Significance of hepatitis B virus genotypes in clinical practice


  • I.A. Zaitsev Bogomolets National Medical University, Kyiv, Ukraine,
  • I.M. Novak Bogomolets National Medical University, Kyiv, Ukraine,
  • O.Ye. Zaitseva Bogomolets National Medical University, Kyiv, Ukraine,
  • V.T. Kiriienko Bogomolets National Medical University, Kyiv, Ukraine,



HBV infection, HBV genotype, natural progression of HBV infection, liver cirrhosis, hepatocellular carcinoma, hepatitis B transmission routes, chronic hepatitis B


Hepatitis B virus (HBV) infection remains a global public health problem with significant morbidity and mortality. During virus replication, numerous mutations are accumulated, and in the process of phylogenesis it leads to the appearance of HBV genotypes and subgenotypes. HBV has been classified into 10 genotypes (A-J). They have a distinct geographical distribution. In Ukraine, as in other European countries, genotypes A and D prevail. A large number of studies showed a correlation between HBV genotype and the natural progression of the disease, the tendency to chronicity, the rate of HBeAg seroconversion and the response to pegylated interferon alpha treatment. This literature review summarizes results of the studies on the influence of HBV genotypes on the natural progression of the disease. The data on the geographical distribution of HBV genotypes in Ukraine and in the world are given, the significance of determining specific genotypes in terms of their influence on the course and outcome of HBV infection is argued.


Blumberg BS, Gerstley BJS, Hungerford DA, London WT, Sutnick AI. A serum antigen (Australia antigen) in Down’s syndrome, leukemia, and hepatitis. Ann Intern Med. 1967 May;66(5):924-31.

Prince AM. An antigen detected in the blood during the incubation period of serum hepatitis. Proc Natl Acad Sci U S A. 1968 Jul;60(3):814-21.

Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet. 1970 Apr 4;1(7649):695-8.

Tiollais P, Charnay P, Vyas GN. Biology of hepatitis B virus. Science. 1981 Jul;213(4506):406-411. doi: 10.1126/science.6264599.

Bruss V, Ganem D. The role of envelope proteins in hepatitis B virus assembly. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):1059-63.

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 Oct;69 ( Pt 10):2575-83. doi: 10.1099/0022-1317-69-10-2575.

Kramvis A, Kew M, Francois G. Hepatitis B virus genotypes. Vaccine. 2005 Mar 31;23(19):2409-23. doi: 10.1016/j.vaccine.2004.10.045.

Yu H, Yuan Q, Ge SX, et al. Molecular and phylogenetic analyses suggest an additional hepatitis B virus genotype “I”. PLoS One. 2010 Feb 19;5(2):e9297. doi: 10.1371/journal.pone.0009297.

Norder H, Courouce AM, Coursaget P, et al. Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology. 2004;47(6):289-309. doi: 10.1159/000080872.

Kramvis A. Genotypes and genetic variability of hepatitis B virus. Intervirology. 2014;57(3-4):141-50. doi: 10.1159/000360947.

Bartholomeusz A, Schaefer S. Hepatitis B virus genotypes: comparison of genotyping methods. Rev Med Virol. 2004 Jan-Feb;14(1):3-16. doi: 10.1002/rmv.400.

Schaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J Gastroenterol. 2007 Jan 7;13(1):14-21.

Kramvis A, Kew MC. Relationship of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy. J Viral Hepat. 2005 Sep;12(5):456-64. doi: 10.1111/j.1365-2893.2005.00624.x.

Tong S, Revill Р. Overview of viral replication and genetic variability. J Hepatol. 2016 Apr;64(1 Suppl):S4-S16. doi: 10.1016/j.jhep.2016.01.027.

Couroucé-Pauty AM, Plançon A, Soulier JP. Distribution of HBsAg subtypes in the world. Vox Sang. 1983;44(4):197-211.

