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Sandmann L, Windzio L, Bremer B, Falak S, Beheim‐Schwarzbach J, Kummrow A, Cornberg M, Wedemeyer H, Maasoumy B, Valiente E. Droplet Digital PCR: A Powerful Tool for Accurate Quantification of Hepatitis D Virus RNA Levels and Verification of Detection Limits. J Viral Hepat 2025; 32:e70036. [PMID: 40372088 PMCID: PMC12080313 DOI: 10.1111/jvh.70036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/19/2025] [Accepted: 05/06/2025] [Indexed: 05/16/2025]
Abstract
Reliable quantification of hepatitis D virus (HDV) RNA levels is necessary for initiating and guiding antiviral treatment. The aim of this work is to develop and validate a digital PCR method for the accurate quantification of HDV RNA, including evaluation of its clinical accuracy, especially for low-concentrated clinical samples. The reverse transcription digital PCR (RT-dPCR) development followed the standard procedure, including primer design, determination of linearity, calculation of recovery and the intermediate precision of the RNA extraction kits, determination of the limit of detection (LOD) and quantification (LOQ), droplet size measurements, conversion factor, and uncertainty budget. The World Health Organisation (WHO)-HDV international standard was used for RT-dPCR development. Commutability of the new method was explored, comparing RT-dPCR with quantification assays applied in clinical routine using clinical plasma samples covering a range of HDV RNA concentrations. The conversion factor from copies/mL to IU/mL was 0.77. LOD and LOQ of the RT-dPCR were 0.7 copies/mL (0.56 IU/mL) and 10 copies/mL (8 IU/mL), respectively. When evaluating the qualitative results of the clinical HDV samples at low concentrations, 31% of the HDV clinical samples tested negative by RT-qPCR were tested positive by RT-dPCR. The RT-qPCR and RT-dPCR quantitative data showed a good correlation with a standard deviation of ±1.12 log IU/mL. RT-dPCR is an accurate method for HDV RNA quantification that may serve as a complement to RT-qPCR, especially when accurate detection is essential for decision making in clinical settings.
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Affiliation(s)
- L. Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
- Excellence Cluster RESISTExcellence Initiative Hannover Medical SchoolHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No. 101057917)HannoverGermany
| | - L. Windzio
- Department 8.3, Biomedical OpticsPhysikalisch‐Technische BundesanstaltBerlinGermany
| | - B. Bremer
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
| | - S. Falak
- Department 8.3, Biomedical OpticsPhysikalisch‐Technische BundesanstaltBerlinGermany
| | | | - A. Kummrow
- Department 8.3, Biomedical OpticsPhysikalisch‐Technische BundesanstaltBerlinGermany
| | - M. Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No. 101057917)HannoverGermany
- German Center for Infection Research (DZIF)Hannover‐BraunschweigGermany
- Center for Individualised Infection Medicine (CiiM)Hannover Medical School/Helmholtz CenterHannoverGermany
| | - H. Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
- Excellence Cluster RESISTExcellence Initiative Hannover Medical SchoolHannoverGermany
- D‐SOLVE Consortium, an EU Horizon Europe Funded Project (No. 101057917)HannoverGermany
- German Center for Infection Research (DZIF)Hannover‐BraunschweigGermany
| | - B. Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and EndocrinologyHannover Medical SchoolHannoverGermany
- German Center for Infection Research (DZIF)Hannover‐BraunschweigGermany
| | - E. Valiente
- Department 8.3, Biomedical OpticsPhysikalisch‐Technische BundesanstaltBerlinGermany
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Jargalsaikhan O, Shao W, Ichimura-Shimizu M, Ishimaru S, Koma T, Nomaguchi M, Ogawa H, Tachibana S, Chimeddorj B, Batchuluun K, Tseveenjav A, Magvan B, Enkhbat B, Lkhagvadorj S, Mendjargal A, Ganbaatar L, Irahara M, Akaike M, Boldbaatar D, Tsuneyama K. Histopathological Features of Hepatocellular Carcinoma in Patients with Hepatitis B and D Virus Infection: A Single-Institution Study in Mongolia. Cancers (Basel) 2025; 17:432. [PMID: 39941800 PMCID: PMC11815750 DOI: 10.3390/cancers17030432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/16/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
Background: Viral hepatitis, particularly hepatitis B (HBV) and hepatitis C (HCV), is highly prevalent in Mongolia. Moreover, Mongolia has the highest prevalence of hepatitis delta virus (HDV) globally, with over 60% of HBV-infected individuals also co-infected with HDV. Since HBV/HDV infections accelerate liver disease progression more compared to HBV infection alone, urgent national health measures are required. Method: This study presents a clinicopathological analysis of 49 hepatocellular carcinoma cases surgically resected at the Mongolia-Japan Hospital of the Mongolian National University of Medical Sciences. Results: HBV infection was found in 27 (55.1%) cases of all HCC cases. Immunohistochemical staining of the liver revealed that 14 (28.6%) cases were HDV antigen-positive in the HCC cases. HDV-positive cases exhibited significantly higher inflammatory activity compared to HDV-negative cases, with lymphocytic infiltrates predominantly composed of CD4-positive cells. Furthermore, HDV-positive cells were spatially distinct from HBs antigen-positive cells, suggesting that HDV-infected cells may interfere with HBV replication. No significant differences in fibrosis or in tumor characteristics were observed between the HDV-positive and negative cases. Early diagnosis of HBV/HDV infections is essential for appropriate treatment and to prevent further domestic transmission of the virus. However, routine testing for HDV infection is rarely conducted in Mongolia. Since HDV-positive cells are morphologically indistinguishable from surrounding HDV-negative cells, routine histopathological analysis may not be sufficient enough to detect HDV infection. Conclusions: Based on this clinicopathological study, CD4 and CD8 immunostaining can be considered an adjunctive diagnostic tool in cases with significant lymphocytic infiltration and hepatocellular damage. Additionally, HDV screening using blood and tissue samples may be recommended to ensure accurate diagnosis.
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Affiliation(s)
- Orgil Jargalsaikhan
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
| | - Wenhua Shao
- Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan;
| | - Mayuko Ichimura-Shimizu
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
| | - Soichiro Ishimaru
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
| | - Takaaki Koma
- Department of Microbiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (T.K.); (M.N.)
| | - Masako Nomaguchi
- Department of Microbiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (T.K.); (M.N.)
| | - Hirohisa Ogawa
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
| | - Shotaro Tachibana
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
| | - Battogtokh Chimeddorj
- Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (K.B.); (A.T.)
- Department of Microbiology and Infection Prevention Control, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia;
| | - Khongorzul Batchuluun
- Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (K.B.); (A.T.)
| | - Anujin Tseveenjav
- Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (K.B.); (A.T.)
| | - Battur Magvan
- Department of Microbiology and Infection Prevention Control, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia;
| | - Bayarmaa Enkhbat
- Department of Pathology and Forensic Medicine, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (B.E.); (S.L.)
| | - Sayamaa Lkhagvadorj
- Department of Pathology and Forensic Medicine, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (B.E.); (S.L.)
- Surgery Department, Mongolia–Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (A.M.); (L.G.)
| | - Adilsaikhan Mendjargal
- Surgery Department, Mongolia–Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (A.M.); (L.G.)
| | - Lkhagvadulam Ganbaatar
- Surgery Department, Mongolia–Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (A.M.); (L.G.)
| | - Minoru Irahara
- Department of Obstetrics and Gynecology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan;
| | - Masashi Akaike
- Department of Medical Education, Graduate School of Biomedical Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan;
| | - Damdindorj Boldbaatar
- Department of Physiology, School of Bio-Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia;
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan; (O.J.); (S.I.); (H.O.); (S.T.); (K.T.)
- Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan;
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Lombardo D, Franzè MS, Caminiti G, Pollicino T. Hepatitis Delta Virus and Hepatocellular Carcinoma. Pathogens 2024; 13:362. [PMID: 38787214 PMCID: PMC11124437 DOI: 10.3390/pathogens13050362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/25/2024] Open
Abstract
The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.
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Affiliation(s)
| | | | | | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University Hospital of Messina, 98124 Messina, Italy; (D.L.); (M.S.F.); (G.C.)
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Acchioni C, Sandini S, Acchioni M, Sgarbanti M. Co-Infections and Superinfections between HIV-1 and Other Human Viruses at the Cellular Level. Pathogens 2024; 13:349. [PMID: 38787201 PMCID: PMC11124504 DOI: 10.3390/pathogens13050349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Co-infection or superinfection of the host by two or more virus species is a common event, potentially leading to viral interference, viral synergy, or neutral interaction. The simultaneous presence of two or more viruses, even distantly related, within the same cell depends upon viral tropism, i.e., the entry of viruses via receptors present on the same cell type. Subsequently, productive infection depends on the ability of these viruses to replicate efficiently in the same cellular environment. HIV-1 initially targets CCR5-expressing tissue memory CD4+ T cells, and in the absence of early cART initiation, a co-receptor switch may occur, leading to the infection of naïve and memory CXCR4-expressing CD4+ T cells. HIV-1 infection of macrophages at the G1 stage of their cell cycle also occurs in vivo, broadening the possible occurrence of co-infections between HIV-1 and other viruses at the cellular level. Moreover, HIV-1-infected DCs can transfer the virus to CD4+ T cells via trans-infection. This review focuses on the description of reported co-infections within the same cell between HIV-1 and other human pathogenic, non-pathogenic, or low-pathogenic viruses, including HIV-2, HTLV, HSV, HHV-6/-7, GBV-C, Dengue, and Ebola viruses, also discussing the possible reciprocal interactions in terms of virus replication and virus pseudotyping.
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Affiliation(s)
| | | | | | - Marco Sgarbanti
- Department of Infectious Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy; (C.A.); (S.S.); (M.A.)
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Khalfi P, Denis Z, McKellar J, Merolla G, Chavey C, Ursic-Bedoya J, Soppa L, Szirovicza L, Hetzel U, Dufourt J, Leyrat C, Goldmann N, Goto K, Verrier E, Baumert TF, Glebe D, Courgnaud V, Gregoire D, Hepojoki J, Majzoub K. Comparative analysis of human, rodent and snake deltavirus replication. PLoS Pathog 2024; 20:e1012060. [PMID: 38442126 PMCID: PMC10942263 DOI: 10.1371/journal.ppat.1012060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 03/15/2024] [Accepted: 02/19/2024] [Indexed: 03/07/2024] Open
Abstract
The recent discovery of Hepatitis D (HDV)-like viruses across a wide range of taxa led to the establishment of the Kolmioviridae family. Recent studies suggest that kolmiovirids can be satellites of viruses other than Hepatitis B virus (HBV), challenging the strict HBV/HDV-association dogma. Studying whether kolmiovirids are able to replicate in any animal cell they enter is essential to assess their zoonotic potential. Here, we compared replication of three kolmiovirids: HDV, rodent (RDeV) and snake (SDeV) deltavirus in vitro and in vivo. We show that SDeV has the narrowest and RDeV the broadest host cell range. High resolution imaging of cells persistently replicating these viruses revealed nuclear viral hubs with a peculiar RNA-protein organization. Finally, in vivo hydrodynamic delivery of viral replicons showed that both HDV and RDeV, but not SDeV, efficiently replicate in mouse liver, forming massive nuclear viral hubs. Our comparative analysis lays the foundation for the discovery of specific host factors controlling Kolmioviridae host-shifting.
