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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: 4] [Impact Index Per Article: 4.0] [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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Alqahtani SA, Sanai FM, Banama MA, Alghamdi MY, Altarrah MY, Abaalkhail FA. Multisociety consensus recommendations on hepatitis delta virus infection. Saudi J Gastroenterol 2025; 31:5-13. [PMID: 39644161 PMCID: PMC11804964 DOI: 10.4103/sjg.sjg_322_24] [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: 09/04/2024] [Revised: 10/22/2024] [Accepted: 10/30/2024] [Indexed: 12/09/2024] Open
Abstract
ABSTRACT Hepatitis D virus (HDV) prevalence data and country-specific HDV guidelines are not widely available in the Gulf Cooperation Council (GCC) states. We developed consensus recommendations to guide healthcare professionals, policymakers, and researchers in improving HDV management and patient health outcomes in three GCC states: Kuwait, Saudi Arabia, and the United Arab Emirates. A consensus panel comprising hepatology experts (n = 6) from the three GCC societies was formed. The panel identified two broader areas related to clinical practice (screening and diagnosis, and treatment and management), addressed critical questions, and developed draft recommendations in February 2024. The strength of the final set of recommendations was subjected to consensus voting in March 2024. A majority was defined apriori with a two-thirds vote (67%). The paper outlines those recommendations alongside showcasing the current epidemiology of HDV in the GCC states, emphasizing the variability in prevalence, demographic patterns, and region-specific risk factors. It also highlights the current state of screening and diagnosis practices, identifying key obstacles, such as access to advanced screening protocols and diagnostic tools. Furthermore, HDV treatment landscape and preventative strategies are outlined, focusing on vaccination, public health initiatives, and the crucial role of public awareness and education. Ethical and sociocultural considerations are discussed, underscoring the importance of culturally sensitive healthcare practices. These recommendations present a comprehensive overview of the challenges and strategies for managing HDV in these states. Policy recommendations are provided to support HDV management, including standardizing care protocols and promoting public health measures.
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Affiliation(s)
- Saleh A. Alqahtani
- Liver, Digestive, and Lifestyle Health Research Section, and Organ Transplant Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Faisal M. Sanai
- Department of Medicine, Gastroenterology Section, King Abdulaziz Medical City, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Ministry of National Guard – Health Affairs, Jeddah, Saudi Arabia
| | - Mohammed A. Banama
- Gastroenterology Unit, Rashid Hospital, Dubai Academic Health Corporation, Dubai, UAE
| | - Mohammed Y. Alghamdi
- Department of Medicine, Gastroenterology Unit, King Fahd Military Complex, Dhahran, Saudi Arabia
| | - Munira Y. Altarrah
- Gastroenterology and Transplant Hepatology Unit, Thunayan Al Ghanim Gastroenterology Center, Al Amiri Hospital, Kuwait
| | - Faisal A. Abaalkhail
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Bruni A, Castellana C, Dajti E, Barbara G, Marasco G, Maida M, Serviddio G, Facciorusso A. Epidemiological, diagnostic, therapeutic and prognostic impact of hepatitis B and D virus infection on hepatocellular carcinoma: A review of the literature. Virology 2024; 600:110273. [PMID: 39454228 DOI: 10.1016/j.virol.2024.110273] [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: 09/07/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for >90% of primary liver cancer cases, and chronic infections with hepatitis B virus (HBV) and hepatitis D virus (HDV) are major contributors. METHODS A comprehensive literature review was conducted using the MEDLINE (PubMed) database, focusing on studies related to HBV, HDV, and HCC. RESULTS HBV contributes to HCC through mechanisms like viral integration into the host genome, chronic inflammation, and immune modulation, leading to genomic instability and altered cell signaling. HDV exacerbates HBV-induced liver damage, accelerating fibrosis and cirrhosis, and significantly increasing HCC risk. Antiviral therapies and vaccinations have majorly reduced the burden of HBV-related HCC, but HDV remains challenging to treat due to limited therapeutic options. Emerging treatments like Bulevirtide showed promising results. CONCLUSION This review highlights the critical impact of HBV and HDV co-infections on HCC development, emphasizing the need for more effective therapeutic strategies. While advances in antiviral therapies have reduced the incidence of HBV-related HCC, the high burden of HDV-related complications persists. Future research should focus on improving treatments for HDV and understanding its unique contribution to HCC pathogenesis.
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Affiliation(s)
- Angelo Bruni
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy
| | - Chiara Castellana
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elton Dajti
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Barbara
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marcello Maida
- Department of Medicine and Surgery, University of Enna 'Kore', Enna, Italy; Gastroenterology Unit, Umberto I Hospital, Enna, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
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Mathur P, Khanam A, Kottilil S. Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review. Microorganisms 2024; 12:2177. [PMID: 39597566 PMCID: PMC11596900 DOI: 10.3390/microorganisms12112177] [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: 10/10/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/29/2024] Open
Abstract
More than 12 million individuals worldwide are chronically infected with the hepatitis D virus (HDV). HDV infection is the most severe form of viral hepatitis since it requires hepatitis B virus co-infection and accelerates progression to cirrhosis and hepatocellular carcinoma. Therefore, treatment modalities to slow the progression of the disease are essential but not yet available. In addition, no antiviral treatment to date has been shown to reliably eradicate HDV. Pegylated interferon (PEG-IFN) is the only universally used treatment to suppress HDV RNA replication and improve liver inflammation and fibrosis. This treatment can be completed in 12-18 months, but cure rates remain low, and success does not reliably increase with the addition of a nucleos(t)ide analog. PEG-IFN therapy is also limited by poor tolerability and multiple adverse effects, including neutropenia, thrombocytopenia, and neuropsychiatric symptoms. Newer antiviral therapies in development target unique aspects of HDV viral replication and show promising results in combination with PEG-IFN for long-term HDV RNA suppression. These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation.
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Affiliation(s)
- Poonam Mathur
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; (A.K.); (S.K.)
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Roulot D, Layese R, Brichler S, Ganne N, Asselah T, Zoulim F, Gordien E, Nahon P, Roudot-Thoraval F. Hepatitis D Virus Infection Markedly Increases the Risk of Hepatocellular Carcinoma in Patients with Viral B Cirrhosis. Clin Gastroenterol Hepatol 2024:S1542-3565(24)00947-9. [PMID: 39461464 DOI: 10.1016/j.cgh.2024.08.046] [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: 02/12/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND & AIMS The specific causative role of hepatitis delta virus (HDV) infection in the development of hepatocellular carcinoma (HCC) remains debated and was not specifically demonstrated in patients with cirrhosis. Here we compared HCC incidence in hepatitis B virus (HBV)-HDV coinfected and HBV monoinfected patients with cirrhosis. METHODS A total of 142 HBV-HDV and 271 HBV-infected patients with cirrhosis from the French ANRSCO12 CirVir and DeltaVir cohorts, with histologically proven cirrhosis and no history of decompensation, were included in the study. RESULTS HBV-HDV patients were younger than HBV patients (37.2 vs 53.8 years), they were more often immigrants from sub-Saharan Africa, and displayed less comorbidities and more altered liver tests. After adjustment for age, cumulative incidences of HCC in coinfected and monoinfected patients at 1, 3, and 5 years were 5.2%, 11.8%, and 20.2% versus 1.1%, 2.5%, and 4.4%, respectively (P < .001). In multivariate analysis, HDV infection was an independent factor associated with the development of HCC (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.19-7.25; P = .019). Other independent factors were age (HR, 1.08; 95% CI, 1.05-1.11; P < .001), overweight (HR, 0.45; 95% CI, 0.22-0.93; P = .031), smoking (HR, 2.26; 95% CI, 1.23-4.16; P = .009), increased γ-glutamyltransferase (HR, 2.73; 95% CI, 1.24-6.00; P = .013), total bilirubin >17 μmol/L (HR, 2.68; 95% CI, 1.33-5.42; P = .006), and platelet count <150.000/mm3 (HR, 3.11; 95% CI, 1.51-6.41; P = .002). HDV coinfection was not an independent factor of liver decompensation, transplantation, or death. CONCLUSIONS The incidence of HCC seems significantly higher in HBV-HDV than in HBV-infected patients with cirrhosis. HDV infection emerges as an independent risk factor for HCC, indicating that in patients with cirrhosis, HDV plays a causative role for HCC independently of HBV.
