Skip to main content

Advertisement

SpringerLink
Log in

Virological and Clinical Characteristics of Hepatitis B Virus Genotype A

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

An Erratum to this article was published on 25 July 2017

This article has been updated

Abstract

Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections in humans. The overall prevalence of hepatitis B surface antigen (HBsAg) is reported to be 3.6%; however, it varies depending upon the geographic area. HBV is classified into ten genotypes (A through J) on the basis of an intergroup genomic divergence of > 8%. Specifically, HBV genotype A exhibits several unique virological and clinical characteristics and can be further classified into seven subtypes. Among them, subtype A2 or Ae (A2/[e]) is occasionally responsible for nosocomial infection and among homosexual males. Regarding virological factors, the G1896A precore mutation is rarely observed in genotype A as it would disrupt an essential stem-loop structure in the ε signal essential for pregenomic RNA packaging. HBV genotype A also harbors a 6-nucleotide C-terminal insertion in the hepatitis B-e antigen (HBeAg) precursor, resulting in a variable-length HBeAg protein product observed in serum of positive patients. These molecular traits likely contribute to the specific clinical presentation of genotype A-infected patients, such as mild acute hepatitis B (AHB), longer persistence of HBsAg positivity in AHB, and increased chronicity after AHB in adults. However, genotype A shows a better response to interferon than other genotypes in chronic hepatitis B patients. Here, we review the virological and clinical characteristics of HBV genotype A that will be useful in elucidating the association among persistent viral infection, host genetic factors, and treatment in future studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 25 July 2017

    An erratum to this article has been published.

Abbreviations

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

nt:

Nucleotide

HBeAg:

Hepatitis B-e antigen

IFN:

Interferon

MSM:

Males who have sex with males

AHB:

Acute hepatitis B

CTLs:

Cytotoxic T lymphocytes

HBsAg:

Hepatitis B surface antigen

NAs:

Nucleos(t)ide analogues

ALT:

Alanine aminotransferase

CHB:

Chronic hepatitis B

References

  1. Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384(9959):2053–63.

    Article  CAS  PubMed  Google Scholar 

  2. Locarnini S, Hatzakis A, Chen DS, et al. Strategies to control hepatitis B: Public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62(1 Suppl):S76–86.

    Article  PubMed  Google Scholar 

  3. Okamoto H, Tsuda F, Sakugawa H, et al. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988;69(Pt 10):2575–83 Epub 1988/10/01.

    Article  CAS  PubMed  Google Scholar 

  4. Norder H, Hammas B, Lofdahl S, et al. Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains. J Gen Virol. 1992;73(Pt 5):1201–8.

    Article  CAS  PubMed  Google Scholar 

  5. Kramvis A, Kew M, Francois G. Hepatitis B virus genotypes. Vaccine. 2005;23(19):2409–23.

    Article  CAS  PubMed  Google Scholar 

  6. Ito K, Kim KH, Lok AS, et al. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol. 2009;83(8):3507–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kurbanov F, Tanaka Y, Mizokami M. Geographical and genetic diversity of the human hepatitis B virus. Hepatol Res. 2010;40(1):14–30.

    Article  PubMed  Google Scholar 

  8. Tanaka Y, Hasegawa I, Kato T, et al. A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology. 2004;40(3):747–55.

    Article  PubMed  Google Scholar 

  9. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003;125(2):444–51.

    Article  PubMed  Google Scholar 

  10. Lin CL, Kao JH. Hepatitis B virus genotypes and variants. Cold Spring Harb Perspect Med. 2015;5(5):a021436.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lin CL, Kao JH. Recent advances in the treatment of chronic hepatitis B. Expert Opin Pharmacother. 2011;12(13):2025–40.

    Article  PubMed  Google Scholar 

  12. Noto H, Terao T, Ryou S, et al. Combined passive and active immunoprophylaxis for preventing perinatal transmission of the hepatitis B virus carrier state in Shizuoka, Japan during 1980–1994. J Gastroenterol Hepatol. 2003;18(8):943–9 Epub 2003/07/16.

    Article  PubMed  Google Scholar 

  13. Yoshikawa A, Suzuki K, Abe A, et al. Effect of selective vaccination on a decrease in the rate of hepatitis B virus-positive Japanese first-time blood donors. Transfus Med. 2009;19(4):172–9 Epub 2009/08/27.