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Affiliation(s)
- Pierre Khalfi
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Zoé Denis
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Joe McKellar
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Giovanni Merolla
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Carine Chavey
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - José Ursic-Bedoya
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Department of hepato-gastroenterology, Hepatology and Liver Transplantation Unit, Saint Eloi University Hospital, Montpellier, France
| | - Lena Soppa
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF, Partner Site Giessen-Marburg-Langen), Justus Liebig University Giessen, Giessen, Germany
| | - Leonora Szirovicza
- Medicum, Department of Virology, University of Helsinki, Helsinki, Finland
| | - Udo Hetzel
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Jeremy Dufourt
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR9004, Montpellier, France
| | - Cedric Leyrat
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Nora Goldmann
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF, Partner Site Giessen-Marburg-Langen), Justus Liebig University Giessen, Giessen, Germany
| | - Kaku Goto
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Eloi Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Dieter Glebe
- Institute of Medical Virology, National Reference Centre for Hepatitis B Viruses and Hepatitis D Viruses, German Center for Infection Research (DZIF, Partner Site Giessen-Marburg-Langen), Justus Liebig University Giessen, Giessen, Germany
| | - Valérie Courgnaud
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Damien Gregoire
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
| | - Jussi Hepojoki
- Medicum, Department of Virology, University of Helsinki, Helsinki, Finland
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
| | - Karim Majzoub
- Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
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Ferrante ND, Kallan MJ, Sukkestad S, Kodani M, Kitahata MM, Cachay ER, Bhattacharya D, Heath S, Napravnik S, Moore RD, Yendewa G, Mayer KH, Reddy KR, Hayden T, Kamili S, Martin JN, Kim HN, Lo Re V. Prevalence and determinants of hepatitis delta virus infection among HIV/hepatitis B-coinfected adults in care in the United States. J Viral Hepat 2023; 30:879-888. [PMID: 37488783 PMCID: PMC10592429 DOI: 10.1111/jvh.13874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 07/07/2023] [Indexed: 07/26/2023]
Abstract
Hepatitis delta virus (HDV) infection increases the risk of liver complications compared to hepatitis B virus (HBV) alone, particularly among persons with human immunodeficiency virus (HIV). However, no studies have evaluated the prevalence or determinants of HDV infection among people with HIV/HBV in the US. We performed a cross-sectional study among adults with HIV/HBV coinfection receiving care at eight sites within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) between 1996 and 2019. Among patients with available serum/plasma specimens, we selected the first specimen on or after their initial HBV qualifying test. All samples were tested for HDV IgG antibody and HDV RNA. Multivariable log-binomial generalized linear models were used to estimate prevalence ratios (PRs) with 95% CIs of HDV IgG antibody-positivity associated with determinants of interest (age, injection drug use [IDU], high-risk sexual behaviour). Among 597 adults with HIV/HBV coinfection in CNICS and available serum/plasma samples (median age, 43 years; 89.9% male; 52.8% Black; 42.4% White), 24/597 (4.0%; 95% CI, 2.4%-5.6%) were HDV IgG antibody-positive, and 10/596 (1.7%; 95% CI, 0.6%-2.7%) had detectable HDV RNA. In multivariable analysis, IDU was associated with exposure to HDV infection (adjusted PR = 2.50; 95% CI, 1.09-5.74). In conclusion, among a sample of adults with HIV/HBV coinfection in care in the US, 4.0% were HDV IgG antibody-positive, among whom 41.7% had detectable HDV RNA. History of IDU was associated with exposure to HDV infection. These findings emphasize the importance of HDV testing among persons with HIV/HBV coinfection, especially those with a history of IDU.
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Affiliation(s)
- Nicole D. Ferrante
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
| | - Michael J. Kallan
- Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Sophia Sukkestad
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Maja Kodani
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Mari M. Kitahata
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - Edward R. Cachay
- Department of Medicine, Division of Infectious Diseases and Global Public Health University of California, San Diego, CA
| | - Debika Bhattacharya
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Sonya Heath
- Division of Infectious Disease, Department of Medicine, University of Alabama, Birmingham, AL
| | - Sonia Napravnik
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Richard D. Moore
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD
| | - George Yendewa
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Kenneth H. Mayer
- The Fenway Institute, Fenway Health, Boston, MA; Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
| | - K. Rajender Reddy
- Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Tonya Hayden
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA
| | - Jeffrey N. Martin
- Department of Epidemiology and Biostatistics, University of California, San Francisco, CA
| | - H. Nina Kim
- Division of Allergy and Infectious Disease, Department of Medicine, University of Washington School of Medicine, Seattle, WA
| | - Vincent Lo Re
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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7
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Mateo R, Xu S, Shornikov A, Yazdi T, Liu Y, May L, Han B, Han D, Martin R, Manhas S, Richards C, Marceau C, Aeschbacher T, Chang S, Manuilov D, Hollnberger J, Urban S, Asselah T, Abdurakhmanov D, Lampertico P, Maiorova E, Mo H. Broad-spectrum activity of bulevirtide against clinical isolates of HDV and recombinant pan-genotypic combinations of HBV/HDV. JHEP Rep 2023; 5:100893. [PMID: 37929228 PMCID: PMC10622701 DOI: 10.1016/j.jhepr.2023.100893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 11/07/2023] Open
Abstract
Background & Aims Bulevirtide (BLV) is a small lipopeptide agent that specifically binds to the sodium taurocholate cotransporting polypeptide (NTCP) bile salt transporter and HBV/HDV receptor on the surface of human hepatocytes and inhibits HDV and HBV entry. As a satellite virus of HBV, HDV virions are formed after assembly of HDV RNA with the HBV envelope proteins (HBsAg). Because both viruses exist as eight different genotypes, this creates a potential for high diversity in the HBV/HDV combinations. To investigate the sensitivity of various combinations of HBV/HDV genotypes to BLV, clinical and laboratory strains were assessed. Methods For the laboratory strains, the different envelopes from HBV genotypes A through H were combined with HDV genotypes 1-8 in cotransfection assays. Clinical plasma isolates were obtained from clinical studies and academic collaborations to maximise the diversity of HBV/HDV genotypes tested. Results The mean BLV EC50 against HDV laboratory strains ranged from 0.44 to 0.64 nM. Regardless of HBV and HDV genotypes, the clinical isolates showed similar sensitivities to BLV with mean values that ranged from 0.2 to 0.73 nM. Conclusions These data support the use of BLV in patients infected with any HBV/HDV genotypes. Impact and implications This study describes the potent activity of BLV against multiple laboratory strains spanning all HBV/HDV A-H/1-8 genotype combinations and the most diverse collection of HDV clinical samples tested to date, including HBV/HDV genotype combinations less frequently observed in the clinic. Overall, all isolates and laboratory strains displayed similar in vitro nanomolar sensitivity to BLV. This broad-spectrum antiviral activity of BLV has direct implications on potential simplified treatment for any patient infected with HDV, regardless of genotype, and supports the new 2023 EASL Clinical Practice Guidelines on HDV that recommend antiviral treatment for all patients with CHD.
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Affiliation(s)
| | - Simin Xu
- Gilead Sciences Inc., Foster City, CA, USA
| | | | | | - Yang Liu
- Gilead Sciences Inc., Foster City, CA, USA
| | | | - Bin Han
- Gilead Sciences Inc., Foster City, CA, USA
| | - Dong Han
- Gilead Sciences Inc., Foster City, CA, USA
| | | | | | | | | | | | | | | | - Julius Hollnberger
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Tarik Asselah
- Université de Paris-Cité, Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Hôpital Beaujon, Department of Hepatology, AP-HP, Clichy, France
| | | | - 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
| | | | - Hongmei Mo
- Gilead Sciences Inc., Foster City, CA, USA
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8
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Abdul Majeed N, Zehnder B, Koh C, Heller T, Urban S. Hepatitis delta: Epidemiology to recent advances in therapeutic agents. Hepatology 2023; 78:1306-1321. [PMID: 36738087 DOI: 10.1097/hep.0000000000000331] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 12/19/2022] [Indexed: 02/05/2023]
Abstract
Hepatitis D virus (HDV) was first described in 1977 and is dependent on the presence of hepatitis B surface antigen (HBsAg) for its entry into cells and on the human host for replication. Due to the envelopment with the hepatitis B virus (HBV) envelope, early phases of HDV entry resemble HBV infection. Unlike HBV, HDV activates innate immune responses. The global prevalence of HDV is estimated to be about 5% of HBsAg positive individuals. However, recent studies have described a wide range of prevalence between 12 to 72 million individuals. Infection can occur as super-infection or co-infection. The diagnosis of active HDV infection involves screening with anti HDV antibodies followed by quantitative PCR testing for HDV RNA in those who are HBsAg positive. The diagnostic studies have evolved over the years improving the validity and reliability of the tests performed. HDV infection is considered the most severe form of viral hepatitis and the HDV genotype may influence the disease course. There are eight major HDV genotypes with prevalence varying by geographic region. HDV treatment has been challenging as HDV strongly depends on the host cell for replication and provides few, if any viral targets. Better understanding of HDV virology has led to the development of several therapeutic agents currently being studied in different phase II and III clinical trials. There is increasing promise of effective therapies that will ameliorate the course of this devastating disease.
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Affiliation(s)
- Nehna Abdul Majeed
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Benno Zehnder
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research (DZIF) - Heidelberg Partner Site, Heidelberg, Germany
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9
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Hollnberger J, Liu Y, Xu S, Chang S, Martin R, Manhas S, Aeschbacher T, Han B, Yazdi T, May L, Han D, Shornikov A, Flaherty J, Manuilov D, Suri V, Asselah T, Lampertico P, Wedemeyer H, Aleman S, Richards C, Mateo R, Maiorova E, Cihlar T, Mo H, Urban S. No virologic resistance to bulevirtide monotherapy detected in patients through 24 weeks treatment in phase II and III clinical trials for chronic hepatitis delta. J Hepatol 2023; 79:657-665. [PMID: 37120031 DOI: 10.1016/j.jhep.2023.04.027] [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: 01/31/2023] [Revised: 04/14/2023] [Accepted: 04/16/2023] [Indexed: 05/01/2023]
Abstract
BACKGROUND & AIMS Bulevirtide (BLV) is a HDV/HBV entry inhibitor that is associated with virologic response (responders, HDV-RNA undetectable or ≥2 log10 IU/ml decrease from baseline) in >50% of patients after a 24-week treatment. However, some patients only achieve a <1 log10 IU/ml decline in HDV-RNA after the 24-week treatment (non-responders). Here, we report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., two consecutive increases in HDV-RNA of ≥1 log10 IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) from the phase II MYR202 and phase III MYR301 study. METHODS Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and Week 24 (WK24). RESULTS No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV n = 1; HDV n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log10 IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms. CONCLUSIONS No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment. IMPACT AND IMPLICATIONS This is the first study investigating the development of resistance in patients treated with BLV. Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed. Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry. CLINICAL TRIAL NUMBERS NCT03546621 and NCT03852719.
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Affiliation(s)
- Julius Hollnberger
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Yang Liu
- Gilead Sciences Inc., Foster City, California, USA.
| | - Simin Xu
- Gilead Sciences Inc., Foster City, California, USA
| | - Silvia Chang
- Gilead Sciences Inc., Foster City, California, USA
| | - Ross Martin
- Gilead Sciences Inc., Foster City, California, USA
| | | | | | - Bin Han
- Gilead Sciences Inc., Foster City, California, USA
| | | | - Lindsey May
- Gilead Sciences Inc., Foster City, California, USA
| | - Dong Han
- Gilead Sciences Inc., Foster City, California, USA
| | | | | | | | - Vithika Suri
- Gilead Sciences Inc., Foster City, California, USA
| | - Tarik Asselah
- Department of Hepatologi, Hôpital Beaujon, AP-HP, Université de Paris-Cité, INSERM UMR 1149, Clichy, France
| | - Pietro Lampertico
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Italy; "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Università degli Studi di Milano, Milan, Italy
| | | | - Soo Aleman
- Karolinska Universitetssjukhuset, Karolinska Institutet, Stockholm, Sweden
| | | | | | | | - Tomas Cihlar
- Gilead Sciences Inc., Foster City, California, USA
| | - Hongmei Mo
- Gilead Sciences Inc., Foster City, California, USA
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.