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Affiliation(s)
- Dominique Roulot
- AP-HP, Hôpital Avicenne, Unité d'Hépatologie, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm U955, équipe 18, Université Paris-Est, Créteil, France.
| | - Richard Layese
- Université Paris-Est Créteil, INSERM, IMRB, CEpiA (Clinical Epidemiology and Ageing Unit) Team, Créteil; AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique (URC Mondor), F-94010 Créteil, France
| | - Ségolène Brichler
- AP-HP, Hôpital Avicenne, Laboratoire de Microbiologie Clinique; Université Sorbonne Paris Nord, Centre National de Référence des Hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil, France
| | - Nathalie Ganne
- AP-HP, Liver Unit, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm, UMR-1138 "Functional Genomics of Solid Tumors," Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Tarik Asselah
- AP-HP, Hôpital Beaujon, Service d'hépatologie, Clichy, France
| | - Fabien Zoulim
- Hospices Civils de Lyon, Hôpital Croix Rousse, Service d'hépatologie; Inserm U1052; Université de Lyon, France
| | - Emmanuel Gordien
- AP-HP, Hôpital Avicenne, Laboratoire de Microbiologie Clinique; Université Sorbonne Paris Nord, Centre National de Référence des Hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil, France
| | - Pierre Nahon
- AP-HP, Liver Unit, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm, UMR-1138 "Functional Genomics of Solid Tumors," Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Françoise Roudot-Thoraval
- Université Paris-Est Créteil, INSERM, IMRB, CEpiA (Clinical Epidemiology and Ageing Unit) Team, Créteil; AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique (URC Mondor), F-94010 Créteil, France; AP-HP, Hôpital Henri-Mondor, Service d'hépatologie, Créteil, France
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Jachs M, Sandmann L, Hartl L, Tergast T, Schwarz M, Bauer DJM, Balcar L, Ehrenbauer A, Hofer BS, Cornberg M, Lenzen H, Deterding K, Trauner M, Mandorfer M, Wedemeyer H, Reiberger T, Maasoumy B. Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta. J Hepatol 2024; 81:248-257. [PMID: 38479612 DOI: 10.1016/j.jhep.2024.03.005] [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: 11/01/2023] [Revised: 02/15/2024] [Accepted: 03/07/2024] [Indexed: 07/26/2024]
Abstract
BACKGROUND & AIMS Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) require validation in patients with hepatitis D virus (HDV)-related compensated advanced chronic liver disease (cACLD). Therefore, we aimed to validate existing NIT algorithms for CSPH in this context. METHODS Patients with HDV-cACLD (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno VII criteria and refined algorithms (Baveno VII-VITRO, Baveno VII-SSM) was evaluated. The prognostic utility of NITs was investigated in the main cohort and an independent, multicenter, validation cohort. RESULTS Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. Patients with CSPH had significantly higher LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p <0.001), VITRO (n = 31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p <0.001), and SSM (n = 20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p <0.001). Composite CSPH risk models yielded excellent AUROCs (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno VII 'grey zone' (41.1%) was significantly reduced by Baveno VII-VITRO or Baveno VII-SSM algorithms, which maintained diagnostic accuracy. Hepatic decompensation within 2 years only occurred in patients who had CSPH or met Baveno VII rule-in criteria. The prognostic value of NITs was confirmed in the validation cohort comprising 92 patients. CONCLUSIONS Standalone and composite NIT/diagnostic algorithms are useful for CSPH diagnosis in patients with HDV-cACLD. Thus, NITs may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against chronic hepatitis D. IMPACT AND IMPLICATIONS Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH) have been developed to identify patients with compensated advanced chronic liver disease (cACLD) at risk of decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study, including 51 patients with HDV-cACLD, LSM- and lab-based NITs yielded high AUROCs for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH risk were at risk of decompensation within 2 years, with the prognostic value of NITs confirmed in a validation cohort. Thus, NITs should be applied and updated in yearly intervals in clinical routine to identify patients with HDV-cACLD at short-term risk of clinical events; NITs may also guide prioritization for novel antiviral treatment options.
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Affiliation(s)
- Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; D-SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917), Germany; Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Germany
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Tammo Tergast
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - David Josef Maria Bauer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Department of Medicine IV, Klinik Ottakring, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alena Ehrenbauer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; D-SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917), Germany; Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Germany; German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany; Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research/Hannover Medical School, Hannover, Germany
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; D-SOLVE Consortium, an EU Horizon Europe Funded Project (No 101057917), Germany; Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Germany; German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany.
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Cadranel JFD, Zougmoré HT, Efole JRN, Hanslik B, Causse X, Rosa I, Lemaitre C, Mokhtari C, Baron A, Thevenot T, Medmoun M, Smadhi R, Fantognon G, Remy AJ, Macaigne G, Arondel Y, Arpurt JP, Bellaiche G, Bourlière M, De Kerguenec C, Heluwaert F, Verlynde J, Halfon P, Roulot D, Carrier P, Loustaud-Ratti V, Lemagoarou T. Hepatitis B Delta: assessment of the knowledge and practices of hepato-gastroenterologists practicing in non-academic settings in France. Eur J Gastroenterol Hepatol 2024; 36:735-741. [PMID: 38683191 DOI: 10.1097/meg.0000000000002707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
BACKGROUND Data on the management of Hepatitis B-Delta (HB-D) by hepatogastroenterologists (HGs) practicing in nonacademic hospitals or private practices are unknown in France. OBJECTIVE We aimed to evaluate the knowledge and practices of HGs practicing in nonacademic settings regarding HB-D. METHODS A Google form document was sent to those HGs from May to September 2021. RESULTS A total of 130 HGs (mean age, 45 years) have participated in this survey. Among HBsAg-positive patients, Delta infection was sought in only 89% of cases. Liver fibrosis was assessed using FibroScan in 77% of the cases and by liver biopsy in 81% of the cases. A treatment was proposed for patients with >F2 liver fibrosis in 49% of the cases regardless of transaminase levels and for all the patients by 39% of HGs. Responding HGs proposed a treatment using pegylated interferon in 50% of cases, bulevirtide in 45% of cases and a combination of pegylated interferon and bulevirtide in 40.5% of cases. Among the criteria to evaluate the treatment efficacy, a decrease or a normalization of transaminases was retained by 89% of responding HGs, a reduction of liver fibrosis score for 70% of them, an undetectable delta RNA and HBsAg for 55% of them and a 2 log 10 decline in delta viremia for 62% of the cases. CONCLUSION Hepatitis Delta screening was not systematically performed in HBsAg-positive patients despite the probable awareness and knowledge of the few responders who were able to prescribe treatments of hepatitis delta.
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Affiliation(s)
| | | | | | | | | | - Isabelle Rosa
- Department of Liver and Digestive Diseases, CHI Créteil
| | | | | | - Aurore Baron
- Department of Liver and Digestive Diseases, Corbeil
| | | | - Mourad Medmoun
- Department of Liver and Digestive Diseases, GHPSO, Creil
| | - Ryad Smadhi
- Department of Liver and Digestive Diseases, GHPSO, Creil
| | | | - André J Remy
- Department of Liver and Digestive Diseases, Perpignan
| | | | - Yves Arondel
- Department of Liver and Digestive Diseases, Haguenau
| | | | - Guy Bellaiche
- Department of Liver and Digestive Diseases, Aulnay-sous-bois
| | | | | | | | | | - Philippe Halfon
- Department of Internal Medicine and Infectious Diseases, Alphabio Laboratory Marseille, Marseille
| | | | - Paul Carrier
- Department of Liver and Digestive Diseases, Limoges
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Sandmann L, Degasperi E, Port K, Aleman S, Wallin JJ, Manuilov D, Da BL, Cornberg M, Lampertico P, Maasoumy B, Wedemeyer H, Deterding K. Liver stiffness measurement as a noninvasive method for the diagnosis of liver cirrhosis in patients with chronic hepatitis D virus infection. Aliment Pharmacol Ther 2024; 59:752-761. [PMID: 38212890 DOI: 10.1111/apt.17878] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/27/2023] [Accepted: 01/02/2024] [Indexed: 01/13/2024]
Abstract
BACKGROUND Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited. AIMS To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients. METHODS We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies. RESULTS Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients. CONCLUSIONS LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients.
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Affiliation(s)
- Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
| | - Elisabetta Degasperi
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Kerstin Port
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Soo Aleman
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Infectious Diseases, Karolinska Institute, Stockholm, Sweden
| | | | | | - Ben L Da
- Gilead Sciences, Inc., Foster City, California, USA
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
- German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany
- Centre for Individualised Infection Medicine, Helmholtz Centre for Infection Research/Hannover Medical School, Hannover, Germany
| | - Pietro Lampertico
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC "A. M. and A. Migliavacca" Center for Liver Disease, University of Milan, Milan, Italy
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- D-SOLVE Consortium, an EU Horizon Europe Funded Project (no. 101057917)
- German Center for Infection Research (DZIF), Hannover/Braunschweig, Germany
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
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9
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Gopalakrishna H, Mironova M, Dahari H, Koh C, Heller T. Advances and Challenges in Managing Hepatitis D Virus: Evolving Strategies. CURRENT HEPATOLOGY REPORTS 2024; 23:32-44. [PMID: 38533303 PMCID: PMC10965034 DOI: 10.1007/s11901-024-00643-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Accepted: 01/14/2024] [Indexed: 03/28/2024]
Abstract
Purpose of Review Hepatitis D Virus (HDV), although a small defective virus, poses a substantial public health challenge due to lack of awareness, underrecognized prevalence, and limited treatment options. Universal HDV screening within hepatitis B virus (HBV) cohorts is essential to address this issue. Despite its aggressive nature, effective HDV therapies have remained elusive for over four decades. Recent Findings Advances in understanding HDV's biology and clinical behavior offer potential therapeutic breakthroughs, fostering optimism. As insights grow, effective and targeted therapies are being developed to improve HDV management. Summary This review delves into HDV's intricate structure and biology, highlighting formidable hurdles in antiviral development. It emphasizes the importance of widespread screening, exploring noninvasive diagnostics, and examining current and emerging innovative therapeutic strategies. Moreover, the review explores models for monitoring treatment response. In essence, this review simplifies the complexities of effectively combating HDV.