    Article  CAS  PubMed  Google Scholar 

  14. Matsuura K, Tanaka Y, Hige S, et al. Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A. J Clin Microbiol. 2009;47(5):1476–83.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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(2):326–34.

    Article  CAS  PubMed  Google Scholar 

  16. Ito K, Yotsuyanagi H, Sugiyama M, et al. Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan. J Gastroenterol Hepatol. 2016;31(1):180–9.

    Article  PubMed  Google Scholar 

  17. Bowyer SM, van Staden L, Kew MC, et al. A unique segment of the hepatitis B virus group A genotype identified in isolates from South Africa. J Gen Virol. 1997;78(Pt 7):1719–29.

    Article  CAS  PubMed  Google Scholar 

  18. Sugauchi F, Kumada H, Acharya SA, et al. Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. J Gen Virol. 2004;85(Pt 4):811–20.

    Article  CAS  PubMed  Google Scholar 

  19. Kimbi GC, Kramvis A, Kew MC. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol. 2004;85(Pt 5):1211–20.

    Article  CAS  PubMed  Google Scholar 

  20. Kurbanov F, Tanaka Y, Fujiwara K, et al. A new subtype (subgenotype) Ac (A3) of hepatitis B virus and recombination between genotypes A and E in Cameroon. J Gen Virol. 2005;86(Pt 7):2047–56.

    Article  CAS  PubMed  Google Scholar 

  21. Olinger CM, Venard V, Njayou M, et al. Phylogenetic analysis of the precore/core gene of hepatitis B virus genotypes E and A in West Africa: new subtypes, mixed infections and recombinations. J Gen Virol. 2006;87(Pt 5):1163–73.

    Article  CAS  PubMed  Google Scholar 

  22. Pourkarim MR, Lemey P, Amini-Bavil-Olyaee S, et al. Novel hepatitis B virus subgenotype A6 in African-Belgian patients. J Clin Virol. 2010;47(1):93–6.

    Article  CAS  PubMed  Google Scholar 

  23. Hubschen JM, Mbah PO, Forbi JC, et al. Detection of a new subgenotype of hepatitis B virus genotype A in Cameroon but not in neighbouring Nigeria. Clin Microbiol Infect. 2011;17(1):88–94.

    Article  CAS  PubMed  Google Scholar 

  24. Pourkarim MR, Amini-Bavil-Olyaee S, Kurbanov F, et al. Molecular identification of hepatitis B virus genotypes/subgenotypes: revised classification hurdles and updated resolutions. World J Gastroenterol. 2014;20(23):7152–68.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ramachandran S, Purdy MA, Xia GL, et al. Recent population expansions of hepatitis B virus in the United States. J Virol. 2014;88(24):13971–80.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dreesman JM, Baillot A, Hamschmidt L, et al. Outbreak of hepatitis B in a nursing home associated with capillary blood sampling. Epidemiol Infect. 2006;134(5):1102–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hallett RL, Ngui SL, Meigh RE, et al. Widespread dissemination in England of a stable and persistent hepatitis B virus variant. Clin Infect Dis. 2004;39(7):945–52.

    Article  CAS  PubMed  Google Scholar 

  28. Pourkarim MR, Verbeeck J, Rahman M, et al. Phylogenetic analysis of hepatitis B virus full-length genomes reveals evidence for a large nosocomial outbreak in Belgium. J Clin Virol. 2009;46(1):61–8.

    Article  CAS  PubMed  Google Scholar 

  29. van Houdt R, Bruisten SM, Geskus RB, et al. Ongoing transmission of a single hepatitis B virus strain among men having sex with men in Amsterdam. J Viral Hepat. 2010;17(2):108–14.

    Article  PubMed  Google Scholar 

  30. Teo CG. Molecular epidemiology of hepatitis B in England and Wales. J Clin Virol. 2005;34(Suppl 1):S13–4.

    Article  CAS  PubMed  Google Scholar 

  31. Fujisaki S, Yokomaku Y, Shiino T, et al. Outbreak of infections by hepatitis B virus genotype A and transmission of genetic drug resistance in patients coinfected with HIV-1 in Japan. J Clin Microbiol. 2011;49(3):1017–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kew MC, Kramvis A, Yu MC, et al. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-Saharan Africans. J Med Virol. 2005;75(4):513–21.