Kramvis A, Arakawa K, Yu MC, Nogueira R, Stram DO, Kew MC. Relationship of serological subtype, basic core promoter and precore mutations to genotypes/subgenotypes of hepatitis B virus. J Med Virol. 2008 Jan;80(1):27-46. doi: 10.1002/jmv.21049.

Sunbul M. Hepatitis B virus genotypes: Global distribution and clinical importance. World J Gastroenterol. 2014 May 14;20(18):5427-34. doi: 10.3748/wjg.v20.i18.5427.

Summers J, Mason WS. Replication of the genome of a hepatitis B—like virus by reverse transcription of an RNA intermediate. Cell. 1982 Jun;29(2):403-15.

Beck J, Nassal M. Hepatitis B virus replication. World J Gastroenterol. 2007 Jan 7;13(1):48-64.

Junker-Niepmann M, Bartenschlager R, Schaller H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J. 1990 Oct;9(10):3389-96.

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

Kato H, Orito E, Gish RG, Bzowej N, et al. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology. 2002 Apr;35(4):922-9. doi: 10.1053/jhep.2002.32096.

Chudy M, Schmidt M, Czudai V, et al. Hepatitis B virus genotype G monoinfection and its transmission by blood components. Hepatology. 2006 Jul;44(1):99-107. doi: 10.1002/hep.21220.

Tatematsu K, Tanaka Y, Kurbanov F, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol. 2009 Oct;83(20):10538-47. doi: 10.1128/JVI.00462-09.

Locarnini S, Littlejohn M, Aziz MN, Yuen L. Possible origins and evolution of the hepatitis B virus (HBV). Semin Cancer Biol. 2013 Dec;23(6 Pt B):561-75. doi: 10.1016/j.semcancer.2013.08.006.

Wang Y, Shan X, Liang Z, et al. Deep sequencing analysis of HBV genotype shift and correlation with antiviral efficiency during adefovir dipivoxil therapy. PLoS One. 2015 Jun 25;10(6):e0131337. doi: 10.1371/journal.pone.0131337.

Shi W, Carr MJ, Dunford L, Zhu C, Hall WW, Higgins DG.Identification of novel inter-genotypic recombinants of human hepatitis B viruses by large-scale phylogenetic analysis. Virology. 2012; 427:51–59. Virology. 2012 May 25;427(1):51-9. doi: 10.1016/j.virol.2012.01.030.

Araujo NM. Hepatitis B virus intergenotypic recombinants worldwide: An overview. Infect Genet Evol. 2015 Dec;36:500-510. doi: 10.1016/j.meegid.2015.08.024.

Pourkarim MR, Amini-Bavil-Olyaee S, Kurbanov F, Van Ranst M, Tacke F. Molecular identification of hepatitis B virus genotypes/subgenotypes: revised classification hurdles and updated resolutions. World J Gastroenterol. 2014 Jun 21;20(23):7152-68. doi: 10.3748/wjg.v20.i23.7152.

Maly VP, Lyadova TI, Gololobova OV, Boyko VV. Clinical and diagnostic characteristics of genotyping of obligate-hepatotropic viruses: the effect of virus genotypes on the clinical manifestations and outcomes of the disease. Aktualʹnaâ Infektologiâ. 2013;1(1):37-43. (in Russian).

Kobayashi M, Arase Y, Ikeda K, , et al. Clinical characteristics of patients infected with hepatitis B virus genotypes A, B, and C. J Gastroenterol. 2002 Jan;37(1):35-9.

Kobayashi M, Arase Y, Ikeda K, et al. Clinical features of hepatitis B virus genotype A in Japanese patients. J Gastroenterol. 2003;38(7):656-62. doi: 10.1007/s00535-003-1118-7.

Mayerat C, Mantegani A, Frei PC. Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection? J Viral Hepat. 1999 Jul;6(4):299-304.