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Affiliation(s)
- Harish Gopalakrishna
- Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Maria Mironova
- Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Harel Dahari
- The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
| | - Christopher Koh
- Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10, Room 4-5722, Bethesda, MD 20892-1800, USA
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10
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Cooke GS. Viral Hepatitis. MANSON'S TROPICAL DISEASES 2024:152-166. [DOI: 10.1016/b978-0-7020-7959-7.00018-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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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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Grecu LI, Sultana C, Pavel-Tanasa M, Ruta SM, Chivu-Economescu M, Matei L, Ursu RG, Iftimi E, Iancu LS. Non-Invasive Prediction Scores for Hepatitis B Virus- and Hepatitis D Virus-Infected Patients-A Cohort from the North-Eastern Part of Romania. Microorganisms 2023; 11:2895. [PMID: 38138039 PMCID: PMC10745361 DOI: 10.3390/microorganisms11122895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/22/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Approximately 62-72 million people are infected worldwide with HDV. Patients with chronic hepatitis D (CHD) have a higher risk of developing cirrhosis or hepatocellular carcinoma (HCC) and an increased mortality rate compared to those with chronic hepatitis B (CHB). The stage of liver fibrosis or the risk of developing HCC can also be estimated by non-invasive scores, which are cost effective, easier to apply, and reproducible. In this study, we aimed to evaluate the predictive value of four non-invasive scores (FIB-4, APRI, AST/ALT ratio, and aMAP) in assessing severe fibrosis/cirrhosis and the presence of HCC in patients with HBV/HDV superinfection, as compared with HBV mono-infection. Our 8-year retrospective analysis revealed that HDV-infected patients had a 2-3 times higher risk of developing cirrhosis and HCC than HBV-mono-infected subjects. High AST and ALT baseline levels qualified as independent predictors for cirrhosis development in both groups. The following fibrosis scores, FIB-4, APRI score, and AAR, were significantly increased when cirrhosis was present at baseline and showed a good prediction for developing cirrhosis in the CHD group. The aMAP score, a risk predictor for HCC, showed significantly higher values in patients with HCC in both groups. Nonetheless, non-invasive scores should always be considered for monitoring patients with CHB and CHD, but only when associated with other diagnosis methods.
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Affiliation(s)
- Laura Iulia Grecu
- Department of Preventive Medicine and Interdisciplinarity, Microbiology Discipline, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.G.); (R.G.U.); (L.S.I.)
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
| | - Camelia Sultana
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
- Virology Discipline, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mariana Pavel-Tanasa
- Department of Immunology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Simona Maria Ruta
- Department of Emerging Viral Diseases, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania;
- Virology Discipline, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania; (M.C.-E.)
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, “Stefan S. Nicolau” Institute of Virology, 030304 Bucharest, Romania; (M.C.-E.)
| | - Ramona Gabriela Ursu
- Department of Preventive Medicine and Interdisciplinarity, Microbiology Discipline, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.G.); (R.G.U.); (L.S.I.)
| | - Elena Iftimi
- Department of Immunology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Luminita Smaranda Iancu
- Department of Preventive Medicine and Interdisciplinarity, Microbiology Discipline, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.G.); (R.G.U.); (L.S.I.)
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14
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Majeed NA, Hitawala AA, Heller T, Koh C. Diagnosis of HDV: From virology to non-invasive markers of fibrosis. Liver Int 2023; 43 Suppl 1:31-46. [PMID: 36621853 PMCID: PMC10329733 DOI: 10.1111/liv.15515] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 11/25/2022] [Accepted: 01/04/2023] [Indexed: 01/10/2023]
Abstract
Hepatitis D viral infection in humans is a disease that requires the establishment of hepatitis B, relying on hepatitis B surface Ag and host cellular machinery to replicate and propagate the infection. Since its discovery in 1977, substantial progress has been made to better understand the hepatitis D viral life cycle, pathogenesis and modes of transmission along with expanding on clinical knowledge related to prevention, diagnosis, monitoring and treatment. The availability of serologic diagnostic assays for hepatitis D infection has evolved over time with current widespread availability, improved detection and standardized reporting. With human migration, the epidemiology of hepatitis D infection has changed over time. Thus, the ability to use diagnostic assays remains essential to monitor the global impact of hepatitis D infection. Separately, while liver biopsy remains the gold standard for the staging of this rapidly progressive and severe form of chronic viral hepatitis, there is an unmet need for clinical monitoring of chronic hepatitis D infection for management of progressive disease. Thus, exploration of the utility of non-invasive fibrosis markers in hepatitis D is ongoing. In this review, we discuss the virology, the evolution of diagnostics and the development of non-invasive markers for the detection and monitoring of fibrosis in patients with hepatitis D infection.
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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
| | - Asif Ali Hitawala
- 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
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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15
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Metin O, Zeybel M, Yurdaydin C. Treatment endpoints for chronic hepatitis D. Liver Int 2023; 43 Suppl 1:60-68. [PMID: 36196680 DOI: 10.1111/liv.15447] [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: 07/12/2022] [Revised: 09/20/2022] [Accepted: 10/03/2022] [Indexed: 02/13/2023]
Abstract
Management of chronic hepatitis D (CHD) has entered a new era. In this new era, the virus entry inhibitor bulevirtide has received conditional approval as a treatment for compensated CHD. Three phase 3 studies with two new compounds are ongoing for the treatment of CHD. In this context, surrogate markers of treatment efficacy have been well defined for chronic hepatitis B (CHB) (7) and chronic hepatitis C (8) but not for CHD. The aim of this review is to give a perspective on treatment endpoints in CHD. For this, we took guidance from CHB studies and tried to make suggestions which differed according to finite versus prolonged treatment durations and also took into account the different characteristics of the new compounds.
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Affiliation(s)
- Olga Metin
- Department of Gastroenterology, Prof. Cemil Taşçioğlu City Hospital, Istanbul, Turkey
| | - Müjdat Zeybel
- Department of Gastroenterology and Hepatology, Koç University Medical School, Istanbul, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology and Hepatology, Koç University Medical School, Istanbul, Turkey
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16
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Abbas Z, Abbas M. An Insight Into the Factors Affecting the Prevalence and Natural History of Hepatitis D. Cureus 2023; 15:e43362. [PMID: 37593072 PMCID: PMC10427805 DOI: 10.7759/cureus.43362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2023] [Indexed: 08/19/2023] Open
Abstract
Epidemiological studies and recent metanalyses addressing hepatitis D have reported a wide variation in the prevalence of the disease. Between 4.5% to 15% of all hepatitis B surface antigen (HBsAg) positive patients are thought to harbor the hepatitis D virus. The emergent variation in prevalence can be attributed to several factors. Unsurprisingly, published literature shows that the prevalence of the disease is higher in areas where aggregate viral hepatitis infections are endemic and amongst groups with high-risk practices facilitating the horizontal transfer. Meanwhile, the natural history of the disease is influenced by the genotype of the virus, the hepatitis D virus (HDV) RNA levels, HBV-HDV codominance, HBsAg titers, HBV genotype, nutritional status, HIV co-infection, and prior treatment. Together these factors contribute to the accelerated development of fibrosis and the increased risk of hepatocellular carcinoma. Superinfection with genotype 1 results in rapid progression to cirrhosis with lower rates of remission. Genotype 3 follows an aggressive course but shows a good response to interferon therapy. Other genotypes have better outcomes. The course of the disease leading to these outcomes can be tracked by HDV-specific models integrating clinical surrogate markers and epidemiological factors such as age, region, alanine aminotransferase (ALT), gamma-glutamyl transferase, albumin, platelets and cholinesterase, and liver stiffness.
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Affiliation(s)
- Zaigham Abbas
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital, Karachi, PAK
| | - Minaam Abbas
- Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, GBR
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17
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Abstract
First discovered over 40 years ago, the hepatitis delta virus (HDV) is a unique RNA virus, requiring hepatitis B virus (HBV) antigens for its assembly, replication, and transmission. HBV and HDV can be acquired at the same time (coinfection) or HDV infection can occur in persons with chronic HBV (superinfection). Screening guidelines for HDV are inconsistent. While some guidelines recommend universal screening for all people with HBV, others recommend risk-based screening. Estimates of the global HDV prevalence range from 4.5 to 14.6% among persons with HBV; thus, there may be up to 72 million individuals with HDV worldwide. HDV is the most severe form of viral hepatitis. Compared to HBV monoinfection, HDV coinfection increases the risk of cirrhosis, hepatocellular carcinoma, hepatic decompensation, mortality, and necessity for liver transplant. Despite the severity of HDV, there are few treatment options. Pegylated interferon (off-label use) has long been the only available treatment, although bulevirtide is conditionally approved in some European countries. There are many potential treatments in development, but as yet, there are few effective and safe therapies for HDV infection. In conclusion, given the severity of HDV disease and the paucity of treatments, there is a great unmet need for HDV therapies.
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Affiliation(s)
- Brian Pearlman
- Department of Internal Medicine, Wellstar Atlanta Medical Center, Medical College of Georgia, Emory School of Medicine, Atlanta, Georgia
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18
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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: 114] [Impact Index Per Article: 57.0] [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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Maasoumy B, Lampertico P. Hepatitis Delta: Ready for primetime? Liver Int 2023; 43 Suppl 1:1-4. [PMID: 37658668 DOI: 10.1111/liv.15679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 07/10/2023] [Indexed: 09/03/2023]
Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research (DZIF), Braunschweig, Germany
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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20
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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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Sandmann L, Tergast TL, Wedemeyer H, Deterding K, Maasoumy B. 3P and 5P models of limited value for the detection of clinically significant portal hypertension in patients with hepatitis delta. J Hepatol 2023; 79:e47-e49. [PMID: 36669702 DOI: 10.1016/j.jhep.2023.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/11/2022] [Accepted: 01/04/2023] [Indexed: 01/19/2023]
Affiliation(s)
- Lisa Sandmann
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Germany; Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Germany
| | - Tammo Lambert Tergast
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Germany
| | - Heiner Wedemeyer
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Germany; Excellence Cluster RESIST, Excellence Initiative Hannover Medical School, Germany; German Center of Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Katja Deterding
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Germany
| | - Benjamin Maasoumy
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Germany; German Center of Infection Research (DZIF), Hannover-Braunschweig, Germany.
