Skip to main content
Top
Published in: Current Infectious Disease Reports 1/2012

01-02-2012 | Intra-abdominal Infections, Hepatitis, and Gastroenteritis (DA Bobak, Section Editor)

Current Concept in the Pathophysiology of Hepatitis Delta Infection

Authors: Grazia Anna Niro, Antonina Smedile

Published in: Current Infectious Disease Reports | Issue 1/2012

Login to get access

Abstract

Hepatitis delta virus (HDV) is a unique human virus, showing similarities with plant viroids. Although impressive knowledge on virus structure and replication has been achieved, several questions like HBV/HDV interaction and post translational modifications of HD antigens remain to be answered. Potential targets for therapeutic strategies are now emerging. To date, eight major genotypes of the HDV have been identified. The HDV-1 is the prevailing genotype in Europe, but migration phenomena may change this profile. Immune response is likely to play an important role in the pathogenesis of HDV-induced liver disease; few data are available on T cells response either during infection and therapy. HDV usually suppresses HBV replication; recent studies show as viral dominances may change over time. Delta infection leads to severe liver disease, with different patterns of progression to liver fibrosis and decompensation. Beside the association between HDV/HBV and HCC is demonstrated a risk specifically related to HDV remains controversial.
Literature
1.
go back to reference Rizzetto M, Canese MG, Aricò S, et al. Immunofluorescence detection of a new antigen-antibody system (delta/anti-delta) associated with hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977;18:997–1003.PubMedCrossRef Rizzetto M, Canese MG, Aricò S, et al. Immunofluorescence detection of a new antigen-antibody system (delta/anti-delta) associated with hepatitis B virus in liver and in serum of HBsAg carriers. Gut. 1977;18:997–1003.PubMedCrossRef
2.
go back to reference •• Rizzetto M, Hepatitis D. Thirty years after. J Hepatol. 2009;50:1043–5. This review summarizes the progress achieved in each field of research in the 30 years that have passed since the discovery of HDV. Particular relevance is reserved to the replicative mechanism of the HDV, the epidemiology of infection and the treatment of delta hepatitis. PubMedCrossRef •• Rizzetto M, Hepatitis D. Thirty years after. J Hepatol. 2009;50:1043–5. This review summarizes the progress achieved in each field of research in the 30 years that have passed since the discovery of HDV. Particular relevance is reserved to the replicative mechanism of the HDV, the epidemiology of infection and the treatment of delta hepatitis. PubMedCrossRef
3.
go back to reference Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31–40.PubMedCrossRef Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31–40.PubMedCrossRef
4.
go back to reference • Pascarella S, Negro F. Hepatitis D virus: un update. Liver Int. 2011;31(1):7–21. The study describes HDV structure and replication, pathogenicity and treatment options. PubMedCrossRef • Pascarella S, Negro F. Hepatitis D virus: un update. Liver Int. 2011;31(1):7–21. The study describes HDV structure and replication, pathogenicity and treatment options. PubMedCrossRef
5.
go back to reference Niro GA, Gioffreda D, Fontana R. Hepatitis delta virus infection: open issues. Dig Liver Dis. 2011;43S:S18–23. Niro GA, Gioffreda D, Fontana R. Hepatitis delta virus infection: open issues. Dig Liver Dis. 2011;43S:S18–23.
6.
go back to reference •• Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364(4):322–31. This study shows, in a large cohort of patients, as treatments with peginterferon alfa-2a for 48 weeks, with or without adefovir, result in sustained HDV RNA clearance in about one quarter of patients with HDV infection. PubMedCrossRef •• Wedemeyer H, Yurdaydìn C, Dalekos GN, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364(4):322–31. This study shows, in a large cohort of patients, as treatments with peginterferon alfa-2a for 48 weeks, with or without adefovir, result in sustained HDV RNA clearance in about one quarter of patients with HDV infection. PubMedCrossRef
7.
go back to reference Glenn JS. Prenylation of HDAg and antiviral drug development. Curr Top Microbiol Immunol. 2006;307:133–49.PubMedCrossRef Glenn JS. Prenylation of HDAg and antiviral drug development. Curr Top Microbiol Immunol. 2006;307:133–49.PubMedCrossRef
8.
go back to reference Sureau C. The role of the HBV envelope proteins in the HDV replication cycle. Curr Top Microbiol Immunol. 2006;307:113–31.PubMedCrossRef Sureau C. The role of the HBV envelope proteins in the HDV replication cycle. Curr Top Microbiol Immunol. 2006;307:113–31.PubMedCrossRef
9.
