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Clinical, epidemiological and virological features of acute hepatitis B in Italy

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Abstract

Purpose

To evaluate the association of hepatitis B virus (HBV) genotypes, basal core promoter (BCP)/precore (PC) and S gene mutations with the clinical-epidemiological characteristics of acute hepatitis B (AHB) in Italy.

Methods

During July 2005–January 2007, 103 symptomatic AHB patients were enrolled and prospectively followed up at 15 national hospitals. HBV genotypes, BCP/PC and S gene variants were determined by nested-PCR and direct sequence analysis.

Results

Genotype D, A and F were detected in 49, 45 and 6 % of patients, respectively. BCP, PC, and BCP plus PC variants were found in 3.1, 11.3 and 7.2 % of patients, respectively. At enrollment, 68.3 % of patients were hepatitis B e antigen (HBeAg)-positive and 31.7 % HBeAg-negative. BCP/PC mutations were more common in HBeAg-negative than in HBeAg-positive patients (p < 0.0001). Compared to genotype D patients, those harboring non-D genotypes were more frequently males (p = 0.023), HBeAg-positive (p < 0.001), had higher bilirubin (p = 0.014) and viremia (p = 0.034) levels and less frequently carried BCP/PC mutations (p < 0.001). Non-D genotype patients more often were from Central Italy (p = 0.001) and reported risky sexual exposure (p = 0.021). Two patients had received vaccination before AHB: one harbored genotype F; the other showed a S gene mutation. Four patients developed fulminant AHB; mutations were found in 2 of 3 patients who underwent BCP/PC sequencing. After a 6-month follow-up, only 2 (2.8 %) patients developed persistent infection.

Conclusion

AHB by non-D genotypes is increasing in Italy and is associated with risky sexual exposure. The ability of some genotypes to cause persistent and/or severe infection in Italy warrants larger studies for clarification.

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References

  1. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373:582–92.

    Article  CAS  PubMed  Google Scholar 

  2. World Health Organization (WHO). Available, from: http://www.who.int/mediacentre/factsheets/fs204/en/. Updated April 2014.

  3. Romanò L, Velati C, Cambiè G, et al. Hepatitis B virus infection among first-time blood donors in Italy: prevalence and correlates between serological patterns and occult infection. Blood Transfus. 2013;1:281–8.

    Google Scholar 

  4. Stroffolini T, Guadagnino V, Rapicetta M, et al. The impact of a vaccination campaign against hepatitis B on the further decrease of hepatitis B virus infection in a southern Italian town over 14 years. Eur J Intern Med. 2012;23:e190–2.

    Article  PubMed  Google Scholar 

  5. Fabris P, Baldo V, Baldovin T, et al. Changing epidemiology of HCV and HBV infections in Northern Italy: a survey in the general population. J Clin Gastroenterol. 2008;42:527–32.

    Article  PubMed  Google Scholar 

  6. Integrated epidemiological system for acute viral hepatitis. Available, from: http://www.iss.it/seieva/. Updated April 2014.

  7. Mele A, Tosti ME, Mariano A, et al. Acute hepatitis B 14 years after the implementation of universal vaccination in Italy: areas of improvement and emerging challenges. Clin Infect Dis. 2008;46:868–75.

    Article  PubMed  Google Scholar 

  8. Palumbo E, Scotto G, Cibelli DC, et al. Immigration and hepatitis B virus: epidemiological, clinical and therapeutic aspects. East Mediterr Health J. 2008;14:784–90.

    CAS  PubMed  Google Scholar 

  9. Fasano M, Saracino A, Carosi G, et al. Hepatitis B and immigrants: a SIMIT multicenter cross-sectional study. Infection. 2013;41:53–9.

    Article  CAS  PubMed  Google Scholar 

  10. Shi YH. Correlation between hepatitis B virus genotypes and clinical outcomes. Jpn J Infect Dis. 2012;65:476–82.

    Article  PubMed  Google Scholar 

  11. Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: recent advances. J Gastroenterol Hepatol. 2011;26:123–30.