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22
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Heller T, Buti M, Lampertico P, Wedemeyer H. Hepatitis D: Looking Back, Looking Forward, Seeing the Reward and the Promise. Clin Gastroenterol Hepatol 2023; 21:2051-2064. [DOI: 10.1016/j.cgh.2023.04.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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23
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Souza Campos M, Villalobos-Salcedo JM, Vieira Dallacqua DS, Lopes Borges Andrade C, Meyer Nascimento RJ, Menezes Freire S, Paraná R, Schinoni MI. Systemic Inflammatory Molecules Are Associated with Advanced Fibrosis in Patients from Brazil Infected with Hepatitis Delta Virus Genotype 3 (HDV-3). Microorganisms 2023; 11:1270. [PMID: 37317244 DOI: 10.3390/microorganisms11051270] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/03/2023] [Accepted: 05/03/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND AND AIMS Hepatitis Delta virus (HDV) genotype 3 is responsible for outbreaks of fulminant hepatitis in Northeastern South America. This study investigates if systemic inflammatory molecules are differentially expressed in patients with advanced fibrosis chronically infected with Hepatitis Delta virusgenotype 3(HDV-3). METHODS Sixty-one patients from the north of Brazil coinfected with hepatitis B virus (HBV)/HDV-3 were analyzed. HDV quantification and genotyping were performed by semi-nested real-time polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP) methodologies. Ninety-two systemic inflammatory molecules (SIMs) were measured by Proximity Extension Assay (PEA) technology. The Shapiro-Wilk, Student's t-test, Mann-Whitney tests, and logistic regression analysis were used when appropriate. RESULTS The median age was 41 years, and all patients were HBeAg negative. Advanced fibrosis or cirrhosis was diagnosed by histological staging in 17 patients, while 44 presented with minimal or no fibrosis. Advanced necroinflammatory activity correlated positively with serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Established non-invasive fibrosis scores (APRI, FIB-4, and AST/ALT ratio) revealed low sensitivities and positive predictive values (PPVs) with an AUROC maximum of 0.586. Among the 92 SIMs analyzed, MCP.4, CCL19, EN.RAGE, SCF, and IL18 showed a positive correlation with fibrosis stage. A combined score including CCL19 and MCP.4 revealed a sensitivity of 81% and an odds ratio of 2.202 for advanced fibrosis. CONCLUSIONS Standard non-invasive fibrosis scores showed poor performance in HDV-3 infection. We here suggest that the determination of CCL19 and MCP.4 may be used to identify patients with advanced fibrosis. Moreover, this study gives novel insights into the immunopathogenesis of HDV-3 infection.
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Affiliation(s)
- Mauricio Souza Campos
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Programa de Pós-Graduação em Processos Interativos de Órgãos e Sistemas, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
| | | | | | - Caio Lopes Borges Andrade
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Programa de Pós-Graduação em Imunologia, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Laboratório de Imunologia e Biologia Molecular, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300,Brazil
| | - Roberto José Meyer Nascimento
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Programa de Pós-Graduação em Imunologia, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Laboratório de Imunologia e Biologia Molecular, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300,Brazil
| | - Songeli Menezes Freire
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Programa de Pós-Graduação em Imunologia, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Laboratório de Imunologia e Biologia Molecular, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300,Brazil
| | - Raymundo Paraná
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Hospital Universitario Professor Edgard Santos, Universidade Federal da Bahia, Salvador 40110-060, Brazil
| | - Maria Isabel Schinoni
- Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Programa de Pós-Graduação em Processos Interativos de Órgãos e Sistemas, Instituto Ciências da Saúde, Universidade Federal da Bahia, Salvador 40231-300, Brazil
- Hospital Universitario Professor Edgard Santos, Universidade Federal da Bahia, Salvador 40110-060, Brazil
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24
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Kalkan Ç, Yılmaz Y, Erdoğan BD, Savaş B, Yurdcu E, Çalışkan A, Keskin O, Gencdal G, Zeybel M, Törüner M, Bozdayi AM, Idilman R, Yurdaydin C. Non-invasive fibrosis markers for assessment of liver fibrosis in chronic hepatitis delta. J Viral Hepat 2023; 30:406-416. [PMID: 36651603 DOI: 10.1111/jvh.13806] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 12/30/2022] [Accepted: 01/03/2023] [Indexed: 01/19/2023]
Abstract
Assessment of liver fibrosis by non-invasive means is clinically important. Studies in chronic hepatitis delta (CHD) are scarce. We evaluated the performance of eight serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), age-platelet index (API), AST-to platelet-ratio-index (APRI), Goteborg University Cirrhosis Index (GUCI), Lok index, cirrhosis discriminant score (CDS) and Hui score] in CHD and chronic hepatitis B (CHB). Liver stiffness was assessed by transient elastography (TE) in CHD. The ability of fibrosis markers to detect significant fibrosis and cirrhosis were evaluated in 202 CHB and 108 CHD patients using published and new cut-offs through receiver operating characteristics (ROC) analysis. The latter was also applied to obtain cut-offs for TE. APRI, Fib-4, API and Hui score were assessed for significant fibrosis, and APRI, GUCI, Lok index, CDS and AAR for cirrhosis determination. Fibrosis markers displayed weak performance in CHB for significant fibrosis with area under ROC (AUROC) curves between 0.62 and 0.71. They did slightly better for CHD. TE displayed an AUROC of 0.92 and performed better than serum fibrosis markers (p < 0.05 for fibrosis markers). For cirrhosis determination, CDS and Lok Index displayed an AUROC of 088 and 0.89 in CHB and GUCI, Lok index and APRI displayed AUROCs around 0.90 in CHD. TE displayed the best AUROC (0.95). Hence TE is superior to serum fibrosis markers for diagnosing significant liver fibrosis and cirrhosis. GUCI, Lok index and APRI displayed a reasonable performance in CHD, which needs further confirmation.
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Affiliation(s)
- Çağdaş Kalkan
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Yusufcan Yılmaz
- Department of Internal Medicine, Ankara University Medical School, Ankara, Turkey
| | | | - Berna Savaş
- Department of Pathology, Ankara University Medical School, Ankara, Turkey
| | - Esra Yurdcu
- Hepatology Institute, Ankara University, Ankara, Turkey
| | - Aysun Çalışkan
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Onur Keskin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Genco Gencdal
- Department of Gastroenterology & Hepatology, Koç University Medical School, Istanbul, Turkey
| | - Müjdat Zeybel
- Department of Gastroenterology & Hepatology, Koç University Medical School, Istanbul, Turkey
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, Nottingham, UK
| | - Murat Törüner
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | | | - Ramazan Idilman
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey
- Department of Gastroenterology & Hepatology, Koç University Medical School, Istanbul, Turkey
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26
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Koffas A, Mak LY, Kennedy PTF. Hepatitis delta virus: Disease assessment and stratification. J Viral Hepat 2022; 30 Suppl 1:11-20. [PMID: 36458851 DOI: 10.1111/jvh.13777] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/26/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis D virus (HDV) causes one of the most severe forms of hepatitis in people with chronic hepatitis B (CHB) infection. Timely and accurate assessment of hepatitis delta virus (HDV) and disease stratification is mandatory for thorough pre-therapeutic evaluation for prioritizing treatment and outcome prediction. Viral biomarkers associated with HDV and hepatitis B virus (HBV) are crucial to aid in diagnosis, and monitoring of serum viral nucleic acids for both viruses is recommended. Liver biopsy remains the gold standard for staging of liver fibrosis and grading of histological activity and should remain central for diagnostic purposes, but is also of importance for research to enhance our understanding of HDV. The emergence of novel non-invasive tests for the assessment of liver fibrosis in HDV patients coupled with the well-recognized potential complications of liver biopsy has resulted in reduced utility of liver biopsy in clinical practice. Preliminary data suggest that these emerging non-invasive modalities appear to be reliable, and their use is supported, similar to other viral hepatitis. Nevertheless, further validation is required before their widespread adoption into clinical practice.