go back to reference Engelke M, Mills K, Seitz S, et al. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology. 2006;43(4):750–60.PubMedCrossRef Engelke M, Mills K, Seitz S, et al. Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology. 2006;43(4):750–60.PubMedCrossRef
10.
go back to reference Yurdaydin C, Idilman R, Bozkaya H, et al. Natural history and treatment of chronic delta hepatitis. J Viral Hepat. 2010;17(11):749–56.PubMedCrossRef Yurdaydin C, Idilman R, Bozkaya H, et al. Natural history and treatment of chronic delta hepatitis. J Viral Hepat. 2010;17(11):749–56.PubMedCrossRef
11.
go back to reference Niro GA, Gravinese E, Martini E, et al. Clearance of hepatitis B surface antigen in chronic carriers of hepatitis delta antibodies. Liver. 2001;21(4):254–9.PubMedCrossRef Niro GA, Gravinese E, Martini E, et al. Clearance of hepatitis B surface antigen in chronic carriers of hepatitis delta antibodies. Liver. 2001;21(4):254–9.PubMedCrossRef
12.
go back to reference Dény P. Hepatitis delta virus genetic variability: from genotype I, II, III to eight major clades? Curr Top Microbiol Immunol. 2006;307:151–71.PubMedCrossRef Dény P. Hepatitis delta virus genetic variability: from genotype I, II, III to eight major clades? Curr Top Microbiol Immunol. 2006;307:151–71.PubMedCrossRef
13.
go back to reference Hsu SC, Syu WJ, Sheen IJ, et al. Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications. Hepatology. 2002;35:665–72.PubMedCrossRef Hsu SC, Syu WJ, Sheen IJ, et al. Varied assembly and RNA editing efficiencies between genotypes I and II hepatitis D virus and their implications. Hepatology. 2002;35:665–72.PubMedCrossRef
14.
go back to reference • Shih HH, Shih C, Wang HW, et al. Pro-205 of large hepatitis delta antigen and Pro-62 of major hepatitis B surface antigen influence the assembly of different genotypes of hepatitis D virus. J Gen Virol. 2010;91:1004–12. Pro-205 of the HDAg-L and Pro-62 of the major HBsAg and their role in the assembly of HDV of different genotypes are investigated. The presence of Pro-205 in genotype 1 HDV may account for its higher assembly efficiencies and wider distribution. PubMedCrossRef • Shih HH, Shih C, Wang HW, et al. Pro-205 of large hepatitis delta antigen and Pro-62 of major hepatitis B surface antigen influence the assembly of different genotypes of hepatitis D virus. J Gen Virol. 2010;91:1004–12. Pro-205 of the HDAg-L and Pro-62 of the major HBsAg and their role in the assembly of HDV of different genotypes are investigated. The presence of Pro-205 in genotype 1 HDV may account for its higher assembly efficiencies and wider distribution. PubMedCrossRef
15.
go back to reference Su C-W, Huang Y-H, Huo T-L, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology. 2006;130:1625–35.PubMedCrossRef Su C-W, Huang Y-H, Huo T-L, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology. 2006;130:1625–35.PubMedCrossRef
16.
go back to reference • Kiesslich D, Crispim MA, Santos C, et al. Influence of hepatitis B virus (HBV) genotype on the clinical course of disease in patients coinfected with HBV and hepatitis delta virus. J Infect Dis. 2009;199:1608–11. This study shows that liver inflammation and HDV load are influenced by HBV genotype in individuals coinfected with HBV and HDV.HBV genotype in individuals coinfected with HBV and HDV.PubMedCrossRef • Kiesslich D, Crispim MA, Santos C, et al. Influence of hepatitis B virus (HBV) genotype on the clinical course of disease in patients coinfected with HBV and hepatitis delta virus. J Infect Dis. 2009;199:1608–11. This study shows that liver inflammation and HDV load are influenced by HBV genotype in individuals coinfected with HBV and HDV.HBV genotype in individuals coinfected with HBV and HDV.PubMedCrossRef
17.
go back to reference Cole SM, Gowans EJ, Macnaughton TB, et al. Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen. Hepatology. 1991;13:845–51.PubMedCrossRef Cole SM, Gowans EJ, Macnaughton TB, et al. Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen. Hepatology. 1991;13:845–51.PubMedCrossRef
18.
go back to reference •Zachou K, Yurdaydin C, Drebber U, et al. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int. 2009: Liver Int. 2010;30(3):430–7. The authors demonstrate that HBsAg levels correlate with HDV viremia in chronic HDV. Biochemical parameters do not accurately indicate the stage and grade of liver disease in chronic HDV; liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients. •Zachou K, Yurdaydin C, Drebber U, et al. Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. Liver Int. 2009: Liver Int. 2010;30(3):430–7. The authors demonstrate that HBsAg levels correlate with HDV viremia in chronic HDV. Biochemical parameters do not accurately indicate the stage and grade of liver disease in chronic HDV; liver biopsy seems to remain the major tool for the evaluation of delta hepatitis patients.