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10
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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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11
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Brancaccio G, Shanyinde M, Puoti M, Gaeta GB, Monforte AD, Vergori A, Rusconi S, Mazzarelli A, Castagna A, Antinori A, Cozzi-Lepri A. Hepatitis delta coinfection in persons with HIV: misdiagnosis and disease burden in Italy. Pathog Glob Health 2023; 117:181-189. [PMID: 35249472 PMCID: PMC9970224 DOI: 10.1080/20477724.2022.2047551] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
Hepatitis Delta virus (HDV) causes severe liver disease. Due to similarities in transmission routes, persons living with HIV (PLWH) are at risk of HDV infection. This analysis investigates the prevalence and the long-term clinical outcome of people with HDV in a large cohort of PLWH. We retrieved HBsAg ± anti-HDV positive PLWH enrolled from 1997 to 2015 in the multicentre, prospective ICONA study. The primary endpoint was a composite clinical outcome (CCO = having experienced ≥1 of the following: Fib4 score >3.25; diagnosis of cirrhosis; decompensation; hepatocellular carcinoma or liver-related death). Kaplan-Meier curves and unweighted and weighted Cox regression models were used for data analysis. Less than half of HBsAg positive patients had been tested for anti-HDV in clinical practice. After testing stored sera, among 617 HBV/HIV cases, 115 (19%) were anti-HDV positive; 405 (65%) HBV monoinfected; 99 (16%) undeterminate. The prevalence declined over the observation period. HDV patients were more often males, intravenous drug users, HCV coinfected. After a median of 26 months, 55/115 (48%) developed CCO among HDV+; 98/403 (24%) among HBV monoinfected; 18/99 (18%) in HDV unknown (p < 0.001). After controlling for geographical region, alcohol consumption, CD4 count, anti-HCV status and IFN-based therapies, the association with HDV retained statistical significance [HR = 1.67 (1.15, 2.95; p = 0.025)]. HDV infection among PLWH is underdiagnosed, although HDV entails an high risk of liver disease progression. Because effective drugs to treat HDV are now available, it is even more crucial to identify PLWH at an early stage of liver disease.
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Affiliation(s)
| | - Milensu Shanyinde
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Massimo Puoti
- Infectious Diseases, Hospital Niguarda, Milan, Italy
| | - Giovanni B Gaeta
- Department of Mental and Physical Health and Preventive Medicine, University L. Vanvitelli, Naples, Italy
| | | | - Alessandra Vergori
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
| | - Stefano Rusconi
- UOC Malattie Infettive, Ospedale Civile di Legnano, ASST Ovest Milanese, Legnano, Italy
| | - Antonio Mazzarelli
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
| | | | - Andrea Antinori
- Infectious Diseases, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy
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12
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Fallon BS, Cooke EM, Hesterman MC, Norseth JS, Akhundjanov SB, Weller ML. A changing landscape: Tracking and analysis of the international HDV epidemiology 1999-2020. PLOS GLOBAL PUBLIC HEALTH 2023; 3:e0000790. [PMID: 37098008 PMCID: PMC10129014 DOI: 10.1371/journal.pgph.0000790] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 03/09/2023] [Indexed: 04/26/2023]
Abstract
The international epidemiology of Hepatitis Delta Virus (HDV) is challenging to accurately estimate due to limited active surveillance for this rare infectious disease. Prior HDV epidemiological studies have relied on meta-analysis of aggregated and static datasets. These limitations restrict the capacity to actively detect low-level and/or geographically dispersed changes in the incidence of HDV diagnoses. This study was designed to provide a resource to track and analyze the international HDV epidemiology. Datasets analyzed collectively consisted of >700,000 HBV and >9,000 HDV reported cases ranging between 1999-2020. Datasets mined from government publications were identified for Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Finland, Germany, Macao, Netherlands, New Zealand, Norway, Sweden, Taiwan, Thailand, United Kingdom, and United States. Time series analyses, including Mann-Kendall (MK) trend test, Bayesian Information Criterion (BIC), and hierarchal clustering, were performed to characterize trends in the HDV timelines. An aggregated prevalence of 2,560 HDV/HBV100,000 cases (95% CI 180-4940) or 2.56% HDV/HBV cases was identified, ranging from 0.26% in Canada to 20% in the United States. Structural breaks in the timeline of HDV incidence were identified in 2002, 2012, and 2017, with a significant increase occurring between 2013-2017. Significant increasing trends in reported HDV and HBV cases were observed in 47% and 24% of datasets, respectively. Analyses of the HDV incidence timeline identified four distinct temporal clusters, including Cluster I (Macao, Taiwan), Cluster II (Argentina, Brazil, Germany, Thailand), Cluster III (Bulgaria, Netherlands, New Zealand, United Kingdom, United States) and Cluster IV (Australia, Austria, Canada, Finland, Norway, Sweden). Tracking of HDV and HBV cases on an international scale is essential in defining the global impact of viral hepatitis. Significant disruptions of HDV and HBV epidemiology have been identified. Increased surveillance of HDV is warranted to further define the etiology of the recent breakpoints in the international HDV incidence.
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Affiliation(s)
- Braden S Fallon
- School of Dentistry, University of Utah, Salt Lake City, UT, United States of America
| | - Elaine M Cooke
- School of Dentistry, University of Utah, Salt Lake City, UT, United States of America
| | - Matthew C Hesterman
- School of Dentistry, University of Utah, Salt Lake City, UT, United States of America
| | - Jared S Norseth
- School of Dentistry, University of Utah, Salt Lake City, UT, United States of America
| | - Sherzod B Akhundjanov
- Department of Applied Economics, Utah State University, Logan, UT, United States of America
| | - Melodie L Weller
- School of Dentistry, University of Utah, Salt Lake City, UT, United States of America
- Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT, United States of America
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13
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Costante F, Stella L, Santopaolo F, Gasbarrini A, Pompili M, Asselah T, Ponziani FR. Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection. J Hepatocell Carcinoma 2023; 10:713-724. [PMID: 37128594 PMCID: PMC10148646 DOI: 10.2147/jhc.s384751] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/06/2023] [Indexed: 05/03/2023] Open
Abstract
Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.
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Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Leonardo Stella
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Tarik Asselah
- Service d’Hépatologie, Hôpital Beaujon UMR 1149 Inserm - Université de Paris, Clichy, France
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
- Correspondence: Francesca Romana Ponziani; Federico Costante, Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, Rome, 00168, Italy, Tel +390630156264, Email ;
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14
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Olivero A, Rosso C, Ciancio A, Abate ML, Nicolosi A, Troshina G, Armandi A, Ribaldone DG, Saracco GM, Bugianesi E, Rizzetto M, Caviglia GP. Clinical Application of Droplet Digital PCR for Hepatitis Delta Virus Quantification. Biomedicines 2022; 10:792. [PMID: 35453541 PMCID: PMC9029565 DOI: 10.3390/biomedicines10040792] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/15/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023] Open
Abstract
Droplet digital PCR (ddPCR) is a novel developed PCR technology providing the absolute quantification of target nucleic acid molecules without the need for a standard curve and regardless PCR amplification efficiency. Our aim was to develop a ddPCR assay for Hepatitis Delta virus (HDV)-RNA viremia quantification and then evaluate its performance in relation to real-time PCR methods. Primers and probe were designed from conserved regions of HDV genome to detect all the 8 HDV genotypes; the World Health Organization (WHO)-HDV international standard was used to calculate the conversion factor transforming results from copies/mL to IU/mL. To evaluate the clinical performance of ddPCR assay, plasma specimens of HDV-infected patients were tested and results were compared with data obtained with two real-time quantitative PCR (RT-qPCR) assays (i.e., in-house assay and commercial RoboGene assay). Analyzing by linear regression a series of 10-fold dilutions of the WHO-HDV International Standard, ddPCR assay showed good linearity with a slope coefficient of 0.966 and R2 value of 0.980. The conversion factor from copies to international units was 0.97 and the quantitative linear dynamic range was from 10 to 1 × 106 IU/mL. Probit analysis estimated at 95% an LOD of 9.2 IU/mL. Data from the evaluation of HDV-RNA in routine clinical specimen of HDV patients exhibited strong agreement with results obtained by RT-qPCR showing a concordance correlation coefficient of 0.95. Overall ddPCR and RT-qPCR showed highly comparable technical performance. Moreover, ddPCR providing an absolute quantification method may allow the standardization of HDV-RNA measurement thus improving the clinical and diagnostic management of delta hepatitis.
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Affiliation(s)
- Antonella Olivero
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Chiara Rosso
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
| | - Alessia Ciancio
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Maria Lorena Abate
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Aurora Nicolosi
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
| | - Giulia Troshina
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
| | - Angelo Armandi
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Giorgio Maria Saracco
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Elisabetta Bugianesi
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
- Division of Gastroenterology, Città della Salute e della Scienza–Molinette Hospital, 10100 Turin, Italy
| | - Mario Rizzetto
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
| | - Gian Paolo Caviglia
- Department of Medical Sciences, University of Turin, 10100 Turin, Italy; (C.R.); (A.C.); (M.L.A.); (A.N.); (G.T.); (A.A.); (D.G.R.); (G.M.S.); (E.B.); (M.R.); (G.P.C.)
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15
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Chen LY, Pang XY, Goyal H, Yang RX, Xu HG. Hepatitis D: challenges in the estimation of true prevalence and laboratory diagnosis. Gut Pathog 2021; 13:66. [PMID: 34717740 PMCID: PMC8557527 DOI: 10.1186/s13099-021-00462-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective single negative chain RNA virus, as its envelope protein synthesis is dependent on hepatitis B virus (HBV). Studies have consistently shown that coinfection of HBV and HDV is the most serious form of viral hepatitis, with accelerated progression to liver cirrhosis and hepatocellular carcinoma. About 74 million of HBV surface antigen (HBsAg) positive patients worldwide are also co-infected with HDV. Besides, patients with intravenous drug use and high-risk sexual behavior are at higher risk of HDV infection. Therapeutic schedules for HDV are limited, and relapse of HDV has been observed after treatment with pegylated interferon alpha. To reduce the transmission of HDV, all people infected with HBV should be screened for HDV. At present, several serological and molecular detection methods are widely used in the diagnosis of HDV. However, due to the lack of international standards diagnostic results from different laboratories are often not comparable. Therefore, the true prevalence of HDV is still unclear. In this manuscript, we have analyzed various factors influencing the estimation of HDV prevalence. We have also discussed about the advantages and disadvantages of currently available HDV laboratory diagnostic methods, in order to provide some ideas for improving the detection of HDV.
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Affiliation(s)
- Lin-Yuan Chen
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiao-Yu Pang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hemant Goyal
- Department of Internal Medicine Macon, Mercer University School of Medicine, Georgia, USA
| | - Rui-Xia Yang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Hua-Guo Xu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
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Lee WC, Chen TK, Han HF, Lin YC, Hwang YM, Kao JH, Chen PJ, Liu CJ. Investigating the prevalence and clinical effects of hepatitis delta viral infection in Taiwan. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2021; 54:901-908. [PMID: 34162528 DOI: 10.1016/j.jmii.2021.03.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/01/2021] [Accepted: 03/19/2021] [Indexed: 12/18/2022]
Abstract
PURPOSE To clarify and investigate the prevalence and clinical impact of hepatitis D virus (HDV) infection in Taiwan's communities. METHODS HDV infection in patients with chronic hepatitis B viral (HBV) infection was examined using an anti-HDV antibody in Yonghe Cardinal Tien Hospital (YCTH), a district hospital in Taiwan. Clinical characteristics of anti-HDV-positive and anti-HDV-negative patients were collected and compared. These characteristics were also compared with the data collected from a medical center. Continuous variables and confounding factor adjustments were compared using the analysis of covariance method, whereas categorical variables were compared using the logistic regression method. RESULTS A total of 346 patients with chronic HBV infection were assessed from 2018 to 2019. Among them, 4 (1.15%) were positive for anti-HDV. The clinical, virological, and biochemical characteristics were similar between anti-HDV-positive and anti-HDV-negative groups. None of the four patients was positive for serum HDV RNA. Another 18 anti-HDV-positive patients were identified from National Taiwan University Hospital (NTUH). The clinical, virological, and biochemical characteristics of anti-HDV-positive patients from YCTH and NTUH were also similar. CONCLUSION The prevalence of HDV and the serum HDV RNA-positive rate were low in district hospitals in Taiwan. Coexisting HDV infection did not influence the clinical manifestation of patients with chronic HBV infection in Taiwan. However, because the number of HDV RNA cases was very small, our findings may not be conclusive. Besides, since the sensitivity of current anti-HDV kit is not 100%, more sensitive methods are needed to achieve reliable prevalence data.
