Hepatology International

, Volume 3, Issue 2, pp 334–342 | Cite as

The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B

  • Brian J. McMahonEmail author
Review Article



Chronic infection with hepatitis B virus (HBV) is associated with a high lifetime risk of developing hepatocellular carcinoma (HCC) and cirrhosis of the liver.


To review the studies published to date regarding the association of HBV genotypes and subgenotypes in the development of adverse sequelae from HBV.


Review of the literature for articles describing studies of HBV genotype/subgenotypes and development of HCC, cirrhosis, and liver-related death.


Eight genotypes of HBV (A through H), which differ from each other in viral genome sequence by more than 8%, and multiple subgenotypes, which differ from each other by 4–8% have been identified. Recently, studies investigating the association between the risks of developing HCC and cirrhosis by specific HBV genotypes and subgenotypes have reported marked differences in outcome. Certain HBV genotypes and subgenotypes, including genotype C, B2-5, and F1, appear to be associated with a higher risk of developing HCC, and others, including genotypes B1, B6, and A2, appear to be associated with a lower risk of complications of HBV. Our understanding of the role of HBV genotypes and subgenotypes on the outcome of HBV infection is limited, as few population-based prospective studies have been performed and most studies compare only the outcome in areas where two genotypes predominate whereas others have not examined subgenotypes.


Studies to date suggest that HBV genotypes/subgenotypes have important influences on the outcome of chronic HBV infection, but more population-based prospective studies examining multiple genotypes are needed.


Hepatitis B virus genotypes Clinical outcome 



The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the Alaska Native Tribal Health Consortium.