    Article  PubMed  Google Scholar 

  12. Ozasa A, Tanaka Y, Orito E, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology. 2006;44:326–34.

    Article  CAS  PubMed  Google Scholar 

  13. Ehata T, Omata M, Chuang WL, et al. Mutations in core nucleotide sequence of hepatitis B virus correlate with fulminant and severe hepatitis. J Clin Invest. 1993;91:1206–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Dal Molin G, Poli A, Crocè LS, D’Agaro P, et al. Hepatitis B virus genotypes, core promoter variants, and precore stop codon variants in patients infected chronically in North-Eastern Italy. J Med Virol. 2006;78:734–40.

    Article  CAS  PubMed  Google Scholar 

  15. Brunetto MR, Giarin MM, Oliveri F, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci USA. 1991;88:4186–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. De Mitri MS, Cassini R, Morsica G, et al. Virological analysis, genotypes and mutational patterns of the HBV precore/core gene in HBV/HCV-related hepatocellular carcinoma. J Viral Hepat. 2006;13:574–81.

    Article  PubMed  Google Scholar 

  17. Coppola N, Masiello A, Tonziello G, et al. Factors affecting the changes in molecular epidemiology of acute hepatitis B in a Southern Italian area. J Viral Hepat. 2010;17:493–500.

    CAS  PubMed  Google Scholar 

  18. Scalia G, Russo R, Palermo I, et al. Clinical, virological and epidemiological aspects of acute B hepatitis in the Catania area (Italy). Infez Med. 2010;18:169–74.

    PubMed  Google Scholar 

  19. Coppola N, Sagnelli C, Pisaturo M, et al. Clinical and virological characteristics associated with severe acute hepatitis B. Clin Microbiol Infect. 2014;20:O991–7. doi:10.1111/1469-0691.12720.

    Article  CAS  PubMed  Google Scholar 

  20. Stroffolini T, Rapicetta M, Lombardo F, et al. Historical study of acute hepatitis B in subjects with or without hepatitis C infection. Eur J Intern Med. 2012;23:e146–9.

    Article  PubMed  Google Scholar 

  21. Rodella A, Galli C, Terlenghi L, et al. Quantitative analysis of HBsAg, IgM anti-HBc and anti-HBc avidity in acute and chronic hepatitis B. J Clin Virol. 2006;37:206–12.

    Article  CAS  PubMed  Google Scholar 

  22. Chan HL, Hussain M, Lok AS. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology. 1999;29:976–84.

    Article  CAS  PubMed  Google Scholar 

  23. Chemin I, Zoulim F, Merle P, et al. High incidence of hepatitis B infections among chronic hepatitis cases of unknown aetiology. J Hepatol. 2001;34:447–54.

    Article  CAS  PubMed  Google Scholar 

  24. Sagnelli C, Ciccozzi M, Pisaturo M, et al. Molecular epidemiology of hepatitis B virus genotypes circulating in acute hepatitis B patients in the Campania region. J Med Virol. 2014;86:1683–93.

    Article  PubMed  Google Scholar 

  25. Kobayashi M, Ikeda K, Arase Y, et al. Change of hepatitis B virus genotypes in acute and chronic infections in Japan. J Med Virol. 2008;80:1880–4.

    Article  PubMed  Google Scholar 

  26. Tamada Y, Yatsuhashi H, Masaki N, et al. Hepatitis B virus strains of subgenotype A2 with an identical sequence spreading rapidly from the capital region to all over Japan in patients with acute hepatitis B. Gut. 2012;61:765–73.

    Article  PubMed  Google Scholar 

  27. Yotsuyanagi H, Okuse C, Yasuda K, et al. Distinct geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan. J Med Virol. 2005;77:39–46.

    Article  CAS  PubMed  Google Scholar 

  28. van Houdt R, Bruisten SM, Koedijk FD, et al. Molecular epidemiology of acute hepatitis B in the Netherlands in 2004: nationwide survey. J Med Virol. 2007;79:895–901.