19.
go back to reference Nisini R, Paroli M, Accapezzato D, et al. Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J Virol. 1997;71:2241–51.PubMed Nisini R, Paroli M, Accapezzato D, et al. Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J Virol. 1997;71:2241–51.PubMed
20.
go back to reference Aslan N, Yurdaydin C, Wiegand J, et al. Cytotoxic CD4 T cells in viral hepatitis. J Viral Hepat. 2006;13:505–14.PubMedCrossRef Aslan N, Yurdaydin C, Wiegand J, et al. Cytotoxic CD4 T cells in viral hepatitis. J Viral Hepat. 2006;13:505–14.PubMedCrossRef
21.
go back to reference Huang YH, Tao MH, Hu CP, et al. Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus. J Gen Virol. 2004;85:3089–98.PubMedCrossRef Huang YH, Tao MH, Hu CP, et al. Identification of novel HLA-A*0201-restricted CD8+ T-cell epitopes on hepatitis delta virus. J Gen Virol. 2004;85:3089–98.PubMedCrossRef
22.
go back to reference Grabowski J, Suneetha PV, Jaroszewicz J, et al. HDV and HBV specific T cell response patterns in patients with delta hepatitis. Hepatology. 2009;50:733A–4. Grabowski J, Suneetha PV, Jaroszewicz J, et al. HDV and HBV specific T cell response patterns in patients with delta hepatitis. Hepatology. 2009;50:733A–4.
23.
go back to reference Casey JL, Tennant BC, Gerin JL. Genetic changes in hepatitis delta virus from acutely and chronically infected woodchucks. J Virol. 2006;80(13):6469–77.PubMedCrossRef Casey JL, Tennant BC, Gerin JL. Genetic changes in hepatitis delta virus from acutely and chronically infected woodchucks. J Virol. 2006;80(13):6469–77.PubMedCrossRef
24.
go back to reference •• Pugnale P, Pazienza V, Guilloux K, et al. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 2008;49:398–406. IFN-alpha-induced intracellular signaling is impaired in HDV-transfected human hepatoma cells. HDV subverts the effect of IFN-alpha by blocking Tyk2 activation, thereby resulting in selective impairment of activation and translocation to the nucleus of STAT1 and STAT2. This interference could induce viral persistence and treatment resistance. CrossRef •• Pugnale P, Pazienza V, Guilloux K, et al. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 2008;49:398–406. IFN-alpha-induced intracellular signaling is impaired in HDV-transfected human hepatoma cells. HDV subverts the effect of IFN-alpha by blocking Tyk2 activation, thereby resulting in selective impairment of activation and translocation to the nucleus of STAT1 and STAT2. This interference could induce viral persistence and treatment resistance. CrossRef
25.
go back to reference Liao FT, Lee YI, Ko JL, et al. Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells. J Gen Virol. 2009;90:1124–34.PubMedCrossRef Liao FT, Lee YI, Ko JL, et al. Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells. J Gen Virol. 2009;90:1124–34.PubMedCrossRef
26.
go back to reference Jardi R, Rodriguez F, Buti M, et al. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology. 2001;34:404–10.PubMedCrossRef Jardi R, Rodriguez F, Buti M, et al. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology. 2001;34:404–10.PubMedCrossRef
27.
go back to reference • Williams V, Brichler S, Radjef N, et al. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol. 2009;90:2759–67. This study examines how HDV proteins inhibit HBV replication. PubMedCrossRef • Williams V, Brichler S, Radjef N, et al. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol. 2009;90:2759–67. This study examines how HDV proteins inhibit HBV replication. PubMedCrossRef
28.
go back to reference Heildrich B, Deterding K, Tillmann HL, et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat. 2009;16:883–94.CrossRef Heildrich B, Deterding K, Tillmann HL, et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J Viral Hepat. 2009;16:883–94.CrossRef
29.
go back to reference • Romeo R, Del Ninno E, Rumi M, et al. A 28-year study of the course of hepatitis delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009;136:1629–38. Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality. PubMedCrossRef • Romeo R, Del Ninno E, Rumi M, et al. A 28-year study of the course of hepatitis delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009;136:1629–38. Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality. PubMedCrossRef
30.
