenne, Laboratoire de microbiologie clinique, Université Paris 13, Centre national de référence des hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil
| | - Richard Layese
- AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique, Université Paris-Est, DHU A-TVB, IMRB- EA 7376 CEpiA (Clinical Epidemiology and Ageing Unit), Créteil
| | - Zahia BenAbdesselam
- AP-HP, Hôpital Avicenne, Unité d'hépatologie et Centre de Recherche Clinique, Bobigny
| | - Fabien Zoulim
- Hospices civils de Lyon, Hôpital Croix Rousse, Service d'hépatologie; Inserm U1052; Université de Lyon
| | | | - Caroline Scholtes
- Hospices civils de Lyon, Hôpital Croix Rousse, Département de virologie, Université de Lyon
| | - Bruno Roche
- AP-HP, Hopital Paul Brousse, Service d'hépatologie, Villejuif
| | | | - Thierry Poynard
- AP-HP, Groupe hospitalier Pitié-Salpêtriere, Service d'hépatologie, Sorbonne Université, Paris
| | - Olivier Chazouillères
- AP-HP, Hopital Saint-Antoine, Service d'hépatologie et Centre de Recherche, Inserm, Sorbonne Université, Paris
| | - Nathalie Ganne
- AP-HP, Hôpital Jean-Verdier, Service d'hépatologie, Bondy, Université Paris 13, Bobigny; Inserm U1162, Université Paris 5, Paris
| | | | - Jerome Gournay
- CHU de Nantes, Hopital Hôtel Dieu, Département d'hépatogastroentérologie, Nantes
| | | | - Frédéric Le Gal
- AP-HP, Hôpital Avicenne, Laboratoire de microbiologie clinique, Université Paris 13, Centre national de référence des hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil
| | - Pierre Nahon
- AP-HP, Hôpital Jean-Verdier, Service d'hépatologie, Bondy, Université Paris 13, Bobigny; Inserm U1162, Université Paris 5, Paris
| | - Françoise Roudot-Thoraval
- AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique, Université Paris-Est, DHU A-TVB, IMRB- EA 7376 CEpiA (Clinical Epidemiology and Ageing Unit), Créteil; AP-HP, Hôpital Henri-Mondor, Service d'hépatologie, Créteil
| | - Emmanuel Gordien
- AP-HP, Hôpital Avicenne, Laboratoire de microbiologie clinique, Université Paris 13, Centre national de référence des hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil
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