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Affiliation(s)
- Apostolos Koffas
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Patrick T F Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Leroy V, Chevaliez S, Decraecker M, Roulot D, Nana J, Asselah T, Causse X, Durantel D, Thibaut V, Ganne-Carrié N, Bureau C, de Lédinghen V, Bourlière M. Non-invasive diagnosis and follow-up of chronic infection with hepatitis B virus. Clin Res Hepatol Gastroenterol 2022; 46:101773. [PMID: 34332134 DOI: 10.1016/j.clinre.2021.101773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/04/2023]
Abstract
Diagnosis of chronic hepatitis B virus (HBV) infection, initial staging of infection and monitoring of treated and untreated patients are mainly based on clinical, biological and imaging criteria allowing a complete non-invasive management for the majority of patients. Along to the conventional virological tools, rapid diagnostic tests and blotting paper tests for HBV DNA are validated alternatives. After diagnosis, the initial work-up should include HIV, HCV and HDV serologies, HBeAg status, and HBsAg and HBV DNA quantification. Assessment of severity (inflammation and fibrosis) is based on ALT serum levels and non-invasive evaluation of liver fibrosis by elastography or blood tests, which must be interpreted cautiously using specific cut-offs and taking into account ALT levels. Taken together, these parameters allow disease classification and treatment decision. Decision of hepatocellular carcinoma screening by ultra-sound every six months may be difficult in non-cirrhotic patients and the use of risk-scores such as PAGE-B is encouraged. Chronic HBV infection often has a dynamic and often unpredictable profile and regular monitoring is mandatory. In untreated patients, regular (3-12 months) follow-up should include ALT and HBV DNA serum levels. Periodical HBsAg quantification and non-invasive evaluation of liver fibrosis may refine disease outcome and prognosis. In treated patients, checking efficacy is mainly based on HBV DNA negativity. In patients with advanced fibrosis, evolution of liver stiffness can be useful for portal hypertension evaluation, but its improvement should not be considered to stop hepatocellular carcinoma screening. Finally, new parameters (HBV RNA, HBcrAg) are promising but their use is still restricted for research.
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Affiliation(s)
- Vincent Leroy
- Service d'hépatologie, Hôpital Henri-Mondor, APHP, & INSERM U955, UPEC, Créteil, France.
| | - Stéphane Chevaliez
- Service d'hépatologie, Hôpital Henri-Mondor, APHP, & INSERM U955, UPEC, Créteil, France
| | - Marie Decraecker
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Dominique Roulot
- Service d'hépatologie, Hôpital Avicenne, APHP; université Sorbonne Paris Nord, Bobigny, France
| | - Jean Nana
- Service d'hépato-gastroentérologie, Centre Hospitalier de Voiron, CHU Grenoble-Alpes, Voiron, France
| | - Tarik Asselah
- Service d'hépatologie, Hôpital Beaujon, APHP, Clichy, France
| | - Xavier Causse
- Service d'hépato-gastroentérologie et oncologie digestive, CHR Orléans, Orléans, France
| | | | | | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP; université Sorbonne Paris Nord, Bobigny, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
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28
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Da BL. Clinical trials in hepatitis D virus: Measuring success. Hepatology 2022; 77:2147-2157. [PMID: 35969089 DOI: 10.1002/hep.32732] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 12/31/2022]
Abstract
Chronic hepatitis D infection results in the most severe form of chronic viral hepatitis but currently lacks effective treatment options. Therapy with pegylated interferon alpha is recommended for finite treatment duration by major liver societies. Still, it is plagued by low rates of sustained virologic response (SVR) and frequent relapses even if SVR is achieved. Recently, a wave of investigational therapies has come under evaluation, including bulevirtide, lonafarnib, pegylated interferon lambda, and REP-2139 creating excitement with this viral infection. However, there has been significant variability in the endpoints used to evaluate these therapeutics. One of the recently introduced endpoints is characterized by a decline in HDV RNA by 2 logs, with or without achieving an undetectable serum hepatitis D virus (HDV) RNA, as a marker of virologic response. Furthermore, this measure has been combined with alanine aminotransferase normalization, also known as a biochemical response, to formulate the primary endpoint of several late-stage studies. Per recent guidance by the US Food and Drug Administration, these should be surrogate endpoints that will ultimately portend long-term clinical benefits. These clinical benefits may include reducing the risk of progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and mortality. However, the optimal way to measure success in HDV clinical trials remains unknown and will continue to evolve.
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Affiliation(s)
- Ben L Da
- Division of Hepatology, Department of Internal Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, New York, USA
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29
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Osiowy C, Swidinsky K, Haylock-Jacobs S, Sadler MD, Fung S, Wong D, Minuk GY, Doucette KE, Wong P, Tam E, Cooper C, Ramji A, Ma M, Nudo C, Tsoi K, Coffin CS. Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada. JHEP Rep 2022; 4:100461. [PMID: 35360523 PMCID: PMC8961228 DOI: 10.1016/j.jhepr.2022.100461] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/26/2022] [Accepted: 02/03/2022] [Indexed: 11/29/2022] Open
Abstract
Background & Aims HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network. Methods Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications. Results Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort. Conclusions Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada. Lay summary Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected patients.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- CHB, chronic HBV infection
- CanHepB Network, Canadian HBV network
- Cirrhosis
- Epidemiology
- Genotype
- HCC, hepatocellular carcinoma
- Hepatitis B virus
- Hepatitis D virus
- IFNα, pegylated interferon-alpha
- INR, international normalised ratio (prothrombin time of blood clotting)
- NAs, nucleos(t)ide analogue inhibitors
- NML, National Microbiology Laboratory
- TE, transient elastography
- bp, base pairs
- gt, genotype
- n, count
- qHBsAg, quantitative HBsAg
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Affiliation(s)
- Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
- University of Manitoba, Winnipeg, MB, Canada
| | - Ken Swidinsky
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | | | | | - Scott Fung
- University of Toronto, Toronto, ON, Canada
| | - David Wong
- University of Toronto, Toronto, ON, Canada
| | | | | | | | | | | | - Alnoor Ramji
- University of British Columbia, Vancouver, BC, Canada
| | - Mang Ma
- University of Alberta, Edmonton, AB, Canada
| | - Carmine Nudo
- Hôpital de la Cité-de-la-Santé, Laval, QC, Canada
| | - Keith Tsoi
- McMaster University, Hamilton, ON, Canada
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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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31
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Li ZB, Chen DD, He QJ, Li L, Zhou G, Fu YM, Deng Y, Niu XX, Chu F, Gao XP, Zou Z, Chen G, Ji D. The LAC Score Indicates Significant Fibrosis in Patients With Chronic Drug-Induced Liver Injury: A Large Biopsy-Based Study. Front Pharmacol 2021; 12:734090. [PMID: 34483945 PMCID: PMC8416439 DOI: 10.3389/fphar.2021.734090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022] Open
Abstract
Currently, there are no satisfactory noninvasive methods for the diagnosis of fibrosis in patients with chronic drug-induced liver injury (DILI). Our goal was to develop an algorithm to improve the diagnostic accuracy of significant fibrosis in this population. In the present study, we retrospectively investigated the biochemical and pathological characteristics of consecutive patients with biopsy-proven chronic DILI, who presented at our hospital from January 2013 to December 2017. A noninvasive algorithm was developed by using multivariate logistic regression, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) to diagnose significant fibrosis in the training cohort, and the algorithm was subsequently validated in the validation cohort. Totally, 1,130 patients were enrolled and randomly assigned into a training cohort (n = 848) and a validation cohort (n = 282). Based on the multivariate analysis, LSM, CHE, and APRI were independently associated with significant fibrosis. A novel algorithm, LAC, was identified with the AUROC of 0.81, which was significantly higher than LSM (AUROC 0.78), CHE (AUROC 0.73), and APRI (AUROC 0.68), alone. The best cutoff value of LAC in the training cohort was 5.4. When the LAC score was used to diagnose advanced fibrosis and cirrhosis stages, the optimal cutoff values were 6.2 and 6.7, respectively, and the AUROC values were 0.84 and 0.90 in the training cohort and 0.81 and 0.83 in the validation cohort. This study proved that the LAC score can contribute to the accurate assessment of high-risk disease progression and the establishment of optimal treatment strategies for patients with chronic DILI.
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Affiliation(s)
- Zhong-Bin Li
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Dan-Dan Chen
- Department II of Hepatology, The Second People's Hospital of Jingzhou City, Jingzhou, China
| | - Qing-Juan He
- Department II of Gastroenterology, The Eighth People's Hospital of Qingdao, QingDao, China
| | - Le Li
- Senior Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Guangde Zhou
- Department of Pathology, Third People's Hospital of Shenzhen, Shenzhen, China
| | - Yi-Ming Fu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ya Deng
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiao-Xia Niu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Fang Chu
- Department of Outpatients, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-Pan Gao
- Department of Clinical Laboratory, Second Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
| | - Guofeng Chen
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,Peking University 302 Clinical Medical School, Beijing, China
| | - Dong Ji
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.,Peking University 302 Clinical Medical School, Beijing, China.,Chinese PLA 307 Medical College of Anhui Medical University, Beijing, China
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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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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: 115] [Impact Index Per Article: 28.8] [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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Abbas Z, Qadeer MA, Mandviwalla HA, Abbas M. The Severity of Hepatitis D in Young Adults of Age 18-25 Years. Cureus 2020; 12:e10855. [PMID: 33052263 PMCID: PMC7546593 DOI: 10.7759/cureus.10855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background Current literature on the prevalence and characteristics of hepatitis D virus (HDV) infection in young adults is limited. This study aims to determine the disease characteristics and severity in young adults. Methods The case records of HDV RNA positive patients of age 18-25 years were analyzed. Results Out of 119 patients, 105 (88%) patients were male. HBV-DNA was detectable in 83 (70%). Hepatitis B e-antigen (HBeAg) was non-reactive in 99 (83%). Cirrhosis was identified in 45 (37.8%) individuals; nine (7.5%) were classified as Child class B or Child class C. Twenty-four (20.2%) had a Model For End-Stage Liver Disease (MELD) score of ≥10, out of these 16 had a score of 15 or more. The risk of decompensation was calculated according to the Baseline-event-anticipation (BEA) score; eight (6.7%) patients were at BEA-A (mild risk), 105 (88.2%) were at BEA-B (moderate risk), and six (5.0%) were at BEA-C (severe risk). Notable findings in patients with cirrhosis included splenomegaly, low total leucocyte counts, low platelets, high bilirubin, elevated aspartate aminotransferase, gamma-glutamyl transferase and international normalization ratio, low albumin, high AST to Platelet Ratio Index (APRI), and high BEA score. The splenic size, platelet count, and albumin levels were independently associated with cirrhosis (p < 0.001, <0.001, and 0.003). A model using a combination of platelet count, albumin, and spleen size was developed to accurately predict cirrhosis in this cohort. It had an area under the receiver operating characteristics (AUROC) of 0.935. Conclusions HDV-infected young adults, age 18-25 years, were at moderate to severe risk of disease progression. About one-third of patients had already developed cirrhosis indicating the aggressive nature of the disease.