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Affiliation(s)
- Wei-Cheng Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzen-Kwan Chen
- Division of Gastroenterology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, Taipei, Taiwan
| | - Hwa-Fa Han
- Division of Gastroenterology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, Taipei, Taiwan
| | - Yu-Chun Lin
- Division of Gastroenterology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, Taipei, Taiwan
| | - Ya-Min Hwang
- Division of Gastroenterology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Pataccini G, Berini CA, Pedrozo WR, Biglione MM, Delfino CM. First molecular epidemiological study of hepatitis B and D in individuals infected with human T-lymphotropic virus 1/2 from Argentina. J Med Virol 2021; 93:3995-3998. [PMID: 32725912 DOI: 10.1002/jmv.26366] [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: 06/14/2020] [Accepted: 07/27/2020] [Indexed: 11/08/2022]
Abstract
Human T-lymphotropic virus 1/2 (HTLV-1/2), hepatitis B virus (HBV), and hepatitis D virus (HDV) share transmission routes. Argentina shows low prevalence of HTLV-1/2, HBV, and HDV infections; however, this situation may vary according to the geographic region and group studied. The aim of this study was to estimate the prevalence of HBV and HDV infections and detect both viral genotypes in HTLV-1/2 individuals from Argentina. A total of 202 HTLV-1/2 confirmed samples (blood donors [BD] and individuals with risk factors for HTLV-1/2 [RF]) were tested for HBsAg and total anti-HBc by enzyme-linked immunosorbent assay. All reactive samples for some HBV markers were analyzed for HBV DNA characterization and HDV serological and molecular analysis. Total prevalence was 1.5% for HBsAg and 6.4% for anti-HBc. Prevalence was 23.1% for anti-HDV in all HBV-reactive samples. No significant difference was observed for HBV and HDV prevalence within HTLV subtypes. The population study showed that prevalence of anti-HBc was higher in the RF than in the BD population, with no significant differences between them. The HBsAg marker and anti-HDV were only found in RF, showing significant differences when compared to BD. Regarding molecular detection, one sample amplified for HBV DNA and none for HDV RNA. HBV sequence was classified as subgenotype F1b. New and updated background on serological markers of HBV and HDV infection in patients with HTLV-1/2 was provided.
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Affiliation(s)
- Gabriela Pataccini
- Laboratorio de Carcinogénesis Hormonal (LdeCH), Instituto de Biología y Medicina Experimental (IByME), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carolina Andrea Berini
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Williams René Pedrozo
- Banco de Sangre Tejidos y Biológicos (BSTB) de la provincia de Misiones, Posadas, Misiones, Argentina
| | - Mirna Marcela Biglione
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Cecilia María Delfino
- Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina
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Machado LFA, Fonseca RRDS, Queiroz MAF, Oliveira-Filho AB, Cayres-Vallinoto IMV, Vallinoto ACR, Ishak MDOG, Ishak R. The Epidemiological Impact of STIs among General and Vulnerable Populations of the Amazon Region of Brazil: 30 years of Surveillance. Viruses 2021; 13:v13050855. [PMID: 34067165 PMCID: PMC8151421 DOI: 10.3390/v13050855] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
Sexually transmitted infections (STIs) represent a worldwide public health problem and, although many of them are curable, they continue to be neglected, especially in areas with a low human development index, such as in the northern region of Brazil. This review describes the results of 30 years of studies at the Virus Laboratory at the Federal University of Pará, including the prevalence and molecular epidemiology of HIV-1, HTLV-1/2, HPV, HBV, Treponema pallidum and Chlamydia trachomatis among urban and non-urban populations, and also in vulnerable groups in the Brazilian Amazon. Control strategies and challenges in preventing STIs are discussed considering this immense geographic region, where essential health services are unable to reach the entire population, especially the most vulnerable, such as female sex workers, people who use illicit drugs, remnants of quilombolos and indigenous communities.
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Affiliation(s)
- Luiz Fernando Almeida Machado
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
- Correspondence:
| | - Ricardo Roberto de Souza Fonseca
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
| | - Maria Alice Freitas Queiroz
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
| | - Aldemir Branco Oliveira-Filho
- Grupo de Estudo e Pesquisa em Populações Vulneráveis, Instituto de Estudos Costeiros, Universidade Federal do Pará, Bragança 68.600-000, Brazil;
| | - Izaura Maria Vieira Cayres-Vallinoto
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
| | - Antonio Carlos Rosário Vallinoto
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
| | - Marluísa de Oliveira Guimarães Ishak
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
| | - Ricardo Ishak
- Laboratório de Virologia, Instituto de Ciências Biológica, Universidade Federal do Pará, Belém 66.075-110, Brazil; (R.R.d.S.F.); (M.A.F.Q.); (I.M.V.C.-V.); (A.C.R.V.); (M.d.O.G.I.); (R.I.)
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HDV Pathogenesis: Unravelling Ariadne's Thread. Viruses 2021; 13:v13050778. [PMID: 33924806 PMCID: PMC8145675 DOI: 10.3390/v13050778] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis Delta virus (HDV) lies in between satellite viruses and viroids, as its unique molecular characteristics and life cycle cannot categorize it according to the standard taxonomy norms for viruses. Being a satellite virus of hepatitis B virus (HBV), HDV requires HBV envelope glycoproteins for its infection cycle and its transmission. HDV pathogenesis varies and depends on the mode of HDV and HBV infection; a simultaneous HDV and HBV infection will lead to an acute hepatitis that will resolve spontaneously in the majority of patients, whereas an HDV super-infection of a chronic HBV carrier will mainly result in the establishment of a chronic HDV infection that may progress towards cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). With this review, we aim to unravel Ariadne’s thread into the labyrinth of acute and chronic HDV infection pathogenesis and will provide insights into the complexity of this exciting topic by detailing the different players and mechanisms that shape the clinical outcome.
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Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis. Proc Natl Acad Sci U S A 2021; 118:2019633118. [PMID: 33888584 DOI: 10.1073/pnas.2019633118] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.
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21
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Isaeva OV, Il'chenko LY, Saryglar AA, Karlsen AA, Kyuregyan KK, Mikhailov MI. [Clinical course and outcomes of chronic viral hepatitis D in patients from Republic of Tuva as endemic region]. Vopr Virusol 2021; 66:74-83. [PMID: 33683068 DOI: 10.36233/0507-4088-29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 03/07/2021] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Hepatitis D (delta, 5) is caused by an RNA virus (hepatitis D virus, HDV) from genus Deltavirus, and is the most severe and difficult to treat disease among both viral hepatitis and infectious diseases in general. The development of HDV infection in the host organism is possible only in the presence of hepatitis B virus (HBV). Coinfection with HBV and HDV is associated with a more rapid progression of chronic viral hepatitis (CVH) to liver cirrhosis (LC) and an unfavorable outcome in comparison with HBV monoinfection. Data on the influence of clinical, biochemical and virological factors on the infectious process in patients with hepatitis D are limited due to the insufficient amount of research on this theme.The study aimed to determine demographic, clinical, biochemical, and virological factors influencing the course and progression of CVH D in patients followed during 10 years, residing in the territory of the Tuva Republic, one of the endemic regions of the Russian Federation. MATERIAL AND METHODS Changes in clinical and laboratory parameters were analyzed in dynamics in 121 HDV infected patients with a different course of the disease, who were under observation from 2009 to 2019. Three groups of patients were identified: group 1 - 61 patients with disease progression of chronic hepatitis to LC (Child-Pugh class B-C), group 2 - 49 patients with non-progressive chronic hepatitis, and group 3 - 11 patients with slowly progressive LC (class A). Demographic data, the presence of detectable HBV DNA, indicators of the functional state of the liver: alanine aminotransferase (ALT/GPT), aspartate aminotransferase (AST/GOT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), and total bilirubin content were analyzed. The severity of hepatic encephalopathy was assessed by the duration of the numbers connection test (NCT). RESULTS All patients belonged to the same ethnic group (Tuvinians), were infected with HDV genotype 1 and were positive for HDV RNA throughout the entire follow-up period. There were no significant differences in sex ratio and mean age at the time of inclusion in the study between the groups. In group 1, the average number of years from inclusion in the study to the formation of LC was 3.65 ± 2.3 years, years to the lethal outcome: 4.5 ± 3 years. Significantly higher levels of AST/GOT, ALP, GGT, total bilirubin (TB) and NCT grade were found in group 1 compared to group 2. ALT/GPT levels did not differ significantly in these groups. When comparing groups with disease progression and slowly progressive LC (groups 1 and 3), no significant differences were found in any of the clinical and biochemical parameters. ALT/GPT, GGT, TB and NCT values were significantly higher in patients with slowly progressive LC (group 3) compared to group 2. No differences in AST/GOT and ALP levels were found between these groups. Detectable HBV DNA was significantly more frequent in patients with progressive disease and with chronic viral hepatitis than in patients with slowly progressive LC. There were no significant differences in the frequency of HBV DNA detection in patients from groups 1 and 2. CONCLUSION The results obtained on a relatively homogeneous cohort demonstrated that age and gender are not the factors influencing the progression of chronic viral hepatitis D to cirrhosis. The lack of detectable HBV DNA is associated with the slow progression of LC. The revealed differences in clinical and biochemical parameters reflect the degree of functional liver damage in chronic viral hepatitis D and HDV-associated cirrhosis.
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Affiliation(s)
- O V Isaeva
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - L Yu Il'chenko
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBSI M.P. Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences; FSAEI HE N.I. Pirogov Russian Research Medical University of the Ministry of Health of Russia
| | | | - A A Karlsen
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - K K Kyuregyan
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
| | - M I Mikhailov
- FSBSI I.I. Mechnikov Research Institute of Vaccines and Sera; FSBEI FPE Russian Medical Academy of Continuous Professional Education of the Ministry of Health of Russia
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Jackson K, Littlejohn M, Gane E, Locarnini S. Molecular Phylogenetics of Hepatitis D Virus in New Zealand and the Implications for Pacific Island Countries. Intervirology 2021; 64:102-107. [PMID: 33647912 DOI: 10.1159/000513685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 12/09/2020] [Indexed: 11/19/2022] Open
Abstract
Hepatitis delta virus (HDV) is considered a satellite virus that requires hepatitis B virus surface antigen for infectivity. HDV is endemic in some Pacific Island (PI) countries, including Kiribati and Nauru, with a unique genotype 1, "Pacific clade." The aims of this study were to determine the HDV genotypes in New Zealand and investigate the link of strains to other PI countries and the rest of the world through phylogenetics. Sequencing and phylogenetic analyses were performed on 16 HDV-positive serum samples from 14 individuals collected between 2009 and 2014 at Auckland Hospital. Thirteen of 14 strains were confirmed as genotype 1 and 1 was genotype 5. Eleven of the 13 genotype 1 strains clustered with the Pacific clade. These were isolated from subjects born in Samoa, Kiribati, Tuvalu, and Niue. Another genotype 1 strain isolated from a Maori health-care worker clustered most closely with a European strain. There was an African genotype 1 and genotype 5 from African-born subjects with HIV coinfection. This study supports the probable transmission of HDV Pacific clade around the PI from Micronesia to Polynesia. The data also confirm the need to screen hepatitis B surface antigen-positive individuals for HDV.
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Affiliation(s)
- Kathy Jackson
- Research and Molecular Development and WHO Regional Reference Laboratory for Hepatitis B/D, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia,
| | - Margaret Littlejohn
- Research and Molecular Development and WHO Regional Reference Laboratory for Hepatitis B/D, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Ed Gane
- Department of Medicine, University of Auckland and New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Stephen Locarnini
- Research and Molecular Development and WHO Regional Reference Laboratory for Hepatitis B/D, Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Ferrante ND, Lo Re V. Epidemiology, Natural History, and Treatment of Hepatitis Delta Virus Infection in HIV/Hepatitis B Virus Coinfection. Curr HIV/AIDS Rep 2020; 17:405-414. [PMID: 32607773 DOI: 10.1007/s11904-020-00508-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Limited data exist on the prevalence, determinants, and outcomes of hepatitis delta virus (HDV) infection among HIV/hepatitis B virus (HBV)-coinfected persons. This review provides current evidence on the epidemiology, natural history, and treatment of HDV infection in patients with HIV/HBV coinfection and highlights future research needs. RECENT FINDINGS Cross-sectional studies in Europe, Africa, South America, and Asia show that the prevalence of HDV among HIV/HBV-coinfected patients ranges from 1.2 to 25%. No studies have evaluated the prevalence of HDV infection among HIV/HBV-coinfected patients in the USA. HDV infection increases the risk of hepatic decompensation and hepatocellular carcinoma among HIV/HBV-coinfected patients. HDV treatment remains limited to pegylated interferon-alpha, which results in sustained virologic response in fewer than 25%. Data on the epidemiology, natural history, and treatment of HDV among HIV/HBV-coinfected persons remain limited. More research is needed to address these knowledge gaps in order to better manage HDV coinfection in HIV/HBV-coinfected patients.