    Article  PubMed  Google Scholar 

  29. Sloan RD, Strang AL, Ramsay ME, et al. Genotyping of acute HBV isolates from England, 1997-2001. J Clin Virol. 2009;44:157–60.

    Article  CAS  PubMed  Google Scholar 

  30. Yotsuyanagi H, Ito K, Yamada N, et al. High levels of hepatitis B virus after the onset of disease lead to chronic infection in patients with acute hepatitis B. Clin Infect Dis. 2013;57:935–42.

    Article  CAS  PubMed  Google Scholar 

  31. Ito K, Yotsuyanagi H, Yatsuhashi H, et al. Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults. Hepatology. 2014;59:89–97.

    Article  CAS  PubMed  Google Scholar 

  32. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA. 1994;91:4077–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Chulanov VP, Shipulin GA, Schaefer S, et al. Kinetics of HBV DNA and HBsAg in acute hepatitis B patients with and without coinfection by other hepatitis viruses. J Med Virol. 2003;69:313–23.

    Article  CAS  PubMed  Google Scholar 

  34. Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis. 1995;20:992–1000.

    Article  CAS  PubMed  Google Scholar 

  35. Schillie SF, Spradling PR, Murphy TV. Immune response of hepatitis B vaccine among persons with diabetes: a systematic review of the literature. Diabetes Care. 2012;35:2690–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Tacke F, Amini-Bavil-Olyaee S, Heim A, et al. Acute hepatitis B virus infection by genotype F despite successful vaccination in an immune-competent German patient. J Clin Virol. 2007;38:353–7.

    Article  CAS  PubMed  Google Scholar 

  37. Ren F, Tsubota A, Hirokawa T, et al. A unique amino acid substitution, T126I, in human genotype C of hepatitis B virus S gene and its possible influence on antigenic structural change. Gene. 2006;383:43–51.

    Article  CAS  PubMed  Google Scholar 

  38. Sticchi L, Caligiuri P, Cacciani R, et al. Epidemiology of HBV S-gene mutants in the Liguria Region, Italy: implications for surveillance and detection of new escape variants. Hum Vaccin Immunother. 2013;9:568–71.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Lorenzo Fantozzi for his technical assistance. This work was supported in part by the project “Sorveglianze speciali” of the Italian Ministry of the Health (Istituto Superiore di Sanità- Fasc. ISS 1M56.) Abbott Diagnostics Italy has supported this study by providing the reagents for the serological assays and sample transportation from the clinical sites to the reference laboratories.

Conflict of interest

All authors, with the exception of Claudio Galli, Alessandro R. Zanetti and Gloria Taliani, do not have potential competing interests. Claudio Galli is currently employed by Abbott Diagnostics Italy as the Scientific Affairs Manager. Abbott Diagnostics Italy has supported this study by providing the reagents for the serological assays and sample transportation from the clinical sites to the reference laboratories. Alessandro R. Zanetti has received a speaker honorarium from Glaxo Smith Kline and a consulting honorarium from Sanofi Pasteur MSD. Gloria Taliani has received speaker’s honoraria form Bristol-Myers Squibb, Gilead, Janssen Cilag, Merck and AbbVie.

Ethical approval

This study has been performed in accordance with the 1964 Declaration of Helsinki and its later amendments and was approved by the Istituto Superiore di Sanità ethics committee.

Author information

Author notes

    Authors and Affiliations

    1. Surveillance and Health Promotion, National Center of Epidemiology, Istituto Superiore di Sanità, Rome, Italy

      Ornella Zuccaro, Alfonso Mele & Maria Elena Tosti

    2. Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

      Luisa Romanò & Alessandro Remo Zanetti

    3. Clinical Research Department, National Institute for Infectious Diseases Lazzaro Spallanzani, Rome, Italy

      Andrea Mariano

    4. Laboratory of Microbiology and Virology, IRCCS San Raffaele, Milan, Italy

      Massimo Clementi

    5. Department of Infectious and Tropical Diseases, Sapienza University of Rome, Rome, Italy

      Gloria Taliani

    6. Scientific Affairs, Abbott Diagnostics, Rome, Italy

      Claudio Galli

    7. Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

      Enea Spada

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    1. Ornella Zuccaro
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    Corresponding author

    Correspondence to Enea Spada.