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Affiliation(s)
- Zaigham Abbas
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital Clifton, Karachi, PAK
| | - Muhammad Ali Qadeer
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital Clifton, Karachi, PAK
| | - Haider A Mandviwalla
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital Clifton, Karachi, PAK
| | - Minaam Abbas
- Gastroenterology and Hepatology, Dr. Ziauddin University Hospital Clifton, Karachi, PAK
- Gastroenterology and Hepatology, School of Clinical Medicine, University of Cambridge, Cambridge, GBR
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35
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Alves Vasconcelos MP, DallÁcqua DV, Wedemeyer H, Witkin SS, Mendes-Corrêa MC, Villalobos-Salcedo JM. Noninvasive Models for Predicting Liver Fibrosis in Individuals with Hepatitis D Virus/Hepatitis B Virus Coinfection in the Brazilian Amazon Region. Am J Trop Med Hyg 2020; 103:169-174. [PMID: 32431268 DOI: 10.4269/ajtmh.19-0688] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis D virus (HDV) genotype III is endemic in the western Amazon basin and is considered to cause the most severe form of chronic viral hepatitis. Recently, noninvasive fibrosis scores to determine the stage of liver fibrosis have been evaluated in individuals positive for HDV genotype I, but their utility in HDV genotype III-positive patients is unknown. In this retrospective study conducted in an outpatient viral hepatitis referral clinic in the Brazilian Amazon region, the aspartate aminotransferase (AST) to Aspartate aminotransferase to Platelet Ratio Index (APRI) and Fibrosis Index for Liver Fibrosis (FIB-4) values were calculated and compared with histological fibrosis stages. Among the 50 patients analyzed, the median age at liver biopsy was 35.6 years, 66% were male, and all had compensated liver disease. Histological staging revealed fibrosis stages 0, 1, 2, 3, and 4 in four (8%), eight (16%), 11 (22), 11 (22%), and 16 (32%) patients, respectively. The area under the receiver operating curve (AUROC) of AST-to-alanine aminotransferase (ALT) ratio, APRI, and FIB-4 for detection of significant fibrosis (F ≥ 2) was 0.550 (P = 0.601), 0.853 (P < 0.001), and 0.853 (P < 0.0001), respectively. Lower AUROC values were obtained for cirrhosis: the AST-to-ALT ratio was 0.640 (P = 0.114), APRI was 0.671 (P = 0.053), and FIB-4 was 0.701 (P = 0.023). The optimal cutoff value for significant fibrosis for APRI was 0.708 (sensitivity 84% and specificity 92%) and for FIB-4 was 1.36 (sensitivity 76% and specificity 92%). Aspartate aminotransferase to Platelet Ratio Index and FIB-4 were less useful to predict cirrhosis. In contrast to recent reports from Europe and North America, both APRI and FIB-4 may identify significant fibrosis in HDV-III-infected patients from northwestern Brazil.
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Affiliation(s)
- Mariana Pinheiro Alves Vasconcelos
- Research Center for Tropical Medicine of Rondônia, Porto Velho, Brazil.,Department of Infectious Diseases, University of São Paulo, School of Medicine, Brazil
| | - Deusilene Vieira DallÁcqua
- Oswaldo Cruz Institute of Rondônia, Porto Velho, Brazil.,Research Center for Tropical Medicine of Rondônia, Porto Velho, Brazil
| | | | - Steven S Witkin
- Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil.,Weill Cornell Medicine, New York, New York
| | - Maria Cássia Mendes-Corrêa
- Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil.,Department of Infectious Diseases, University of São Paulo, School of Medicine, Brazil
| | - Juan Miguel Villalobos-Salcedo
- Oswaldo Cruz Institute of Rondônia, Porto Velho, Brazil.,Research Center for Tropical Medicine of Rondônia, Porto Velho, Brazil
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Da BL, Surana P, Takyar V, Kleiner DE, Heller T, Koh C. Vibration-controlled transient elastography for the detection of cirrhosis in chronic hepatitis D infection. J Viral Hepat 2020; 27:428-436. [PMID: 31742822 PMCID: PMC7080586 DOI: 10.1111/jvh.13235] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 10/07/2019] [Accepted: 11/11/2019] [Indexed: 12/15/2022]
Abstract
Noninvasive detection of cirrhosis via vibration-controlled transient elastography (VCTE) has revolutionized the management of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. However, VCTE has not been studied in chronic hepatitis D virus (HDV) infection and accuracy remains in question due to the significant hepatic inflammation associated with this infection. Consecutive HBV, HCV and HDV patients who underwent VCTE (2006-2019) were evaluated. Diagnosis of cirrhosis was made via liver biopsy or clinical findings. VCTE was compared with other noninvasive serum fibrosis tests using AUROC curves. The performance of VCTE in HBV/HCV/HDV was also compared. We evaluated 319 patients (HBV-112; HCV-132; HDV-75), 278(87%) patients had histology for evaluation. HDV patients had evidence of higher hepatic inflammation as evidence by aspartate aminotransferase, alanine aminotransferase and histology activity index. Cirrhotic HDV patients had higher mean liver stiffness measurements compared with noncirrhotic patients (29.0 vs 8.3 kPa, P < .0001). VCTE demonstrated excellent diagnostic accuracy for the detection of cirrhosis with an AUROC of 0.90 compared with APRI (0.83), FIB-4 (0.88), AAR (0.73) and RPR (0.85). Performance of VCTE in HDV was comparable with HBV (0.93) and HCV (0.94). At the optimized cut-off value of ≥14.0 kPa for determining cirrhosis in HDV, VCTE had a sensitivity of 0.78, specificity of 0.86, NPV of 0.93 and PPV of 0.64. Hence, VCTE is a useful noninvasive test in HDV for determining cirrhosis despite the presence of significant hepatic inflammation.
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Affiliation(s)
- Ben L. Da
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Varun Takyar
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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37
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Anastasiou OE, Wedemeyer H. Hepatitis D. LIVER IMMUNOLOGY 2020:287-298. [DOI: 10.1007/978-3-030-51709-0_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Palom A, Rodríguez-Tajes S, Navascués CA, García-Samaniego J, Riveiro-Barciela M, Lens S, Rodríguez M, Esteban R, Buti M. Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia. Aliment Pharmacol Ther 2020; 51:158-166. [PMID: 31721254 DOI: 10.1111/apt.15521] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/14/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)-RNA on disease progression and interferon treatment in a real-world cohort has been barely explored. AIM To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV-RNA METHODS: Multicentre study at four academic hospitals in Spain included anti-HDV-positive patients with compensated liver disease with a follow-up ≥12 months. RESULTS Among 2888 HBsAg-positive subjects, 151 (5.2%) tested positive for anti-HDV, and 118 were included (58% men; median age, 49 years; 73% detectable HDV-RNA and 30% cirrhosis, most often in subjects with HDV-RNA). After a median follow-up of 8 years, subjects with initially detectable HDV-RNA were more prone to developing cirrhosis (31% vs 0%, P = .002) and/or liver decompensation (28% vs 3%, P = .019). Mortality rate was 0.44 per 1000 person-months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline-event-anticipation score. HDV-RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P = .29). Liver decompensation was reduced in interferon-treated patients (13% vs 38%, P = .026). CONCLUSIONS Subjects with persistently positive HDV-RNA had a worse prognosis in terms of clinical events. Baseline-event-anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.
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Affiliation(s)
- Adriana Palom
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Sergio Rodríguez-Tajes
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Carmen A Navascués
- Liver Unit, Division of Gastroenterology & Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Javier García-Samaniego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.,Hepatology Unit, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Manuel Rodríguez
- Liver Unit, Division of Gastroenterology & Hepatology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Rafael Esteban
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Da BL, Surana P, Kleiner DE, Heller T, Koh C. The Delta-4 fibrosis score (D4FS): A novel fibrosis score in chronic hepatitis D. Antiviral Res 2019; 174:104691. [PMID: 31837393 DOI: 10.1016/j.antiviral.2019.104691] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 12/04/2019] [Accepted: 12/10/2019] [Indexed: 01/04/2023]
Abstract
BACKGROUND Chronic Hepatitis D virus (HDV) infection results in the most severe form of viral hepatitis with a rapid progression to cirrhosis. However, non-invasive fibrosis tests that can accurately predict cirrhosis have not been adequately validated. We aimed to develop a clinically useful non-invasive score that can accurately detect cirrhosis. MATERIAL AND METHODS Patients with chronic HDV diagnosed by liver histology or serum PCR were evaluated. Data regarding demographics, laboratory, imaging, vibration-controlled transient elastography (VCTE), and liver biopsy were collected. The total cohort was randomized into a training and validation cohort. The training cohort was used to develop a novel score, the Delta-4 fibrosis score (D4FS) which was then compared to other non-invasive tests in the validation cohort by area under receiver operating characteristics (AUROC). RESULTS 77 patients with chronic HDV were evaluated: mean age 42.6 (SD:11.1) years, 59.7% male, and 57.1% Asian. The total cohort was then separated into a training (n = 45) and validation (n = 32) cohort with no significant differences in terms of clinical characteristics between the two. From the training cohort, the D4FS was derived from variables of statistical and clinical interest (gamma-glutamyl transpeptidase (GGT), platelet count, alanine aminotransferase (ALT), and liver stiffness measurement (LSM)). The D4FS demonstrated the best AUROC in the validation cohort (0.94) followed by VCTE (0.90), FIB-4 (0.86), APRI (0.81), and AAR (0.71). DISCUSSION The D4FS is a clinically useful non-invasive fibrosis score that can accurately detect cirrhosis in patients with chronic HDV infection. Further studies should be performed to further validate clinical utility.