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Affiliation(s)
- Nicole D Ferrante
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA
| | - Vincent Lo Re
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA.
- Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine University of Pennsylvania, Philadelphia, PA, USA.
- Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees. mBio 2020; 11:mBio.02580-20. [PMID: 33203756 PMCID: PMC7683399 DOI: 10.1128/mbio.02580-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1β. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic.IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.
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Jang TY, Wei YJ, Hsu CT, Hsu PY, Liu TW, Lin YH, Liang PC, Hsieh MH, Ko YM, Tsai YS, Chen KY, Lin CC, Tsai PC, Wang SC, Huang CI, Yeh ML, Lin ZY, Chen SC, Chuang WL, Huang JF, Dai CY, Huang CF, Yu ML. Serial serologic changes of hepatitis D virus in chronic hepatitis B patients receiving nucleos(t)ides analogues therapy. J Gastroenterol Hepatol 2020; 35:1886-1892. [PMID: 32247291 DOI: 10.1111/jgh.15061] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/30/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM The serial serologic changes of hepatitis D virus (HDV) infection among chronic hepatitis B virus (HBV) infected patients who received oral nucleotide/nucleoside analogues are elusive. METHODS Serum anti-HDV and HDV RNA among chronic hepatitis B (CHB) patients were tested at the time of initiating anti-HBV therapy and subsequently during the follow-up period. RESULTS The seropositive rate of anti-HDV and HDV RNA among 2850 CHB patients, was 2.7% and 0.9%, respectively. Factors associated with anti-HDV seropositivity were platelet counts (odds ratio [OR]/95% confidence intervals [CI]: 0.995/0.992-0.999; P = 0.006), HBV DNA levels (OR/CI: 0.81/0.70-0.94; P = 0.005), and hepatitis B e-antigen (HBeAg) seropositivity (OR/CI: 0.22/0.05-0.95; P = 0.04). The only factor associated with HDV RNA positivity among anti-HDV seropositive patients was age (OR/CI: 0.95/0.90-1.00; P = 0.03). The spontaneous clearance rate of serum anti-HDV antibody was 3.0 per 100 person-years with a median follow-up period of 3.5 years (range 2-12 years), whereas the seroclearance rate of HDV RNA was 4.3 per 100 person-years among anti-HDV seropositive patients after a median follow-up period of 6.0 years (range 2-11 years). A baseline anti-HDV titer < 0.5 cut-off index was the only factor predictive of anti-HDV seroclearance (hazard ratio [HR]/CI: 30.11/3.73-242.85; P = 0.001). CONCLUSIONS HDV infection was not common among patients treated for HBV in Taiwan. Seroclearance of anti-HDV and HDV RNA did occur over time, albeit the chance is rare.
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Affiliation(s)
- Tyng-Yuan Jang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
| | - Yu-Ju Wei
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Cheng-Ting Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Yao Hsu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ta-Wei Liu
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Chih Lin
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Faculty of Internal Medicine and Hepatitis Research Center, School of Medicine, College of Medicine, and Center for Cancer Research and Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B) and Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
- Center for Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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Bhuva M, Moore M, Sen S. ‘Double-hit’ pegylated interferon-alpha successfully treats Hepatitis B and Hepatitis D co-infection. Oxf Med Case Reports 2020; 2020:omaa084. [PMID: 33343908 PMCID: PMC7733525 DOI: 10.1093/omcr/omaa084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 11/14/2022] Open
Abstract
Abstract
Hepatitis delta (HDV) infection is either acquired simultaneously with, or as a superinfection to, existing Hepatitis B (HBV). It leads to a serious form of chronic viral hepatitis and accelerated liver-related morbidity and mortality including hepatocellular carcinoma. Current treatment regimes propose Pegylated interferon-alpha for 48 weeks however sustained virological response (SVR) rates remain low. We report a patient who initially responded to Pegylated interferon treatment for HBV-HDV co-infection. Although initial improvement in viraemia from both virsues was seen, SVR was not achieved with ongoing progression of liver injury biochemically. However, the summative effect of a second course of Pegylated interferon 2 years later led to HDV cure (SVR 12 months post-treatment), very low level HBV carrier status (with persistently undetectable viral load) and ongoing biochemical normalization. This case illustrates a successful treatment strategy for persistent HBV-HDV co-infection where proposed treatment regimes elicit an initial response but SVR is not achieved.
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Affiliation(s)
| | - Marie Moore
- Hepatology Department, Luton and Dunstable University Hospital, Luton, UK
| | - Sambit Sen
- Hepatology Department, Luton and Dunstable University Hospital, Luton, UK
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Jankowski R. Virus et épidémies virales dans la théorie métabolique de l’évolution. ANNALES FRANÇAISES D'OTO-RHINO-LARYNGOLOGIE ET DE PATHOLOGIE CERVICO-FACIALE 2020. [PMCID: PMC7833959 DOI: 10.1016/j.aforl.2020.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Les virus, dont l’épidémie de SARS-CoV-2 actuelle, représentent une clé dans la compréhension de la vie et de l’évolution. La cellule a pu naître d’un enfermement aqueux dans une enveloppe lipidique incrustée de chromophores capturant les photons solaires. L’incorporation d’azote dans la chimie cellulaire primordiale autorisait la synthèse des acides aminés et nucléiques, prélude de l’ARN qui aurait précédé l’ADN. La métagénomique permet d’accéder aux sédiments nucléoprotéiques synthétisés par le gogol de cellules métaboliquement différenciées qui ont jalonné l’évolution du vivant. La réplication d’un virus, particule nucléoprotéique, se déroule passivement dans une cellule compétente. Un virus ne semble connu que par l’épidémie qu’il déclenche en étant transporté d’un hôte à l’autre. En décomposant la particule virale, la cellule hôte paraît ressusciter la fonction métabolique de l’acide nucléique qui synthétise sans contrôle ses composants. Ceux-ci s’auto-assemblent et sont exportés par exocytose ou cytolyse. Sans cellule, les virus ne paraissent que matière inerte. La contamination intracellulaire d’un virus ne parvient cependant pas toujours à la réplication : le génome viral peut disparaître, rester latent, se réveiller, rester inséré dans le génome cellulaire, devenir un oncogène ou induire l’auto-immunité. Les rétrovirus endogènes des cellules eucaryotes soulèvent la question de leur rôle dans l’évolution.
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Abstract
Viruses, including the SARS-CoV-2 virus responsible for the current COVID-19 epidemic, are a key to the understanding of life and evolution. Cells may have arisen from aqueous sequestration inside a lipid envelope studded with chromophores capable of capturing solar photons. Nitrogen incorporation in the primordial cell chemistry allowed synthesis of amino acids and nucleic acids, a prelude to RNA and subsequently DNA. Metagenomics provides access to nucleoprotein sediments synthesised by a googol of metabolically differentiated cells that have marked the evolution of life. Replication of a virus, a nucleoprotein particle, occurs passively in competent cells. Viruses are only identified in the context of the epidemic that they induce as a result of transmission from one host to another. By breaking down the viral particle, the host cell appears to resurrect the metabolic function of the nucleic acid, which synthesises its components without any form of control. Viral products undergo self-assembly and are exported by either exocytosis or cytolysis. In the absence of cells, viruses appear to be inert. However, intracellular contamination of a virus does not always result in replication: the viral genome can disappear, remain latent, wake up, remain embedded in the cellular genome, become an oncogene or induce auto-immunity. The presence of endogenous retroviruses in eukaryotic cells raises the question of their possible role in evolution.
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Affiliation(s)
- R Jankowski
- ORL et Chirurgie Cervico-Faciale, Hôpital de Brabois, CHRU de Nancy, Université de Lorraine, Bâtiment Louis-Mathieu, 54500 Vandoeuvre-les-Nancy, France; EA 3450 DevAH-Développement, Adaptation et Handicap, Régulations Cardio-Respiratoires et de la Motricité, Faculté de Médecine, Université de Lorraine, 54505, Vandoeuvre-les-Nancy, France; UMR_S 1256 INSERM, Nutrition, génétique et expositions aux risques environnementaux, Faculté de Médecine, 9, avenue de la Forêt-de-Haye, 54500 Vandœuvre-lès-Nancy, France.
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Hepatitis B and D in the Pacific Islands of Kiribati. J Clin Virol 2020; 129:104527. [PMID: 32645613 DOI: 10.1016/j.jcv.2020.104527] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 06/23/2020] [Accepted: 06/27/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Historical reports indicate that hepatitis B and hepatitis D are highly endemic in the Pacific Island of Kiribati but current levels are unknown. OBJECTIVES To determine current prevalence of HBV and HDV in Kiribati, characterize the strains in both mono-infection and co-infection and assess individuals for antiviral therapy. STUDY DESIGN Sera obtained from 219 patients were screened for HBsAg, HBeAg, HBV DNA, anti-HD, and HDV RNA. 61 HBV isolates were sequenced for genotype, phylogenetic analysis and detection of pre-core and basal core promoter mutations. 82 HDV isolates were also sequenced. RESULTS 55.7 % HBsAg positive samples had antibodies to HDV and 73.2 % had detectable HDV RNA, indicating that 40.8 % HBsAg-positive individuals had current HBV/HDV co-infection. There were 42 co-infected males and 40 females; the youngest individual was a 4 year-old boy. HBV isolates were genotype D4, and HDV strains formed a distinct Pacific clade of genotype 1. Undetectable HBV DNA loads were statistically more frequent in the co-infected sub-population (p < 0.0001). Basal core promoter and pre-core mutations were present in both mono and co-infection. CONCLUSION Kiribati has one of the highest HBV/HDV co-infection rates in the world. The epidemiology of co-infection in this population was unusual with males and females equally represented and the presence of co-infection in a 4 year old child suggesting neonatal or early horizontal transmission, which is extremely rare. Coinfection with HDV resulted in statistically significant suppression of HBV DNA levels. The HDV strain identified in Kiribati was unique to the Pacific Islands.
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Jung S, Altstetter SM, Protzer U. Innate immune recognition and modulation in hepatitis D virus infection. World J Gastroenterol 2020; 26:2781-2791. [PMID: 32550754 PMCID: PMC7284172 DOI: 10.3748/wjg.v26.i21.2781] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/30/2020] [Accepted: 05/23/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV’s immune evasion strategy and identify where additional research is required.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Coinfection/complications
- Coinfection/immunology
- Coinfection/pathology
- Coinfection/virology
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B virus/metabolism
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/virology
- Hepatitis D, Chronic/complications
- Hepatitis D, Chronic/immunology
- Hepatitis D, Chronic/pathology
- Hepatitis D, Chronic/virology
- Hepatitis Delta Virus/genetics
- Hepatitis Delta Virus/immunology
- Hepatitis Delta Virus/metabolism
- Hepatitis delta Antigens/immunology
- Hepatitis delta Antigens/metabolism
- Humans
- Immune Evasion
- Immunity, Innate
- Interferon-Induced Helicase, IFIH1/metabolism
- Liver/immunology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Organic Anion Transporters, Sodium-Dependent/metabolism
- RNA, Viral/immunology
- RNA, Viral/metabolism
- Receptors, Pattern Recognition/immunology
- Receptors, Pattern Recognition/metabolism
- Satellite Viruses/genetics
- Satellite Viruses/immunology
- Satellite Viruses/metabolism
- Symporters/metabolism
- Virus Replication/immunology
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Affiliation(s)
- Stephanie Jung
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich D-81675, Germany
| | | | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich D-81675, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich D-81675, Germany
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Akande KO, Fowotade A, Adekanmbi O. The effect of Hepatitis D co-infection on the immunologic and molecular profile of Hepatitis B in asymptomatic Chronic Hepatitis B patients in southwest Nigeria. J Immunoassay Immunochem 2020; 41:272-280. [PMID: 32096684 DOI: 10.1080/15321819.2020.1728542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Introduction: Hepatitis D infection causes severe form of viral hepatitis in humans and only affects those with hepatitis B either as a co-infection or superinfection. The aim of this study was to determine the prevalence of Hepatitis D and its effect on the immunologic and molecular profile of Hepatitis B among asymptomatic Chronic Hepatitis B patients in Abeokuta.Methodology: A cross-sectional study of 99 chronic HBV patient who met the inclusion criteria. All the patients were tested for HBsAg, anti HCV, HDV antigen, anti HDV, HBsAg quantification, and HBV DNA quantification. Associations were tested for and P value less than 0.05 was considered significant.Results: The participants included 53 (58%) male and 38 (42%) females with ages ranging from 18 to 69 (means 39 ± 11) years. Ten (11%) participants were positive for HDV-Ag while 1 (1.1%) was positive for anti-HDV. Five (5.5%) were positive for HIV 1 &2 while 1 (1.1%) was positive for anti HCV. HBV DNA quantification ranged from 15 to 17,000,000 IU/ml while HBsAg quantification ranged from 0.25 to45,520 IU/ml. There was no statistically significant relationship between HDV-Ag and age (p = .51), sex (p = .73), HBV DNA (p = .8) and HBsAg quantification (p = 1).Conclusion: The prevalence of HDV-Ag among asymptomatic treatment naïve chronic hepatitis B patients in Abeokuta was 11% and there was no significant difference in the levels of HBV DNA and HBsAg among those with or without hepatitis D.