Kidd-Ljunggren K1, Myhre E, Bläckberg J. Clinical and serologicl variation between patients infected with different hepatitis B virus genotypes J Clin Microbiol. 2004 Dec;42(12):5837-41. doi: 10.1128/JCM.42.12.5837-5841.2004.

Shi Y. Correlation between Hepatitis B Virus Genotypes and Clinical Outcomes. Jpn J Infect Dis. 2012;65(6):476-82.

Yurchenko, Stepchenkova Т, Karnets I, et al. The results of a study on the prevalence of HIV, HCV and HBV genotypes in some regions of Ukraine. Retrovirology. 2012;9(Suppl 1):P55. doi: 10.1186/1742-4690-9-S1-P55.

Velkov S, Ott J, Protzer U, Michler T. The Global Hepatitis B Virus Genotype Distribution Approximated from Available Genotyping Data. Genes (Basel). 2018 Oct 15;9(10). pii: E495. doi: 10.3390/genes9100495.

Klushkina V, Kyuregyan K, Kozhanova T, et al. Impact of Universal Hepatitis B Vaccination on Prevalence, Infection-Associated Morbidity and Mortality, and Circulation of Immune Escape Variants in Russia. PLoS One. 2016 Jun 9;11(6):e0157161. doi: 10.1371/journal.pone.0157161.

Gasich EL, Eremin VF. Genetic diversity of hepatitis c virus in the republic of Belarus. Zdravookhranenie. 2016;(10). Available from:

Mitsura V, Volchenko A, Tserashkou D, Zapolskaya V. The incidence and dynamics of morbidity from different forms of hepatitis B virus infection in the Republic of Belarus. Clinical infectology and parasitology. 2018;(3):370-380.

Constantinescu I, Nedelcu F, Toader MA, Daniela V. Clinical and Therapeutical Importance of HBV genotyping in Romania. J Med Life. 2008 Apr-Jun;1(2):165-73.

Świderska M, Pawłowska M, Mazur W, et al. Distribution of HBV genotypes in Poland. Clin Exp Hepatol. 2015 May;1(1):1-4. doi: 10.5114/ceh.2015.51372.

Deterding K, Constantinescu I, Nedelcu FD, et al. Prevalence of HBV genotypes in Central and Eastern Europe. J Med Virol. 2008 Oct;80(10):1707-11. doi: 10.1002/jmv.21294.

Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res. 2007 Jul;37(s1):S9-S19. DOI: 10.1111/j.1872-034X.2007.00098.x.

ChangMH. Natural history and clinicalmanagement of chronic hepatitis B virus infection in children. Hepatol Int. 2008 May;2(Supplement 1):28-36. doi: 10.1007/s12072-008-9050-9.

Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol. 2005 Sep;43(3):411-7. doi: 10.1016/j.jhep.2005.03.018.

Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med. 2004 Jun 15;116(12):829-34. doi: 10.1016/j.amjmed.2003.12.040.

Candotti D, Danso K, Allain JP. Maternofetal transmission of hepatitis B virus genotype E in Ghana, west Africa. J Gen Virol. 2007 Oct;88(Pt 10):2686-95. doi: 10.1099/vir.0.83102-0.

Mason W, Jilbert A, Summers J. Clonal expansion of hepatocytes during chronic woodchuck hepatitis virus infection. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1139-44. doi: 10.1073/pnas.0409332102.

Pournik O, Alavian SM, Ghalichi L, Hajibeigi B, Razavi AR, Eslami S. Lower intrafamilial transmission rate of hepatitis B in patients with hepatitis d coinfection: a data-mining approach. Hepat Mon. 2013 May 23;13(5):e7652. doi: 10.5812/hepatmon.7652.

Yuasa R, Takahashi K, Dien BV, et al. Properties of hepatitis B virus genome recovered from Vietnamese patients with fulminant hepatitis in comparison with those of acute hepatitis. J Med Virol. 2000 May;61(1):23-8.

Tong S, Li J, Wands JR, Wen Y. Hepatitis B virus genetic variants: biological propertiesand clinical implications. Emerg Microbes Infect. 2013 Mar;2(3):e10. doi: 10.1038/emi.2013.10.