    Article  CAS  PubMed  Google Scholar 

  33. Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res. 2007;37(s1):S9–19.

    Article  PubMed  Google Scholar 

  34. Gopalakrishnan D, Keyter M, Shenoy KT, et al. Hepatitis B virus subgenotype A1 predominates in liver disease patients from Kerala. India. World J Gastroenterol. 2013;19(48):9294–306.

    Article  PubMed  Google Scholar 

  35. Tong S, Revill P. Overview of hepatitis B viral replication and genetic variability. J Hepatol. 2016;64(1 Suppl):S4–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kramvis A, Kew MC. Molecular characterization of subgenotype A1 (subgroup Aa) of hepatitis B virus. Hepatol Res. 2007;37(s1):S27–32.

    Article  CAS  PubMed  Google Scholar 

  37. Bocharov G, Ludewig B, Bertoletti A, et al. Underwhelming the immune response: effect of slow virus growth on CD8+-T-lymphocyte responses. J Virol. 2004;78(5):2247–54 Epub 2004/02/14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sugiyama M, Tanaka Y, Kato T, et al. Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology. 2006;44(4):915–24.

    Article  CAS  PubMed  Google Scholar 

  39. Sugiyama M, Tanaka Y, Kurbanov F, et al. Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes. Gastroenterology. 2009;136(2):652-62 e3.

  40. Okamoto H, Yotsumoto S, Akahane Y, et al. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol. 1990;64(3):1298–303 Epub 1990/03/01.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Carman WF, Jacyna MR, Hadziyannis S, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989;2(8663):588–91 Epub 1989/09/09.

    Article  CAS  PubMed  Google Scholar 

  42. Ahn SH, Kramvis A, Kawai S, et al. Sequence variation upstream of precore translation initiation codon reduces hepatitis B virus e antigen production. Gastroenterology. 2003;125(5):1370–8.

    Article  CAS  PubMed  Google Scholar 

  43. Kramvis A, Kew MC. Structure and function of the encapsidation signal of hepadnaviridae. J Viral Hepat. 1998;5(6):357–67.

    Article  CAS  PubMed  Google Scholar 

  44. Tong S. Impact of viral genotypes and naturally occurring mutations on biological properties of hepatitis B virus. Hepatol Res. 2007;37(s1):S3–8.

    Article  CAS  PubMed  Google Scholar 

  45. Milich D, Liang TJ. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology. 2003;38(5):1075–86 Epub 2003/10/28.

    Article  CAS  PubMed  Google Scholar 

  46. Chen YC, Sheen IS, Chu CM, et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology. 2002;123(4):1084–9.

    Article  PubMed  Google Scholar 

  47. Liaw YF, Sheen IS, Chen TJ, et al. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991;13(4):627–31.

    Article  CAS  PubMed  Google Scholar 

  48. Simonetti J, Bulkow L, McMahon BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology. 2010;51(5):1531–7.

    Article  PubMed  Google Scholar 

  49. Sanchez-Tapias JM, Costa J, Mas A, et al. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology. 2002;123(6):1848–56.

    Article  PubMed  Google Scholar 

  50. Chu CM, Liaw YF. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion. J Viral Hepat. 2007;14(3):147–52.

    Article  PubMed  Google Scholar 

  51. Janssen HL, van Zonneveld M, Senturk H, et al. PEGylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365(9454):123–9.

    Article  CAS  PubMed  Google Scholar 

  52. Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa. Gastroenterology. 2009;137(6):2002–9.

    Article  CAS  PubMed  Google Scholar 

  53. Hou J, Schilling R, Janssen HL, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance. J Med Virol. 2007;79(8):1055–63.

    Article  CAS  PubMed  Google Scholar 

  54. Wiegand J, Hasenclever D, Tillmann HL. Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence. Antivir Ther. 2008;13(2):211–20.

    CAS  PubMed  Google Scholar 

  55. Akuta N, Suzuki F, Kobayashi M, et al. The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol. 2003;38(3):315–21.

    Article  CAS  PubMed  Google Scholar 

  56. Buti M, Cotrina M, Valdes A, et al. Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine? J Hepatol. 2002;36(3):445–6.

    Article  PubMed  Google Scholar 

  57. Kobayashi M, Suzuki F, Akuta N, et al. Response to long-term lamivudine treatment in patients infected with hepatitis B virus genotypes A, B, and C. J Med Virol. 2006;78(10):1276–83.