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Affiliation(s)
| | - Adeola Fowotade
- Medical Microbiology and Parasitology, University of Ibadan College of Medicine, Ibadan, Nigeria
- Medical Microbiology and Parasitology, University College Hospital, Ibadan, Nigeria
| | - Olukemi Adekanmbi
- Medical Microbiology, University of Ibadan College of Medicine, Ibadan, Nigeria
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Intrinsically disordered proteins of viruses: Involvement in the mechanism of cell regulation and pathogenesis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 174:1-78. [PMID: 32828463 PMCID: PMC7129803 DOI: 10.1016/bs.pmbts.2020.03.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intrinsically disordered proteins (IDPs) possess the property of inherent flexibility and can be distinguished from other proteins in terms of lack of any fixed structure. Such dynamic behavior of IDPs earned the name "Dancing Proteins." The exploration of these dancing proteins in viruses has just started and crucial details such as correlation of rapid evolution, high rate of mutation and accumulation of disordered contents in viral proteome at least understood partially. In order to gain a complete understanding of this correlation, there is a need to decipher the complexity of viral mediated cell hijacking and pathogenesis in the host organism. Further there is necessity to identify the specific patterns within viral and host IDPs such as aggregation; Molecular recognition features (MoRFs) and their association to virulence, host range and rate of evolution of viruses in order to tackle the viral-mediated diseases. The current book chapter summarizes the aforementioned details and suggests the novel opportunities for further research of IDPs senses in viruses.
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Vlachogiannakos J, Papatheodoridis GV. New epidemiology of hepatitis delta. Liver Int 2020; 40 Suppl 1:48-53. [PMID: 32077599 DOI: 10.1111/liv.14357] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis D virus (HDV) is a defective pathogen that needs hepatitis B virus (HBV) for infection. Co-infection of HBsAg-positive individuals with HDV is commonly associated with a more rapid progression to cirrhosis, a higher incidence of hepatocellular carcinoma (HCC) and increased mortality. Initial studies have shown that about 5% of chronic HBV carriers worldwide (15-20 millions) were also infected with HDV. However, recent studies suggest that the prevalence of HDV is at least two- to three-fold higher than previous estimations. Improved diagnostic techniques have shown that HDV infection remains endemic in certain areas of the world. Injection drug users, individuals with high-risk sexual behaviour and patients co-infected with human immunodeficiency virus (HIV) represent the major reservoir of the disease in the Western world. Although the burden of HDV infection significantly decreased in Europe in the nineties, there has been no further decrease in the last decade, probably because of migration from HDV endemic countries. Until new and more effective therapies are available, public health measures should be reinforced by increasing prophylactic HBV vaccination programs, preventing transmission of the virus among parenteral drug users and implementing universal HDV screening of all HBV-infected individuals.
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Affiliation(s)
- Jiannis Vlachogiannakos
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", Athens, Greece
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35
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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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Brancaccio G, Gaeta GB. Treatment of chronic hepatitis due to hepatitis B and hepatitis delta virus coinfection. Int J Antimicrob Agents 2019; 54:697-701. [PMID: 31541699 DOI: 10.1016/j.ijantimicag.2019.09.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 09/07/2019] [Accepted: 09/15/2019] [Indexed: 02/07/2023]
Abstract
An estimated 20-40 million individuals worldwide are infected with hepatitis delta virus (HDV), mostly with rapidly evolving liver disease. Therapy of chronic HDV infection remains an unmet need. To date, only interferon (IFN)-based therapy is recommended for HDV infection and response rates are unsatisfactory; in addition, many patients are intolerant to or ineligible for IFN treatment. In recent years, innovative approaches have been in development, including the following: targeting virus entry into hepatocytes; inhibition of the host enzyme farnesyltransferase by prenylation inhibitors, leading to inhibition of complete virion formation and release; blockade of hepatitis B surface antigen (HBsAg) secretion, inhibiting virus release; and IFN-lambda, which causes fewer adverse effects than IFN-alfa. Clinical trials are ongoing with encouraging preliminary results.
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Affiliation(s)
- Giuseppina Brancaccio
- Infectious Diseases, Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Giovanni B Gaeta
- Infectious Diseases, Department of Mental and Physical Health, Campania University, Naples, Italy.
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Yurdaydin C, Keskin O, Kalkan Ç, Karakaya F, Çaliskan A, Kabaçam G, Önder FO, Karatayli S, Karatayli E, Deda X, Bozkaya H, Bozdayi AM, Idilman R. Interferon Treatment Duration in Patients With Chronic Delta Hepatitis and its Effect on the Natural Course of the Disease. J Infect Dis 2019; 217:1184-1192. [PMID: 29425306 DOI: 10.1093/infdis/jix656] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 01/16/2018] [Indexed: 12/18/2022] Open
Abstract
Background Interferon is the only treatment option in chronic delta hepatitis (CDH). A CDH database (333 patients, 161 with interferon treatment history) was analyzed for effects of treatment duration on virologic response and clinical outcomes. Methods Ninety-nine CDH patients who received at least 6 months of interferon were selected. Maintained virologic response (MVR) was defined as hepatitis D virus RNA negative for 2 years after treatment discontinuation. Cumulative median interferon treatment duration was 24 months (range 6-126 months), with a median of 2 courses (range 1-8). Post-treatment median follow-up was 55 months (24-225 months). Results Thirty-five patients achieved MVR. Cumulative probability of MVR increased with treatment duration and reached 50% at 5 years. Patients with MVR were less likely to die from liver disease or develop complications compared to patients without MVR (P = .032, P = .006, respectively). Cirrhosis at baseline and no response to therapy (odds ratio 16.1 and 5.23, respectively) predicted an adverse endpoint. Hepatitis B surface antigen clearance occurred in 37% of patients with MVR. Conclusion Viral response to interferon increases with treatment duration and favorably affects the natural course of disease. Interferon treatment duration has to be individualized with careful post-treatment assessment.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara Medical School, Turkey
- Hepatology Institute, University of Ankara, Turkey
| | - Onur Keskin
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - Çagdas Kalkan
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - Fatih Karakaya
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - Aysun Çaliskan
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - Gökhan Kabaçam
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - F Oguz Önder
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | | | | | - Xheni Deda
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | - Hakan Bozkaya
- Department of Gastroenterology, University of Ankara Medical School, Turkey
| | | | - Ramazan Idilman
- Department of Gastroenterology, University of Ankara Medical School, Turkey
- Hepatology Institute, University of Ankara, Turkey
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Jackson K, MacLachlan J, Cowie B, Locarnini S, Bowden S, Higgins N, Karapanagiotidis T, Nicholson S, Littlejohn M. Epidemiology and phylogenetic analysis of hepatitis D virus infection in Australia. Intern Med J 2019; 48:1308-1317. [PMID: 29761607 DOI: 10.1111/imj.13967] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/08/2018] [Accepted: 05/08/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The incidence and trends of the hepatitis D virus (HDV) in Australia have not been recently assessed, and the circulating genotypes have never been determined. AIM To characterise the current virology and epidemiology of HDV. METHODS Notifiable disease surveillance and laboratory testing data were analysed to assess demographics, risk factors and trends. HDV serology and RNA testing were performed on requested samples from 2010 to 2016. Sequencing of a 500-nucleotide amplicon of the delta antigen and phylogenetic analysis of the strains from 2009 to 2016 were also conducted. RESULTS Ninety HDV notifications were reported to the Victorian Department of Health and Human Services between 2010 and 2016. The majority (64.4%) of those diagnosed were born overseas, most commonly in Sudan, Pakistan and Vietnam. Over the same period, 190 patients tested positive for anti-HDV serology and 166 for HDV RNA. Sequencing of isolates from 169 individuals between 2009 and 2016 found that 80.5% strains were genotype 1, 16% genotype 5 and 3.5% genotype 2. Phylogenetic analysis confirmed the relatedness of strains from birth country, demonstrated the presence of the 'Pacific Island' genotype 1 strain in Queensland and supported possible transmission in correctional facilities and within families. CONCLUSIONS This study demonstrates the ongoing need for routine HDV screening and engagement in clinical care for people living with HBV in Australia. Epidemiological findings highlight the diversity in those affected and provide insights into local and global geographic distribution and transmission patterns.
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Affiliation(s)
- Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Jennifer MacLachlan
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Benjamin Cowie
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Nasra Higgins
- Department of Health and Human Services Victoria, Melbourne, Victoria, Australia
| | - Theo Karapanagiotidis
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Suellen Nicholson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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Hepatitis Delta Antigen Regulates mRNA and Antigenome RNA Levels during Hepatitis Delta Virus Replication. J Virol 2019; 93:JVI.01989-18. [PMID: 30728256 DOI: 10.1128/jvi.01989-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/18/2019] [Indexed: 01/17/2023] Open
Abstract
Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of acute and chronic liver disease. HDV produces three processed RNAs that accumulate in infected cells: the circular genome; the circular antigenome, which serves as a replication intermediate; and lesser amounts of the mRNA, which encodes the sole viral protein, hepatitis delta antigen (HDAg). The HDV genome and antigenome RNAs form ribonucleoprotein complexes with HDAg. Although HDAg is required for HDV replication, it is not known how the relative amounts of HDAg and HDV RNA affect replication, or whether HDAg synthesis is regulated by the virus. Using a novel transfection system in which HDV replication is initiated using in vitro-synthesized circular HDV RNAs, HDV replication was found to depend strongly on the relative amounts of HDV RNA and HDAg. HDV controls these relative amounts via differential effects of HDAg on the production of HDV mRNA and antigenome RNA, both of which are synthesized from the genome RNA template. mRNA synthesis is favored at low HDAg levels but becomes saturated at high HDAg concentrations. Antigenome RNA accumulation increases linearly with HDAg and dominates at high HDAg levels. These results provide a conceptual model for how HDV antigenome RNA production and mRNA transcription are controlled from the earliest stage of infection onward and also demonstrate that, in this control, HDV behaves similarly to other negative-strand RNA viruses, even though there is no genetic similarity between them.IMPORTANCE Hepatitis delta virus (HDV) is a satellite of hepatitis B virus that increases the severity of liver disease; approximately 15 million people are chronically infected worldwide. There are no licensed therapies available. HDV is not related to any known virus, and few details regarding its replication cycle are known. One key question is whether and how HDV regulates the relative amounts of viral RNA and protein in infected cells. Such regulation might be important because the HDV RNA and protein form complexes that are essential for HDV replication, and the proper stoichiometry of these complexes could be critical for their function. Our results show that the relative amounts of HDV RNA and protein in cells are indeed important for HDV replication and that the virus does control them. These observations indicate that further study of these regulatory mechanisms is required to better understand replication of this serious human pathogen.