Ogawa M, Hasegawa K, Naritomi T, Torii N, Hayashi N. Clinical features and viral sequences of various genotypes of hepatitis B virus compared among patients with acute hepatitis B. Hepatol Res. 2002 Jul;23(3):167-177.

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 May;76(1):33-9. doi: 10.1002/jmv.20320.

Zhang HW, Yin JH, Li YT, et al. Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China. Gut. 2008 Dec;57(12):1713-20. doi: 10.1136/gut.2008.157149.

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 Sep;39(9):844-50. doi: 10.1007/s00535-004-1400-3.

Wai CT, Fontana RJ, Polson J, et al. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat. 2005 Mar;12(2):192-8. doi: 10.1111/j.1365-2893.2005.00581.x.

Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: Recent advances. J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:123-30. doi: 10.1111/j.1440-1746.2010.06541.x.

Hsia CC, Purcell RH, Farshid M, Lachenbruch PA, Yu MY. Quantification of hepatitis B virus genomes and infectivity in human serum samples. Transfusion. 2006 Oct;46(10):1829-35. doi: 10.1111/j.1537-2995.2006.00974.x.

Jegaskanda S, Ahn SH, Skinner N, et al. Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen. J Virol. 2014 Sep;88(18):10412-20. doi: 10.1128/JVI.00111-14.

Visvanathan K, Lang T, Ryan K, et al. Toll-IL1 receptor-mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated-IFN in HBeAg-positive CHB patients. J Viral Hepat. 2016 Mar;23(3):170-9. doi: 10.1111/jvh.12477.

Tran A, Kremsdorf D, Capel F, et al. Emergence of and takeover by hepatitis B virus (HBV) with rearrangements in the pre-S/S and pre-C/C genes during chronic HBV infection. J Virol. 1991 Jul;65(7):3566-74.

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 Dec 28;19(48):9294-306. doi: 10.3748/wjg.v19.i48.9294.

Kramvis A, Kew MC. Molecular characterization of subgenotype A1 (subgroup Aa) of hepatitis B virus. Hepatol Res. 2007 Jul;37(s1):S27-32. doi: 10.1111/j.1872-034X.2007.00100.x.

Livingston SE, Simonetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology. 2007 Nov;133(5):1452-7. doi: 10.1053/j.gastro.2007.08.010.

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 Sep;40(3):747-55. doi: 10.1002/hep.20365.

Maeshiro T, Arakaki S, Watanabe T, et al. Different natural courses of chronic hepatitis B with genotypes B and C after the fourth decade of life. World J Gastroenterol. 2007 Sep 14;13(34):4560-5.

Xibing G, Xiaojuan Y, Juanhua W, Zhong H. Relationship between HBV genotypes B, C and follicular helper T cells in patients with chronic hepatitis B and its significance. Hepat Mon. 2013 Jan 20;13(1):e6221. doi: 10.5812/hepatmon.6221.

Livingston SE, Simonetti JP, McMahon BJ, et al. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis. 2007 Jan 1;195(1):5-11. doi: 10.1086/509894.

Kao JH, Chen PJ, Lai MY, Chen DS. Clinical and virological aspects of blood donors infected with hepatitis B virus genotypes B and C. J Clin Microbiol. 2002 Jan;40(1):22-5.

Victoria Fda S, Oliveira CM, Victoria MB, Victoria CB, Ferreira LC. Characterization of HBeAg-negative chronic hepatitis B in Western Brazilian Amazonia. Brazil. Braz J Infect Dis. 2008 Feb;12(1):27-37.

Candotti D, Opare-Sem O, Rezvan H, Sarkodie F, Allain JP. Molecular and serological characterization of hepatitis B virus in deferred Ghanaian blood donors with and without elevated alanine aminotransferase. J Viral Hepat. 2006 Nov;13(11):715-24.