  1. 1.
    Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11(2):97–107. doi: 10.1046/j.1365-2893.2003.00487.x.PubMedCrossRefGoogle Scholar
  2. 2.
    Lok ASK, McMahon B. AASLD practice guidelines: chronic hepatitis B. Hepatology 2007;45:507–539. doi: 10.1002/hep.21513.PubMedCrossRefGoogle Scholar
  3. 3.
    Fung SK, Lok A. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? Hepatology 2004;40(4):790–792.PubMedGoogle Scholar
  4. 4.
    Kramvis A, Kew M. Relationships of genotypes of hepatitis B virus to mutations, disease progression and response to antiviral therapy. J Viral Hepat 2004;12:456–464. doi: 10.1111/j.1365-2893.2005.00624.x.CrossRefGoogle Scholar
  5. 5.
    Kramvis A, Kew M, Francois G. Hepatitis B virus genotypes. Vaccine 2005;23:2409–2423. doi: 10.1016/j.vaccine.2004.10.045.PubMedCrossRefGoogle Scholar
  6. 6.
    Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology 2003;46:329–338. doi: 10.1159/000074988.PubMedCrossRefGoogle Scholar
  7. 7.
    Schaefer S. Hepatitis B virus: significance of genotypes. J Viral Hepat 2005;12:111–124. doi: 10.1111/j.1365-2893.2005.00584.x.PubMedCrossRefGoogle Scholar
  8. 8.
    Chu CJ, Keefe E, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology 2003;125:444–451. doi: 10.1016/S0016-5085(03)00895-3.PubMedCrossRefGoogle Scholar
  9. 9.
    Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2005;54(RR-16):1–31.PubMedGoogle Scholar
  10. 10.
    Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;2(8359):1099–1102. doi: 10.1016/S0140-6736(83)90624-4.PubMedCrossRefGoogle Scholar
  11. 11.
    Beasley RP, Hwang LY, Lin CC, et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis 1982;146(2):198–204.PubMedGoogle Scholar
  12. 12.
    McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151(4):599–603.PubMedGoogle Scholar
  13. 13.
    Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2006;55(RR16):1–25.PubMedGoogle Scholar
  14. 14.
    Mast EE, Alter MJ, Margolis HS. Strategies to prevent and control hepatitis B and C virus infections: a global perspective. Vaccine 1999;17(13–14):1730–1733. doi: 10.1016/S0264-410X(98)00415-0.PubMedCrossRefGoogle Scholar
  15. 15.
    Livingston SE, Simonetti J, Bulkow L, Homan CE, Snowball MM, Cagle HH, et al. Clearance of Hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D and F. Gastroenterology 2007;133:1452–1457. doi: 10.1053/j.gastro.2007.08.010.PubMedCrossRefGoogle Scholar
  16. 16.
    Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. Increased hepatocarcinogenic potential of hepatitis B virus genotype in Bantu-speaking sub-Saharan Africans. J Med Virol 2005;75:513–521. doi: 10.1002/jmv.20311.PubMedCrossRefGoogle Scholar
  17. 17.
    Kramvis A, Kew M, Bukofzer S. Hepatitis B precore mutants in serum and liver of Southern African Blacks with hepatocellular carcinoma. J Hepatol 1998;28:132–141. doi: 10.1016/S0168-8278(98)80212-2.PubMedCrossRefGoogle Scholar
  18. 18.
    Kimbi G, Kramvis A, Kew M. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol 2004;85:1211–1220. doi: 10.1099/vir.0.19749-0.PubMedCrossRefGoogle Scholar
  19. 19.
    Norder H, Courouce A, Coursaget P, Echevarria JM, Lee SD, Mushahwar IK, 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.PubMedCrossRefGoogle Scholar
  20. 20.
    Langer BCA, Frosner G, Von Brunn A. Epidemiological study of viral hepatitis types A, B, C, D, and E among Inuits in West Greenland. J Viral Hepat 1997;4:339–349. doi: 10.1046/j.1365-2893.1997.00063.x.PubMedCrossRefGoogle Scholar
  21. 21.
    Livingston SE, Simonetti J, McMahon B, Bulkow L, Hurlburt KJ, Homan CE, et al. Hepatitis B virus genotypes in Alaska Native People with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis 2007;195:5–11. doi: 10.1086/509894.PubMedCrossRefGoogle Scholar
  22. 22.
    Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J. Influence of hepatitis B viral genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 2002;123:1848–1856. doi: 10.1053/gast.2002.37041.PubMedCrossRefGoogle Scholar
  23. 23.
    Kurbanov F, Tanaka Y, Fujiqara 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;86:2047–2056. doi: 10.1099/vir.0.80922-0.PubMedCrossRefGoogle Scholar
  24. 24.
    Sakamoto T, Tanaka YSJ, Osiowy C, Børresen ML, Koch A, Kurbanov F, et al. Classification of hepatitis B virus genotype B into two major forms based on characterization of a novel subgenotype in the Arctic indigenous populations. J Infect Dis 2007;196:1487–1492. doi: 10.1086/523111.PubMedCrossRefGoogle Scholar