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Brancaccio G, Fasano M, Grossi A, Santantonio TA, Gaeta GB. Clinical outcomes in patients with hepatitis D, cirrhosis and persistent hepatitis B virus replication, and receiving long-term tenofovir or entecavir. Aliment Pharmacol Ther 2019; 49:1071-1076. [PMID: 30793345 DOI: 10.1111/apt.15188] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 08/20/2018] [Accepted: 01/22/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Suppression of hepatitis B virus (HBV) replication with nucelos(t)ide analogues should be considered for patients with chronic hepatitis D virus (HDV) infection and ongoing HBV replication. AIM To verify the clinical outcome after long-term entecavir or tenofovir treatment in patients with advanced fibrosis/cirrhosis, ineligible to peg-interferon therapy. METHODS Patients were prospectively followed-up at 3-6 month intervals; measured outcomes were decompensation, hepatocellular carcinoma (HCC), liver transplant and liver related death. HBV monoinfected patients receiving the same treatment served as reference after 1:1 matching by age, gender, platelet count, albumin level, bilirubin and INR. RESULTS 56 HDV patients (48 with cirrhosis; median follow-up 50 months) were enrolled; all achieved HBV DNA suppression. Death or liver transplant occurred in 19 patients, with a rate (n/1000 patient-months) of 2.92 in HDV patients vs 0.38 in HBV monoinfected patients (P < 0.001); similarly, decompensation occurred at a rate of 1.53 vs 0.13 (P = 0.015), respectively, and the rate of HCC was almost thrice in HDV cohort (3.12 vs 1.12; P = 0.02) Platelet count, Child-Pugh score and marginally HDV infection were associated with HCC development. CONCLUSION Patients with HDV infection and advanced liver disease maintain an increased risk of severe clinical events as compared with HBV monoinfected patients, during prolonged HBV DNA suppression with potent NA.
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Affiliation(s)
- Giuseppina Brancaccio
- Infectious Diseases, Campania University "Luigi Vanvitelli", Naples, Italy.,Department of Molecular Medicine, University of Padua, Padua, Italy
| | - Massimo Fasano
- Infectious Diseases, University of Foggia, Foggia, Italy
| | - Adriano Grossi
- Infectious Diseases, Campania University "Luigi Vanvitelli", Naples, Italy
| | | | - Giovanni B Gaeta
- Infectious Diseases, Campania University "Luigi Vanvitelli", Naples, Italy
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41
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Jackson C, Gunson RN, Bradley-Stewart A, Bennett S, Black H, Kennedy N, Bell DJ. Epidemiology and patient characteristics of hepatitis D virus infection in the West of Scotland 2011-2016. J Viral Hepat 2018; 25:1395-1396. [PMID: 29851188 DOI: 10.1111/jvh.12939] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/25/2018] [Indexed: 12/31/2022]
Affiliation(s)
- C Jackson
- West of Scotland Specialist Virology Centre, Glasgow Royal Infirmary, Glasgow, UK.,The Brownlee Centre, Gartnavel General Hospital, Glasgow, UK
| | - R N Gunson
- West of Scotland Specialist Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - A Bradley-Stewart
- West of Scotland Specialist Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - S Bennett
- West of Scotland Specialist Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - H Black
- Monklands Hospital, Airdrie, UK
| | | | - D J Bell
- The Brownlee Centre, Gartnavel General Hospital, Glasgow, UK
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Daw MA, Daw AM, Sifennasr NEM, Draha AM, Daw AM, Daw AM, Ahmed MO, Mokhtar ES, El-Bouzedi A, Daw IM. The Epidemiology of Hepatitis D Virus in North Africa: A Systematic Review and Meta-Analysis. ScientificWorldJournal 2018; 2018:9312650. [PMID: 30356409 PMCID: PMC6178169 DOI: 10.1155/2018/9312650] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/25/2018] [Accepted: 08/27/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hepatitis D virus (HDV) infection has been considered a serious neglected pandemic, particularly in developing countries. The virus causes a more severe disease than mono infection with hepatitis B virus (HBV). The epidemiology of HDV is not well documented in North Africa, which is known to be endemic for HBV. In this study, we explored the prevalence of HDV infection and also attempted to identify factors associated with hepatitis D positive status among chronic hepatitis B patients in North Africa. METHODS The electronic databases PubMed, Embase, Scopus, Science Direct, Web of Science, and Google Scholar were comprehensively searched for all papers published between January 1, 1998, and December 31, 2017, using appropriate strategies containing all related keywords, including North Africa, names of countries in the region, and all permutations of hepatitis D virus. The estimated prevalence of HDV in North Africa was calculated as an average of the pooled infection prevalence in each country weighted by the ratio of the country's hepatitis D virus population to the study's sample size in the survey data analysis. FINDINGS A total of 312 studies were identified and 32 were included in this study, with a total sample of 4907 individuals screened for HDV. There was considerable variability in the prevalence estimates of HDV within the countries of the region. The overall prevalence of HDV in the general population of North Africa was 5·01% (95% CI: 1·25-8·27) and in liver disease patients it was 20.7% (95% CI:9.87-44.53). Genotype-1 was the most prominent genotype reported in five published studies. Ten studies reported on HDV RNA in participants who were seropositive for HDV, and four studies highlighted the impact of demographic factors (sex and age). No study showed the impact of risk factors on the prevalence of HDV in North Africa. INTERPRETATION This review provides a comprehensive assessment of the burden of HDV in Northern Africa. There were significant differences in seroprevalence, study population, and diagnostic testing between the countries in the region. The results presented here will alert health professionals to implement clear policies based on evidence to diminish the burden of HDV infection. Such measures may include but are not restricted to improving the laboratory diagnostic tests and initiating patient data registries and blood screening. Further epidemiological and research studies are needed to explore the risk factors, coinfections, and approaches to increase testing for HDV, particularly in high-risk subpopulations, such as intravenous drug users and immigrants, and to define the consequences of HDV infection in North Africa.
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Affiliation(s)
- Mohamed A. Daw
- Department of Medical Microbiology & Immunology, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Amina M. Daw
- Department of General Medicine, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Nadia E. M. Sifennasr
- Department of Medical Microbiology & Immunology, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Aisha M. Draha
- Department of Pharmacology, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Ahmed M. Daw
- Tripoli Medical Centre, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Ali M. Daw
- Tripoli Medical Centre, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Mohamed O. Ahmed
- Department of Microbiology and Parasitology, Faculty of Veterinary Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Ebtisam S. Mokhtar
- Department of Medical Microbiology & Immunology, Faculty of Medicine, University of Tripoli, CC 82668, Tripoli, Libya
| | - Abdallah El-Bouzedi
- Department of Laboratory Medicine, Faculty of Biotechnology, University of Tripoli, CC 82668, Tripoli, Libya
| | - Ibrahem M. Daw
- Department of Planning, Faculty of Engineering, University of Tripoli, CC 82668, Tripoli, Libya
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Baig S, Abidi SH, Azam Z, Majid S, Khan S, Khanani MR, Ali S. Evolution of HBV S-gene in the backdrop of HDV co-infection. J Med Virol 2018; 90:1328-1336. [PMID: 29663447 DOI: 10.1002/jmv.25200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/22/2018] [Indexed: 12/15/2022]
Abstract
HBV-HDV co-infected people have a higher chance of developing cirrhosis, fulminant hepatitis, and hepatocellular carcinoma (HCC) compared to those infected only with HBV. The present study was conducted to investigate HBV genotypes and phylogeny among HBV mono-infected and HBV-HDV co-infected patients, as well as analyze mutations in the surface gene of HBV in mono-infected and co-infected patients. A total of 100 blood samples (50 co-infected with HBV and HDV, and 50 mono-infected with HBV only) were collected for this study. HBV DNA was extracted from patient sera and partial surface antigen gene was amplified from HBV genome using polymerase chain reaction. HBV S gene was sequenced from 49 mono-infected and 36 co-infected patients and analyzed to identify HBV genotypes and phylogenetic patterns. Subsequently, HBV S amino acid sequences were analyzed for mutational differences between sequences from mono- and co-infected patients. HBV genotype D was predominantly found in both mono-infected as well as co-infected patients. Phylogenetic analysis showed the divergence of HBV sequences, between mono- and co-infected patients, into two distinct clusters. HBV S gene mutation analysis revealed certain mutations in HBV-HDV co-infected subjects to be distinct from those found in mono-infected patients. This might indicate the evolution of HBV S gene under selection pressures generated from HDV coinfection.
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Affiliation(s)
- Samina Baig
- Department of Microbiology, Dow University of Health Sciences, Karachi, Pakistan
| | - Syed H Abidi
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | - Zahid Azam
- National Institute of Liver and Gastrointestinal Diseases, Dow University of Health Sciences, Karachi, Pakistan
| | - Shahid Majid
- National Institute of Liver and Gastrointestinal Diseases, Dow University of Health Sciences, Karachi, Pakistan
| | - Saeed Khan
- Department of Pathology and Dow Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences, Karachi, Pakistan
| | - Muhammad R Khanani
- Department of Pathology and Dow Institute of Biotechnology and Biomedical Sciences, Dow University of Health Sciences, Karachi, Pakistan
| | - Syed Ali
- Department of Biomedical Sciences, Nazarbayev School of Medicine, Nazarbayev University, Astana, Kazakhstan.,Department of Pathology, Dow University of Health Sciences, Karachi, Pakistan
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Meysami P, Alavian SM, Monavari SH, Mozhgani SH, Taghizadeh M, Farahani M, Ansari N, Keyvani H. Molecular characterization of hepatitis D virus genotypes circulating in Iran. Future Virol 2018. [DOI: 10.2217/fvl-2017-0156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Aim: To determine the molecular epidemiology and characterization of hepatitis D virus (HDV) genotypes circulating in different provinces of Iran. Patients & methods: In this study, the presence of HDV RNA was tested in sera that were positive for hepatitis B surface antigen and HDV antibody by nested-PCR. HDV genotypes were subsequently analyzed using restriction fragment length polymorphism (RFLP) assay and then confirmed by sequencing. Results: 86.5% of positive PCR patients had genotype I and 8.1% had genotype II while the genotype of 5.4% of the patients remained undetermined by RFLP. Sequencing followed by phylogenetic analysis demonstrated that all the Iranian isolates were from genotype I. Conclusion: Although analyzing the RFLP of RT-PCR is a simpler method, the gold standard of genotyping of HDV is the phylogenetic analysis based on sequencing.
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Affiliation(s)
- Parisa Meysami
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran 1471613151, Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology & Liver Disease, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran
| | - Seyed Hamidreza Monavari
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sayed-Hamidreza Mozhgani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran 1471613151, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran 1471613151, Iran
| | - Morteza Taghizadeh
- Research & Development Viral Vaccine Department, Razi Vaccine & Serum Research Institute, Karaj 31975/148, Iran
| | - Maryam Farahani
- Department of Microbiology, Tehran Medical Branch, Islamic Azad University, Tehran 19395/1495, Iran
| | - Nastaran Ansari
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran 1471613151, Iran
| | - Hossein Keyvani
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
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Sellier PO, Maylin S, Brichler S, Berçot B, Lopes A, Chopin D, Pogliaghi M, Munier AL, Delcey V, Simoneau G, Evans J, Gordien E, Simon F, Bergmann JF. Hepatitis B Virus-Hepatitis D Virus mother-to-child co-transmission: A retrospective study in a developed country. Liver Int 2018; 38:611-618. [PMID: 28834623 DOI: 10.1111/liv.13556] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/15/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Hepatitis B Virus (HBV) DNA during chronic infection can reach levels at which mother-to-child (MTC) transmission frequently occurs despite passive-active immunization of newborns. Hepatitis D Virus (HDV) RNA can reach high levels, we assessed HBV/HDV MTC co-transmission. METHODS Monocentric retrospective study (registered in ClinicalTrials.gov (NCT02044055)), after informed consent in HBV/HDV co-infected women pregnant between 01/01/2004 and 01/01/2015 in Paris, France. The children were tested when 24 months of age or older. RESULTS Twenty-two (3%) of 742 HBV infected women, HDV co-infected, gave birth to 54 children during the study period. HBV DNA was above 5 Log10 I.U/mL in 10 pregnancies previous any treatment, with HDV RNA of less than 2.3 Log10 I.U/mL. HDV RNA was above 5 Log10 I.U/mL in eight pregnancies previous any treatment, with HBV DNA of less than 1.5 Log10 I.U/mL. Inverse patterns of HBV DNA and HDV RNA were observed in 17 of 35 (49%) pregnancies: 13 (76%) received no HBV treatment; four (24%) were treated. HBV DNA was under 5 Log10 I.U/mL in 46 of the 50 assessed women (92%) at birth. Of the 36 assessed children, given passive-active immunization, 24 (66%) were protected, 10 (28%) were neither infected nor protected, one was chronically HBV infected, and one had a past HBV infection. HDV Ab was negative in the 36 children. CONCLUSIONS These results suggest that HBV/HDV MTC co-transmission is exceptional. Studies are needed, mainly in developing countries.