go back to reference • Niro GA, Smedile A, Ippolito AM, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53:834–40. HDV liver disease lasts several decades. Half of all patients who develop cirrhosis later will advance to liver failure. Interferon therapy is effective to slow or alter the natural course of liver disease. PubMedCrossRef • Niro GA, Smedile A, Ippolito AM, et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol. 2010;53:834–40. HDV liver disease lasts several decades. Half of all patients who develop cirrhosis later will advance to liver failure. Interferon therapy is effective to slow or alter the natural course of liver disease. PubMedCrossRef
31.
go back to reference Wu JC, Chen TZ, Huang YS, et al. Natural history of hepatitis D viral superinfection: significance of viremia detected by polymerase chain reaction. Gastroenterology. 1995;108:796–802.PubMedCrossRef Wu JC, Chen TZ, Huang YS, et al. Natural history of hepatitis D viral superinfection: significance of viremia detected by polymerase chain reaction. Gastroenterology. 1995;108:796–802.PubMedCrossRef
32.
go back to reference Raimondo G, Brunetto MR, Pontisso P, et al. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology. 2006;43(1):100–7.PubMedCrossRef Raimondo G, Brunetto MR, Pontisso P, et al. Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology. 2006;43(1):100–7.PubMedCrossRef
33.
go back to reference • Schaper M, Rodriguez-Frias F, Jardi R, et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol. 2010;52: 658–64. Longitudinal evaluation of viremia shows a complex interaction between HBV and HDV and is essential to understand the pathophysiology of chronic HDV infection. PubMedCrossRef • Schaper M, Rodriguez-Frias F, Jardi R, et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol. 2010;52: 658–64. Longitudinal evaluation of viremia shows a complex interaction between HBV and HDV and is essential to understand the pathophysiology of chronic HDV infection. PubMedCrossRef
35.
go back to reference Antonucci G, Vairo F, Iacomi F, et al. Role of hepatitis B virus, hepatitis D virus and other determinants on suppression of hepatitis C viraemia in HIV infected patients with chronic HCV infection: a longitudinal evaluation. Scand J Infect Dis. 2008;40:928–34.PubMedCrossRef Antonucci G, Vairo F, Iacomi F, et al. Role of hepatitis B virus, hepatitis D virus and other determinants on suppression of hepatitis C viraemia in HIV infected patients with chronic HCV infection: a longitudinal evaluation. Scand J Infect Dis. 2008;40:928–34.PubMedCrossRef
36.
go back to reference Sheldon J, Ramos B, Toro C, et al. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients? Antivir Ther. 2008;13:97–102.PubMed Sheldon J, Ramos B, Toro C, et al. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients? Antivir Ther. 2008;13:97–102.PubMed
37.
go back to reference • Buti M, Homs M, Rodriguez-Frias F, et al. Clinical outcome of acute and chronic hepatitis over time: a long-term follow-up study. J Viral Hepat. 2011;18:434–42. This study indicates an outbreak of HDV at the end of the 1980s and the beginning of the 1990s. Currently, patients with chronic HDV disease are older, and factors associated with worse prognosis include the presence of cirrhosis and age at the time of diagnosis. PubMedCrossRef • Buti M, Homs M, Rodriguez-Frias F, et al. Clinical outcome of acute and chronic hepatitis over time: a long-term follow-up study. J Viral Hepat. 2011;18:434–42. This study indicates an outbreak of HDV at the end of the 1980s and the beginning of the 1990s. Currently, patients with chronic HDV disease are older, and factors associated with worse prognosis include the presence of cirrhosis and age at the time of diagnosis. PubMedCrossRef
38.
go back to reference Rosina F, Conoscitore P, Cuppone R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology. 1999;117:161–6.PubMedCrossRef Rosina F, Conoscitore P, Cuppone R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology. 1999;117:161–6.PubMedCrossRef
Metadata
Title
Current Concept in the Pathophysiology of Hepatitis Delta Infection
Authors
Grazia Anna Niro
Antonina Smedile
Publication date
01-02-2012
Publisher
Current Science Inc.
Published in
Current Infectious Disease Reports / Issue 1/2012
Print ISSN: 1523-3847
Electronic ISSN: 1534-3146
DOI
https://doi.org/10.1007/s11908-011-0233-5

Other articles of this Issue 1/2012

Current Infectious Disease Reports 1/2012 Go to the issue

HIV/AIDS (RD MacArthur, Section Editor)

Kidney Disease in HIV-Infected Persons

Intra-abdominal Infections, Hepatitis, and Gastroenteritis (DA Bobak, Section Editor)

Gastrointestinal Infections in the Setting of Natural Disasters

HIV/AIDS (RD MacArthur, Section Editor)

HIV/AIDS in Women and Racial/Ethnic Minorities in the U.S.

Intra-abdominal Infections, Hepatitis, and Gastroenteritis (DA Bobak, Section Editor)

Update on Cytomegalovirus Infections of the Gastrointestinal System in Solid Organ Transplant Recipients

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.