    Article  CAS  PubMed  Google Scholar 

  58. Hosaka T, Suzuki F, Kobayashi M, et al. Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study. J Gastroenterol. 2013;48(8):930–41.

    Article  CAS  PubMed  Google Scholar 

  59. Orito E, Ichida T, Sakugawa H, et al. Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology. 2001;34(3):590–4.

    Article  CAS  PubMed  Google Scholar 

  60. Sugauchi F, Orito E, Ohno T, et al. Spatial and chronological differences in hepatitis B virus genotypes from patients with acute hepatitis B in Japan. Hepatol Res. 2006;36(2):107–14.

    Article  CAS  PubMed  Google Scholar 

  61. Suzuki Y, Kobayashi M, Ikeda K, et al. Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol. 2005;76(1):33–9 Epub 2005/03/22.

    Article  PubMed  Google Scholar 

  62. Takeda Y, Katano Y, Hayashi K, et al. Difference of HBV genotype distribution between acute hepatitis and chronic hepatitis in Japan. Infection. 2006;34(4):201–7.

    Article  CAS  PubMed  Google Scholar 

  63. Kobayashi M, Suzuki F, Arase Y, et al. Infection with hepatitis B virus genotype A in Tokyo, Japan during 1976 through 2001. J Gastroenterol. 2004;39(9):844–50 Epub 2004/11/27.

    Article  PubMed  Google Scholar 

  64. 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(1):89–97.

    Article  CAS  PubMed  Google Scholar 

  65. Suzuki Y, Kobayashi M, Ikeda K, et al. Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol. 2005;76(1):33–9.

    Article  PubMed  Google Scholar 

  66. Sherlock S, Dooley J. Diseases of the Liver and Billiary System-Eleventh Edition. London: Blackwell Scientific; 2002.

    Google Scholar 

  67. Chang MH. Hepatitis B virus infection. Semin Fetal Neonatal Med. 2007;12(3):160–7.

    Article  PubMed  Google Scholar 

  68. 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(5):765–73.

    Article  PubMed  Google Scholar 

  69. Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41(5):591–5.

    Article  CAS  PubMed  Google Scholar 

  70. Mbarek H, Ochi H, Urabe Y, et al. A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum Mol Genet. 2011;20(19):3884–92.

    Article  CAS  PubMed  Google Scholar 

  71. Nishida N, Sawai H, Matsuura K, et al. Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS One. 2012;7(6):e39175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hu Z, Liu Y, Zhai X, et al. New loci associated with chronic hepatitis B virus infection in Han Chinese. Nat Genet. 2013;45(12):1499–503.

    Article  CAS  PubMed  Google Scholar 

  73. Nishida N, Sawai H, Kashiwase K, et al. New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. PLoS One. 2014;9(2):e86449.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wasityastuti W, Yano Y, Ratnasari N, et al. Protective effects of HLA-DPA1/DPB1 variants against Hepatitis B virus infection in an Indonesian population. Infect Genet Evol. 2016;41:177–84.

    Article  CAS  PubMed  Google Scholar 

  75. Fletcher GJ, Samuel P, Christdas J, et al. Association of HLA and TNF polymorphisms with the outcome of HBV infection in the South Indian population. Genes Immun. 2011;12(7):552–8.

    Article  CAS  PubMed  Google Scholar 

  76. Vermehren J, Lotsch J, Susser S, et al. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS One. 2012;7(3):e32605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Albayrak A, Ertek M, Tasyaran MA, et al. Role of HLA allele polymorphism in chronic hepatitis B virus infection and HBV vaccine sensitivity in patients from eastern Turkey. Biochem Genet. 2011;49(3–4):258–69.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant No. 16736857).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan

    Kiyoaki Ito, Masashi Yoneda & Kazumasa Sakamoto

  2. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan

    Masashi Mizokami

Authors
  1. Kiyoaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashi Yoneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazumasa Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masashi Mizokami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kiyoaki Ito.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

An erratum to this article is available at https://doi.org/10.1007/s00535-017-1373-7.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ito, K., Yoneda, M., Sakamoto, K. et al. Virological and Clinical Characteristics of Hepatitis B Virus Genotype A. J Gastroenterol 53, 18–26 (2018). https://doi.org/10.1007/s00535-017-1367-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-017-1367-5

Keywords

Search

Navigation