    Additional information

    Ornella Zuccaro and Luisa Romanò contributed equally to this work.

    Members of the Study Group are listed in the Appendix.

    Appendix

    Appendix

    Members of the Study Group include:

    Enzo Raise (Department of Tropical and Infectious Disease, Ospedale dell’Angelo, Mestre, Venezia, Italy); Franklyn Esoka Eseme (Department of Tropical and Infectious Disease, Ospedale dell’Angelo, Mestre, Venezia, Italy); Giuseppe Maio (Division of Infectious Diseases, G. Rummo Hospital, Benevento, Italy); Patrizia Maio (Infectious Diseases Unit, S.G. Moscati Hospital, Avellino, Italy); Cinzia Di Giuli (Infectious Diseases Clinic, Santa Maria Hospital, Terni, Italy); Pietro Bellissima (Infectious Diseases Unit, Gravina Hospital, Caltagirone, Catania, Italy); Salvatore Bonfante (Infectious Diseases Unit, Gravina Hospital, Caltagirone, Catania, Italy); Piergiorgio Chiriacò (Infectious Diseases Unit, A. Perrino Hospital, Brindisi, Italy); Bruno Cacopardo (Department of Clinical and Molecular Biomedicine, Division of Infectious Diseases, University of Catania, Italy); Pierluigi Blanc (Infectious Diseases Unit, Malattie infettive. S. Maria Annunziata Hospital, Firenze, Italy); Stefania Palattella (Clinic of Infectious Diseases, University of Bari, Bari, Italy); Teresa Santantonio (Clinic of Infectious Diseases, University of Bari, Bari, Italy); Angela Guastadisegni (Clinic of Infectious Diseases, University of Bari, Bari, Italy); Pietro Amoroso (Department of Infectious Diseases, Cotugno Hospital, Naples, Italy); Paolo Fabris (Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy); Maria Teresa Giordani (Department of Infectious Diseases and Tropical Medicine, S. Bortolo Hospital, Vicenza, Italy); Vincenzo Vullo (Department of Public Health and Infectious Diseases,University of Rome “Sapienza”Rome Italy), Claudia D’Agostino (Department of Public Health and Infectious Diseases,University of Rome “Sapienza”Rome Italy); Tiziana Giuberti (Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy); Simona Schivazzappa (Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy); Michele Trezzi (Division of Infectious Diseases, “Santa Maria della Misericordia” Hospital, Grosseto, Italy); Gabriella Verucchi (Infectious Diseases Section, Department of Internal Medicine, Geriatric Medicine and Nephrology, University of Bologna, Bologna, Italy); Carlo Biagetti (Infectious Diseases Section, Department of Internal Medicine, Geriatric Medicine and Nephrology, University of Bologna, Bologna, Italy); Daria Pocaterra (Infectious Diseases Section, Department of Internal Medicine, Geriatric Medicine and Nephrology, University of Bologna, Bologna, Italy); Evangelista Sagnelli (Department of Public Medicine, Second University of Naples, Naples, Italy); Vincenzo Messina (Infectious Diseases Unit, A.O.R.N. Sant’Anna e San Sebastiano, Caserta, Italy); Giorgio Antonucci (Clinical Department of Infectious Diseases, National Institute for Infectious Disease, L. Spallanzani, Rome, Italy); Francesco Vairo (Clinical Department of Infectious Diseases, National Institute for Infectious Disease, L. Spallanzani, Rome, Italy); Marcello Marinelli, (Microbiology, IRCCS San Raffaele, Milan, Italy); Sara Paladini, Catia Tagliacarne (University of Milan, Department of Biomedical Sciences for Health, Milan, Italy).

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    Zuccaro, O., Romanò, L., Mele, A. et al. Clinical, epidemiological and virological features of acute hepatitis B in Italy. Infection 43, 431–441 (2015). https://doi.org/10.1007/s15010-015-0747-0

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