  25. 25.
    Kobayashi M, Fumitaka S, Akuta N, Tsubota A, Ikeda K, Arase Y, et al. Virological differences between patients infected with subtypes Ba and Bj or hepatitis B virus genotype B. J Gastroenterol Hepatol 2005;20:570–576. doi: 10.1111/j.1440-1746.2005.03798.x.PubMedCrossRefGoogle Scholar
  26. 26.
    Saugauchi F, Orito E, Ichida T, Kato H, Sakugawa H, Kakumu S, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C. Gastroenterology 2003;124:925–932. doi: 10.1053/gast.2003.50140.CrossRefGoogle Scholar
  27. 27.
    Ozasa A, Tanaka Y, Orito E, Sugiyama M, Kang JH, Hige S, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology 2006;44:326–334. doi: 10.1002/hep.21249.PubMedCrossRefGoogle Scholar
  28. 28.
    Orito E, Mizokami M. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan. Intervirology 2003;46:408–412. doi: 10.1159/000075000.PubMedCrossRefGoogle Scholar
  29. 29.
    Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan. Intervirology 2003;46:400–407. doi: 10.1159/000074999.PubMedCrossRefGoogle Scholar
  30. 30.
    Chen HC, Eng HL, Lee CM, Fang YK, Kuo FY, Lu SN, et al. Correlations between hepatitis B virus genotype and cirrhotic or non-cirrhotic hepatoma. Hepatogastroenterology 2004;51:552–555.PubMedGoogle Scholar
  31. 31.
    Kao JH, Chen PJ, Lai MY, Chen DS. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol 2002;40:1207–1209. doi: 10.1128/JCM.40.4.1207-1209.2002.PubMedCrossRefGoogle Scholar
  32. 32.
    Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers. J Med Virol 2004;72:363–369. doi: 10.1002/jmv.10534.PubMedCrossRefGoogle Scholar
  33. 33.
    Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004;53:1494–1498. doi: 10.1136/gut.2003.033324.PubMedCrossRefGoogle Scholar
  34. 34.
    Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554–559. doi: 10.1016/S0016-5085(00)70261-7.PubMedCrossRefGoogle Scholar
  35. 35.
    Lee CM, Chen CH, Lu SN, Tung HD, Chou WJ, Wang JH, et al. Prevalence and clinical implications of hepatitis B virus genotypes in southern Taiwan. Scand J Gastroenterol 2003;38:95–101. doi: 10.1080/00365520310003048.PubMedCrossRefGoogle Scholar
  36. 36.
    Tangkijvanich P, Mahachai V, Komolmit P, Fongsarun J, Theamboonlers A, Poovorawan Y. Hepatitis B virus genotypes and hepatocellular carcinoma in Thailand. World J Gastroenterol 2005;11(15):2238–2243.PubMedGoogle Scholar
  37. 37.
    Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology 2003;124:327–334. doi: 10.1053/gast.2003.50053.PubMedCrossRefGoogle Scholar
  38. 38.
    Chu CM, Laiw 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;43:411–417. doi: 10.1016/j.jhep.2005.03.018.PubMedCrossRefGoogle Scholar
  39. 39.
    Sumi H, Yokosuka O, Seki N, Arai M, Imazeki F, Kurihara T, et al. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease. Hepatology 2003;37:19–26. doi: 10.1053/jhep.2003.50036.PubMedCrossRefGoogle Scholar
  40. 40.
    Watanabe K, Takahashi T, Takahashi S, Okoshi S, Ichida T, Aoyagi Y. Comparative study of genotype B and C hepatitis B virus-induced chronic hepatitis in relation to the basic core promoter and precore mutations. J Gastroenterol Hepatol 2005;20:441–449. doi: 10.1111/j.1440-1746.2004.03572.x.PubMedCrossRefGoogle Scholar
  41. 41.
    Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005;97:265–272.PubMedCrossRefGoogle Scholar
  42. 42.
    Yuen MF, Sablon E, Yuan HJ, Wong DKH, Hui CL, Wong BCY, et al. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma. Hepatology 2003;37:562–567. doi: 10.1053/jhep.2003.50098.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006;295(1):65–73. doi: 10.1001/jama.295.1.65.PubMedCrossRefGoogle Scholar
  44. 44.
    Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130(3):678–686. doi: 10.1053/j.gastro.2005.11.016.PubMedCrossRefGoogle Scholar
  45. 45.
    Chan HL, Tse AM, Mo F, Koh J, Wong VWS, Wong GLH, et al. High viral load and hepatitis B virus subgenotype Ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 2008;26(2):177–182. doi: 10.1200/JCO.2007.13.2043.PubMedCrossRefGoogle Scholar
  46. 46.
    Naoumov NV, Schneider R, Grotzinger T, et al. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology 1992;102:538.PubMedGoogle Scholar
  47. 47.
    McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis 2005;25(Suppl 1):3–8. doi: 10.1055/s-2005-915644.PubMedCrossRefGoogle Scholar