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Affiliation(s)
- Ben L Da
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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Gilman C, Heller T, Koh C. Chronic hepatitis delta: A state-of-the-art review and new therapies. World J Gastroenterol 2019; 25:4580-4597. [PMID: 31528088 PMCID: PMC6718034 DOI: 10.3748/wjg.v25.i32.4580] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 07/03/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.
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MESH Headings
- Antiviral Agents/pharmacology
- Antiviral Agents/therapeutic use
- Coinfection/drug therapy
- Coinfection/epidemiology
- Coinfection/virology
- Drug Therapy, Combination/methods
- Global Burden of Disease
- Hepatitis B Surface Antigens/immunology
- Hepatitis B Surface Antigens/metabolism
- Hepatitis B virus/immunology
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/epidemiology
- Hepatitis B, Chronic/virology
- Hepatitis D, Chronic/drug therapy
- Hepatitis D, Chronic/epidemiology
- Hepatitis D, Chronic/virology
- Hepatitis Delta Virus/immunology
- Hepatitis Delta Virus/pathogenicity
- Humans
- Interferon-alpha/pharmacology
- Interferon-alpha/therapeutic use
- Lipopeptides/pharmacology
- Lipopeptides/therapeutic use
- Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors
- Organic Anion Transporters, Sodium-Dependent/metabolism
- Piperidines/pharmacology
- Piperidines/therapeutic use
- Pyridines/pharmacology
- Pyridines/therapeutic use
- Randomized Controlled Trials as Topic
- Review Literature as Topic
- Superinfection/drug therapy
- Superinfection/epidemiology
- Superinfection/virology
- Symporters/antagonists & inhibitors
- Symporters/metabolism
- Therapies, Investigational/methods
- Treatment Outcome
- Virus Assembly/drug effects
- Virus Internalization/drug effects
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Affiliation(s)
- Christy Gilman
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
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Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, Gane EJ, Gish RG, Glenn JS, Hamid S, Heller T, Koh C, Lampertico P, Lurie Y, Manns M, Parana R, Rizzetto M, Urban S, Wedemeyer H. Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy. J Hepatol 2019; 70:1008-1015. [PMID: 30982526 DOI: 10.1016/j.jhep.2018.12.022] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 12/18/2018] [Accepted: 12/20/2018] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, Ankara University, Ankara, and Department of Internal Medicine, Koc University, Istanbul, Turkey.
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Maria Buti
- Liver Unit, Hospital Universitario Vall d'Hebron and Ciber-ehd, Instituto Carlos III, Barcelona, Spain
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Rafael Esteban
- Liver Unit, Hospital Universitario Vall d'Hebron and Ciber-ehd, Instituto Carlos III, Barcelona, Spain
| | - Ohad Etzion
- Institute of Gastroenterology and Liver Diseases Soroka University Medical Center Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
| | | | - Robert G Gish
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Jeffrey S Glenn
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA
| | - Saeed Hamid
- Aga Khan University Hospital, Department of Medicine, Karachi, Pakistan
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pietro Lampertico
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Yoav Lurie
- Central Virology Laboratory, Ministry of Health, Chaim Sheba Medical Center, Tel - Hashomer, 52621 Ramat Gan, Israel
| | - Michael Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Raymundo Parana
- Hepatology Centre of the University Hospital Professor Edgar Santos, Federal University of Bahia, Salvador, Brazil
| | - Mario Rizzetto
- Department of Gastroenterology, University of Turin, Turin, Italy
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
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Coffin CS, Fung SK, Alvarez F, Cooper CL, Doucette KE, Fournier C, Kelly E, Ko HH, Ma MM, Martin SR, Osiowy C, Ramji A, Tam E, Villeneuve JP. Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada. CANADIAN LIVER JOURNAL 2018; 1:156-217. [PMID: 35992619 PMCID: PMC9202759 DOI: 10.3138/canlivj.2018-0008] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 08/01/2023]
Abstract
Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.
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Affiliation(s)
- Carla S. Coffin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta
| | - Scott K. Fung
- Faculty of Medicine, University of Toronto, Toronto, Ontario
| | - Fernando Alvarez
- Centre hospitalier de l’université de Montréal (CHUM)—CHU Sainte-Justine, Montreal, Québec
| | - Curtis L. Cooper
- Division of Infectious Diseases, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Karen E. Doucette
- Division of Infectious Diseases, University of Alberta, Edmonton, Alberta
| | - Claire Fournier
- Department of Medicine, Université de Montréal, Montreal, Québec
| | - Erin Kelly
- Division of Gastroenterology, Department of Medicine, University of Ottawa, Ottawa, Ontario
| | - Hin Hin Ko
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia
| | - Mang M Ma
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta
| | | | - Carla Osiowy
- Viral Hepatitis and Bloodborne Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba
| | - Alnoor Ramji
- St. Paul’s Hospital, Vancouver, British Columbia
| | - Edward Tam
- LAIR Centre, Vancouver, British Columbia
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Lutterkort GL, Wranke A, Hengst J, Yurdaydin C, Stift J, Bremer B, Hardtke S, Keskin O, Idilman R, Manns MP, Dienes HP, Falk C, Wedemeyer H, Heidrich B. Viral dominance patterns in chronic hepatitis delta determine early response to interferon alpha therapy. J Viral Hepat 2018; 25:1384-1394. [PMID: 29888837 DOI: 10.1111/jvh.12947] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 04/30/2018] [Indexed: 12/17/2022]
Abstract
Chronic hepatitis D is caused by coinfection of hepatitis B and hepatitis D virus. While HDV is the dominant virus over HBV in the majority of cases, mechanisms and consequences of viral dominance are largely unknown. We aimed to investigate associations between viral dominance patterns and patients' characteristics and inflammatory features; 109 HDV-infected patients treated with PEG-IFNa-2α within the international multicentre, prospective HIDIT-2 trial were studied. Patients were classified as D- or B-dominant if the viral load of one virus exceeded that of the other virus by more than 1log10 . Otherwise, no viral dominance (ND) was described. We used Luminex-based multiplex technology to study 50 soluble immune mediators (SIM) in pretreatment samples of 105 HDV RNA-positive patients. Dominance of HDV was evident in the majority (75%) of cases. While only 7% displayed B-dominance, 17% showed nondominance. D-dominance was associated with downregulation of 4 interleukins (IL-2ra, IL-13, IL-16 and IL-18) and 5 chemokines/cytokines (CTACK (CCL27), MCP-1 (CCL2), M-CSF, TRAIL and ICAM-1) while no analyte was increased. In addition, D-dominance could be linked to a delayed HDV RNA response to pegylated interferon as patients with B-dominance or nondominance showed higher early HDV RNA responses (61% at week 12) than D-dominant patients (11%; P < .001). In conclusion, this study revealed unexpected effects of viral dominance on clinical and immunological features in chronic hepatitis delta patients. Individualizing PEG-IFNa-2α treatment duration should consider viral dominance. Overall, our findings suggest an activated but exhausted IFN system in D-dominant patients.
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Affiliation(s)
- G L Lutterkort
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - A Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - J Hengst
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - C Yurdaydin
- Department of Gastroenterology, Ankara University Medical Faculty, Ankara, Turkey
| | - J Stift
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - B Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - S Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research (DZIF), partner site Hannover-Braunschweig, HepNet Study-House, Hannover, Germany
| | - O Keskin
- Department of Gastroenterology, Ankara University Medical Faculty, Ankara, Turkey
| | - R Idilman
- Department of Gastroenterology, Ankara University Medical Faculty, Ankara, Turkey
| | - M P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research (DZIF), partner site Hannover-Braunschweig, HepNet Study-House, Hannover, Germany
| | - H P Dienes
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - C Falk
- Institute of Transplant Immunology, Hannover Medical School, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover, Germany
| | - H Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research (DZIF), partner site Hannover-Braunschweig, HepNet Study-House, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany
| | - B Heidrich
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infectious Disease Research (DZIF), partner site Hannover-Braunschweig, HepNet Study-House, Hannover, Germany
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44
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Ricco G, Popa DC, Cavallone D, Iacob S, Salvati A, Tabacelia D, Oliveri F, Mascolo G, Bonino F, Yuan Q, Xia NS, Gheorghe L, Brunetto MR. Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection. J Viral Hepat 2018; 25:911-919. [PMID: 29577518 DOI: 10.1111/jvh.12895] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/28/2018] [Indexed: 12/31/2022]
Abstract
The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross-sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti-HIV-negative patients (71 males; median age 49.8 [21.7-66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV-DNA, HBcrAg, total anti-HBc, HDV-RNA, IgM and total anti-HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti-HBc/IgM anti-HDV ratio (OR 0.990, 95% CI 0.981-0.999, P = .038), whereas disease activity was associated with higher total anti-HDV (OR 10.105, 95% CI 1.671-61.107, P = .012) and HDV-RNA levels (OR 2.366, 95% CI 1.456-3.844, P = .001). HDV-RNA serum levels showed a positive correlation with HBV-DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV-RNA, IgM anti-HDV, total anti-HDV, total anti-HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.