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Affiliation(s)
- Pierre O Sellier
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Sarah Maylin
- Département de microbiologie, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Ségolène Brichler
- Laboratoire de Virologie, CNR des hépatites delta, Hôpital Avicenne, AP-HP, Bobigny, France
| | - Béatrice Berçot
- Département de microbiologie, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Amanda Lopes
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Dorothée Chopin
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Manuela Pogliaghi
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Anne-Lise Munier
- Département de Maladies Infectieuses, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Véronique Delcey
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Guy Simoneau
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - John Evans
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Emmanuel Gordien
- Laboratoire de Virologie, CNR des hépatites delta, Hôpital Avicenne, AP-HP, Bobigny, France
| | - François Simon
- Département de microbiologie, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
| | - Jean-François Bergmann
- Département de Médecine Interne, GH Saint-Louis/Lariboisière-Fernand Widal, AP-HP, Paris, France
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Global Mortality Burden of Cirrhosis and Liver Cancer Attributable to Injection Drug Use, 1990-2016: An Age-Period-Cohort and Spatial Autocorrelation Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15010170. [PMID: 29361804 PMCID: PMC5800269 DOI: 10.3390/ijerph15010170] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 01/19/2018] [Accepted: 01/20/2018] [Indexed: 12/19/2022]
Abstract
We analyzed the temporal and spatial variations in mortality burden of cirrhosis and liver cancer attributable to injection drug use (IDU) from 1990 to 2016. Mortality data of IDU-attributable cirrhosis and IDU-attributable liver cancer on the global and national scales from 1990 to 2016 were collected from the Global Burden of Disease (GBD) studies. Age-period-cohort (APC) model analysis was used to analyze the global mortality trends of target disease, and spatial autocorrelation analysis based on Geographic Information System was applied to illustrate the clusters of the most epidemic countries. Globally, from 1990 to 2015, mortality rates (age-standardized, per 100,000) of IDU-attributable cirrhosis increased continually from 1.5 to 1.9, while from 0.4 to 0.9 for IDU-attributable liver cancer. The APC model analysis indicated that the increases of mortality were mainly driven by period effects, with the mortality risk increasing by 6.82-fold for IDU-attributable cirrhosis and 3.08-fold for IDU-attributable liver cancer. The spatial analysis suggested that IDU-attributable cirrhosis mortality were geographically clustered from 1990 to 2016, and hot spots were mainly located in less well developed countries of Latin America, East and Central Europe and Central Asia. Our study provides epidemiological evidence for global interventions against advanced liver disease among injection drug users (IDUs).
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Abstract
Negative-sense single-stranded RNA virus (NSRV) is featured by their ribonucleoprotein (RNP) complex composed by viral polymerase and genomic RNA enwrapped by nucleocapsid protein (NP). The RNP is packaged in virions and plays a central role throughout virus lifecycle. In the past decade, structural biology presents molecular insights into NPs encoded by most representative NSRVs, helping to understand the mechanism of RNP formation. Interestingly, works initiated from structural biology also reveal unexpected biological functions of virus NP beyond a structural protein. All these further the knowledge of virus NP and provide great potential for the discovery of antiviral agents to target virus RNP formation. In this chapter, we will summarize the structures and functions of viral NPs, as well as the attempt of NP-targeted antiviral development.
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Affiliation(s)
- Zhiyong Lou
- MOE Key Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing, China.
- Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.
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48
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Chen X, Oidovsambuu O, Liu P, Grosely R, Elazar M, Winn VD, Fram B, Boa Z, Dai H, Dashtseren B, Yagaanbuyant D, Genden Z, Dashdorj N, Bungert A, Dashdorj N, Glenn JS. A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians. Hepatology 2017; 66:1739-1749. [PMID: 27880976 PMCID: PMC5441964 DOI: 10.1002/hep.28957] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 11/09/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022]
Abstract
Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis. HDV requires a hepatitis B virus (HBV) coinfection to provide HDV with HBV surface antigen envelope proteins. The net effect of HDV is to make the underlying HBV disease worse, including higher rates of hepatocellular carcinoma. Accurate assessments of current HDV prevalence have been hampered by the lack of readily available and reliable quantitative assays, combined with the absence of a Food and Drug Administration-approved therapy. We sought to develop a convenient assay for accurately screening populations and to use this assay to determine HDV prevalence in a population with abnormally high rates of hepatocellular carcinoma. We developed a high-throughput quantitative microarray antibody capture assay for anti-HDV immunoglobulin G wherein recombinant HDV delta antigen is printed by microarray on slides coated with a noncontinuous, nanostructured plasmonic gold film, enabling quantitative fluorescent detection of anti-HDV antibody in small aliquots of patient serum. This assay was then used to screen all HBV-infected patients identified in a large randomly selected cohort designed to represent the Mongolian population. We identified two quantitative thresholds of captured antibody that were 100% predictive of the sample either being positive on standard western blot or harboring HDV RNA detectable by real-time quantitative PCR. Subsequent screening of the HBV+ cohort revealed that a remarkable 57% were RNA+ and an additional 4% were positive on western blot alone. CONCLUSION The quantitative microarray antibody capture assay's unique performance characteristics make it ideal for population screening; its application to the Mongolian HBV surface antigen-positive population reveals an apparent ∼60% prevalence of HDV coinfection among these HBV-infected Mongolian subjects, which may help explain the extraordinarily high rate of hepatocellular carcinoma in Mongolia. (Hepatology 2017;66:1739-1749).
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Affiliation(s)
- Xiaohua Chen
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | | | - Ping Liu
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Rosslyn Grosely
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Menashe Elazar
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Virginia D. Winn
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, California
| | - Benjamin Fram
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
| | - Zhang Boa
- Department of Chemistry, Stanford University, Palo Alto, California
| | - Hongjie Dai
- Department of Chemistry, Stanford University, Palo Alto, California
| | - Bekhbold Dashtseren
- Liver Center, Ulaanbaatar, Mongolia
- Onom Foundation, Ulaanbaatar, Mongolia
- Mongolian National University of Health Sciences
| | - Dahgwahdorj Yagaanbuyant
- Liver Center, Ulaanbaatar, Mongolia
- Onom Foundation, Ulaanbaatar, Mongolia
- Mongolian National University of Health Sciences
| | - Zulkhuu Genden
- Liver Center, Ulaanbaatar, Mongolia
- Onom Foundation, Ulaanbaatar, Mongolia
| | | | | | | | - Jeffrey S. Glenn
- Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California
- Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, California
- Veterans Administration Medical Center, Palo Alto, California
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49
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Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, Schmid P, Le Gal F, Gordien E, Krawczyk A, Mijočević H, Karimzadeh H, Roggendorf M, Vaillant A. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2017; 2:877-889. [PMID: 28964701 DOI: 10.1016/s2468-1253(17)30288-1] [Citation(s) in RCA: 188] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 08/11/2017] [Accepted: 08/11/2017] [Indexed: 02/06/2023]
Affiliation(s)
| | - Victor Pântea
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Valentin Cebotarescu
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Lilia Cojuhari
- Department of Infectious Diseases, State University of Medicine and Pharmacy 'Nicolae Testemitanu', Chișinău, Moldova
| | - Pavlina Jimbei
- Toma Ciorbă Hospital of Infectious Diseases, Chișinău, Moldova
| | | | - Peter Schmid
- National Genetics Institute, Los Angeles, CA, USA
| | - Frédéric Le Gal
- Laboratoire de Microbiologie Clinique, Centre National de référence des hépatites B, C et Delta, Hôpitaux Universitaires de Paris Seine-Saint-Denis, Université Sorbonne Paris Cité, Paris, France
| | - Emmanuel Gordien
- Laboratoire de Microbiologie Clinique, Centre National de référence des hépatites B, C et Delta, Hôpitaux Universitaires de Paris Seine-Saint-Denis, Université Sorbonne Paris Cité, Paris, France
| | - Adalbert Krawczyk
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Hrvoje Mijočević
- Institute for Virology, Technical University of Munich, Munich, Germany
| | - Hadi Karimzadeh
- Institute for Virology, Technical University of Munich, Munich, Germany
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Luma HN, Eloumou SA, Okalla C, Donfack-Sontsa O, Koumitana R, Malongue A, Nko’Ayissi GB, Noah DN. Prevalence and Characteristics of Hepatitis Delta Virus Infection in a Tertiary Hospital Setting in Cameroon. J Clin Exp Hepatol 2017; 7:334-339. [PMID: 29234199 PMCID: PMC5715454 DOI: 10.1016/j.jceh.2017.05.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/15/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS Hepatitis B virus (HBV) and hepatitis D virus (HDV) coinfection is associated with more severe liver disease than HBV alone. More knowledge on the epidemiology and clinical impact of HDV-infected individuals is needed in Cameroon.We aimed at determining the frequency of anti-HDV antibody testing in hepatitis B surface antigen (HBsAg) positive patients, the proportion of anti-HDV positivity, and the characteristics of anti-HDV positive compared to anti-HDV negative patients in a tertiary hospital setting in Cameroon. METHODS A cross-sectional study was conducted. Clinical records of chronic HBV-infected patients attending the gastroenterology unit at the Douala General Hospital from 2010 to 2014 were reviewed. RESULTS Of 365 files of HBsAg-positive patients defined as chronic HBV infection, 80.5% (294) were tested for anti-HDV antibodies, among whom 10.5% (31/294) were positive. Median aspartate aminotransferase (P < 0.0001), alanine aminotransferase (P < 0.0001), and gamma glutaryl transpeptidase (P < 0.0001) were significantly higher while platelets count (P < 0.002) and prothrombin time (P < 0.0001) were significantly lower in anti-HDV positive compared to anti-HDV negative patients. Liver necroinflammation (P < 0.0001), fibrosis score (P < 0.0001), and decompensated cirrhosis (P < 0.0001) were also significantly associated with anti-HDV positivity. CONCLUSION The proportion of anti-HDV antibody positivity remains high in this setting and was significantly associated with more severe liver disease compared to those who were anti-HDV negative. More studies are needed to evaluate rates of HDV testing in other centers in Cameroon and the subregion. Preventive strategies for HBV prevention, which also apply to HDV, must still be reinforced by healthcare providers and policy makers.
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Key Words
- AFP, alpha-fetoproteins
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Cameroon
- ELISA, enzyme-linked immunosorbent assay
- GGT, gamma glutaryl transpeptidase
- HBV
- HBV, hepatitis B virus
- HBe ab, hepatitis B e antibody
- HBeAg, hepatitis B e antigen
- HBsAg, hepatitis B surface antigen
- HCC, hepatocellular carcinoma
- HDV
- HDV, hepatitis delta virus
- HIV, human immunodeficiency virus
- PT, prothrombin time
- fibrosis
- testing
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Affiliation(s)
- Henry N. Luma
- Internal Medicine Service, Douala General Hospital, Douala, Cameroon,Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon,Address for correspondence: Henry Namme Luma, P.O. Box 4856, Douala, Cameroon. Tel.: +237 699960059; fax: +237 243 37 01 46.Henry Namme Luma, P.O. Box 4856DoualaCameroon
| | - Servais A.F.B. Eloumou
- Internal Medicine Service, Douala General Hospital, Douala, Cameroon,Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
| | - Cécile Okalla
- Internal Medicine Service, Douala General Hospital, Douala, Cameroon,Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
| | | | - Ruth Koumitana
- Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
| | - Agnes Malongue
- Internal Medicine Service, Douala General Hospital, Douala, Cameroon
| | | | - Dominique N. Noah
- Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
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