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Affiliation(s)
- G Ricco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - D C Popa
- Department of Biochemistry, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Bone Marrow Transplant Laboratory, Fundeni Clinical Institute, Bucharest, Romania
| | - D Cavallone
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - S Iacob
- Department of Gastroenterology and Hepatology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Center for Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - A Salvati
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - D Tabacelia
- Center for Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - F Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - G Mascolo
- Dia.Pro Diagnostic Bioprobes Srl, Sesto San Giovanni, Milan, Italy
| | - F Bonino
- University of Pittsburgh Medical Center (UPMC) Institute for Health, Chianciano Terme, Siena and Fondazione Italiana Fegato (FIF), AREA Science Park, Trieste, Italy
| | - Q Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - N-S Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - L Gheorghe
- Department of Gastroenterology and Hepatology, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Center for Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - M R Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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45
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Couto I, Victoria M, Veloso VG, Rodrigues L, Grinsztejn B, Lacerda M, Victoria F, Perazzo H. Prevalence and predictors for compensated Advanced Chronic Liver Disease (c-ACLD) in patients with chronic Hepatitis Delta Virus (HDV) infection. PLoS One 2017; 12:e0174453. [PMID: 28329027 PMCID: PMC5362235 DOI: 10.1371/journal.pone.0174453] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 03/09/2017] [Indexed: 02/07/2023] Open
Abstract
Objective The study aimed to evaluate the prevalence and predictor factors for compensated advanced chronic liver disease (c-ACLD) in patients with hepatitis Delta virus (HDV) infection. Methods This cross-sectional study included consecutive HDV-infected patients defined by positive anti-HDV. Patients with hepatitis C coinfection, liver transplantation or presence of conditions that limit liver (LSM) or spleen stiffness measurement (SSM) were excluded. Blood tests, abdominal ultrasound, SSM and LSM by transient elastography (FibroScan®) were performed at the same day. Alcohol consumption was quantified using the AUDIT score and c-ACLD was defined by LSM ≥ 15 kPa performed by an experimented operator blinded for clinical and laboratory data. Results 101 patients were eligible and few patients were excluded due to negative anti-HDV (n = 7), hepatitis C coinfection (n = 2), liver transplantation (n = 10) and limitation for LSM or SSM (n = 5). Therefore, 77 patients [61% male, age = 43 (IQR,36–52) years] were included. The prevalence of c-ACLD was 57% (n = 44/77). Patients with c-ACLD had a higher rate of detectable HBV viral load (p = 0.039), higher levels of transaminases, GGT, alkaline phosphatases, total bilirubin and INR (p<0.001 for all), as well as lower platelet count and albumin levels (p>0.001 for both) compared to those without c-ACLD. Patients with c-ACLD had higher SSM [65.2 (IQR,33.8–75.0) vs 21.8 (16.5–32.0) kPa; p<0.001] and higher splenic volume [475 (IQR,311–746) vs 154 (112–283) cm3; p<0.001] compared to those without. Detectable HBV viral load (>10 UI/ml), alkaline phosphatase (per IU/L) and GGT levels (per IU/L) were independently associated with c-ACLD in all multivariate models. Splenic volume [per cm3,OR = 1.01 (95%CI,1.01–1.02);p = 0.002], SSM [per kPa, OR = 1.04 (1.01–1.07);p = 0.012] and splenomegaly [yes vs no,OR = 28.45 (4.42–182.95);p<0.001] were independently associated with c-ACLD. Conclusions The prevalence of c-ACLD was high in patients with chronic HDV infection in western Amazon basin. HBV viral load, liver enzymes and splenic features can be used to predict severe liver disease in HDV-infected patients.
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Affiliation(s)
- Ingrid Couto
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT HVD), Manaus, Amazonas, Brazil
| | - Marilu Victoria
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT HVD), Manaus, Amazonas, Brazil
| | - Valdiléa G. Veloso
- Laboratório de Pesquisa Clínica em DST/AIDS (LAPCLIN-AIDS), Instituto Nacional de Infectologia Evandro Chagas - Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil
| | - Lorena Rodrigues
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT HVD), Manaus, Amazonas, Brazil
| | - Beatriz Grinsztejn
- Laboratório de Pesquisa Clínica em DST/AIDS (LAPCLIN-AIDS), Instituto Nacional de Infectologia Evandro Chagas - Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil
| | - Marcus Lacerda
- Diretoria de Ensino e Pesquisa, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT HVD), Manaus, Brazil
- Instituto de Pesquisas Leônidas & Maria Deane - Fundação Oswaldo Cruz (FIOCRUZ), Manaus, Brazil
| | - Flamir Victoria
- Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT HVD), Manaus, Amazonas, Brazil
| | - Hugo Perazzo
- Laboratório de Pesquisa Clínica em DST/AIDS (LAPCLIN-AIDS), Instituto Nacional de Infectologia Evandro Chagas - Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil
- * E-mail: ,
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Takyar V, Koh C. Letter: need to re-evaluate non-invasive markers for staging fibrosis in chronic delta hepatitis - authors' reply. Aliment Pharmacol Ther 2017; 45:575-576. [PMID: 28074516 PMCID: PMC5240045 DOI: 10.1111/apt.13898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Varun Takyar
- Liver Diseases Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Maryland, USA
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Takyar V, Surana P, Kleiner DE, Wilkins K, Hoofnagle JH, Liang TJ, Heller T, Koh C. Noninvasive markers for staging fibrosis in chronic delta hepatitis. Aliment Pharmacol Ther 2017; 45:127-138. [PMID: 27813124 PMCID: PMC5135658 DOI: 10.1111/apt.13834] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 08/21/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Serum fibrosis markers are useful in staging chronic hepatitis B (HBV) and C (HCV) virus but have not been evaluated in chronic hepatitis D virus (HDV). AIM To evaluate the utility of serum fibrosis markers [fibrosis-4 score (FIB-4), aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, aspartate aminotransferase ratio (AAR), age-platelet index (API), AST-to-platelet-ratio-index (APRI) and Hui score] in HDV infection. METHODS Clinical and histologic laboratory data from HBV, HCV and HDV patients were evaluated and serum fibrosis markers were calculated. The ability of fibrosis markers to detect advanced fibrosis (Ishak ≥4) and cirrhosis (Ishak = 6) were evaluated and compared between viral infections. RESULTS A total of 1003 subjects (HCV = 701, HBV = 240 and HDV = 62) with mean age of 46 ± 11 and 66% male were evaluated. HDV subjects had higher ALT and AST than HCV and lower platelets than both HBV and HCV. Histologically, HDV had the greatest percentage of Ishak ≥4 and necroinflammation. FIB-4 performed best in detecting advanced fibrosis and cirrhosis in all viral cohorts. In HDV, area under the receiver operator curve (AUROC) 95% confidence intervals for detecting advanced fibrosis were: FIB-4 = 0.70 (0.55-0.84), API = 0.69 (0.55-0.82), APRI = 0.68 (0.54-0.82), Hui score = 0.63 (0.49-0.78), AAR = 0.63 (0.48-0.77). The AUROC for detecting cirrhosis in HDV were: FIB-4 = 0.83 (0.69-0.97), API = 0.80 (0.66-0.95), APRI = 0.75 (0.61-0.89), Hui score = 0.70 (0.49-0.91) and AAR = 0.70 (0.48-0.93). Adjustment of published cut-offs led to marginal improvements in FIB4 for advanced fibrosis and of APRI for cirrhosis in HDV. CONCLUSIONS Serum fibrosis markers have lower performance accuracy in chronic HDV infected patients compared to HBV and HCV patients. Other noninvasive fibrosis markers should be explored to assist in the management of these patients.
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Affiliation(s)
- Varun Takyar
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Pallavi Surana
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Kenneth Wilkins
- Office of the Director, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jay H. Hoofnagle
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Wranke A, Wedemeyer H. Antiviral therapy of hepatitis delta virus infection - progress and challenges towards cure. Curr Opin Virol 2016; 20:112-118. [PMID: 27792905 DOI: 10.1016/j.coviro.2016.10.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 10/03/2016] [Accepted: 10/10/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis B-/D-virus co-infection causes the most severe form of viral hepatitis, frequently leading to liver cirrhosis, hepatic decompensation and consecutive liver-related mortality. Treatment options for hepatitis delta are limited. The only recommended therapy is pegylated interferon alpha which leads to virological responses in about 25-30% of patients. However, interferon therapy is associated with frequent side-effects and late HDV RNA relapses have been described during long-term follow even in patients who were HDV RNA negative 24 weeks after the end of therapy. Thus, alternative treatment options are urgently needed. Clinical studies have been performed exploring prenylation inhibitors, viral entry inhibitors and nucleic acid polymers to block particle release. We here summarize the progress and challenges towards cure of HDV infection.
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Affiliation(s)
- Anika Wranke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Side HepNet Study-House, Hannover, Germany; HepNet Study-House, Hannover, Germany; Integrated Research and Treatment Center Transplantation, Hannover Medical School, Germany.
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