  48. 48.
    Zacharakis GH, Koskinas J, Kotsiou S, Papoutselis M, Tzara F, Vafeiadis N, et al. Natural history of chronic HBV infection: a cohort with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-Project). J Med Virol 2005;77:173–179. doi: 10.1002/jmv.20434.PubMedCrossRefGoogle Scholar
  49. 49.
    Grandjacques C, Pradat P, Stuyver L, et al. Rapid detection of genotypes and mutations in the pre-core promoter and the pre-core region of hepatitis B virus genome: correlation with viral persistence and disease severity. J Hepatol 2000;33(3):430–439. doi: 10.1016/S0168-8278(00)80279-2.PubMedCrossRefGoogle Scholar
  50. 50.
    Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34(4 pt 1):617–624. doi: 10.1053/jhep.2001.27834.PubMedCrossRefGoogle Scholar
  51. 51.
    Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol 2002;36(2):263–270. doi: 10.1016/S0168-8278(01)00266-5.PubMedCrossRefGoogle Scholar
  52. 52.
    Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AP, Han SH, et al. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat 2005;12:192–198. doi: 10.1111/j.1365-2893.2005.00581.x.PubMedCrossRefGoogle Scholar
  53. 53.
    Thukar V, Guptan RC, Kazim SN, Malhotra V, Sarin SK. Profile, spectrum and significance of HBV genotypes in chronic liver disease patients in the Indian subcontinent. J Gastroenterol Hepatol 2002;17(2):165–170. doi: 10.1046/j.1440-1746.2002.02605.x.CrossRefGoogle Scholar
  54. 54.
    Hurlburt KJ, McMahon BJ, Simonetti J, Livingston SE, Bulkow LR, Snowball MM, et al. Hepatitis B-associated vasculitis in Alaska Natives: viral genotype, clinical and serologic outcome. Liver Int 2007;27:627–632. doi: 10.1111/j.1478-3231.2007.01473.x.PubMedCrossRefGoogle Scholar
  55. 55.
    Suzuki S, Sugauchi F, Orito E, Kato H, Usuda S, Siransy L, et al. Distribution of hepatitis B virus (HBV) genotypes among HBV carriers in the Cote d’Ivoire: complete genome sequence and phylogenetic relatedness of HBV genotype E. J Med Virol 2003;69:459–465. doi: 10.1002/jmv.10331.PubMedCrossRefGoogle Scholar
  56. 56.
    Bekondi C, Olinger CM, Boua N, Talmarmin A, Muller CP, Le Foau A, et al. Central African Republic is part of the West African hepatitis B virus genotype E crescent. J Gen Virol 2007;88(10):2686–2695. doi: 10.1099/vir.0.83102-0.CrossRefGoogle Scholar
  57. 57.
    Mulders MN, Vernard V, Njayou M, Edorh P, Oyefolu AOB, Kehinde MO, et al. Low genetic diversity despite hyperenemicity of hepatitis B virus throughout West Africa. J Infect Dis 2004;190:400–408. doi: 10.1086/421502.PubMedCrossRefGoogle Scholar
  58. 58.
    Stuyver L, De Gendt S, Van Geyt C, Zoulim F, Fried M, Schinazi RF, et al. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness. J Gen Virol 2000;81:61–74.Google Scholar
  59. 59.
    Kato H, Orito E, Gish RG, Bzowej N, Newsom M, Sugauchi F, et al. Hepatitis B e antigen in sera from individuals infected with hepatitis B virus of genotype G. Hepatology 2002;35:922–929. doi: 10.1053/jhep.2002.32096.PubMedCrossRefGoogle Scholar
  60. 60.
    Chudy M, Schimdt M, Czudai V, Scheiblauer H, Nick S, Moseback M, et al. Hepatitis B virus genotype G monoinfection and its transmission by blood components. Hepatology 2006;44:99–107. doi: 10.1002/hep.21220.PubMedCrossRefGoogle Scholar
  61. 61.
    Suygiyama M, Tanaka Y, Sakamoto T, Maruyama I, Shimada T, Takahashi S, et al. Early dynamics of hepatitis B virus in chimeric mice carrying human hepatocytes monoinfected or coinfected with genotype G. Hepatology 2007;45:929–937. doi: 10.1002/hep.21584.CrossRefGoogle Scholar
  62. 62.
    Lacombe K, Massari V, Girard PM, Serfaty L, Gozlan J, Pialoux G, et al. Major role of hepatitis B genotypes in liver fibrosis during coinfection with HIV. AIDS 2006;20(3):419–427. doi: 10.1097/01.aids.0000200537.86984.0e.PubMedCrossRefGoogle Scholar
  63. 63.
    Devesa M, Rodriguez C, Leon G, Liprandi F, Pujol FH. Clade analysis and surface antigen polymorphism of hepatitis B virus American genotypes. J Med Virol 2004;72:377–384. doi: 10.1002/jmv.20015.PubMedCrossRefGoogle Scholar
  64. 64.
    Devesa M, Loureiro CL, Rivas Y, Monsalve F, Cardona N, Duarte MC, et al. Subgenotype diversity of hepatitis B virus American genotype F in Amerindians from Venezuela and the general population of Colombia. J Med Virol 2008;80(1):20–26. doi: 10.1002/jmv.21024.PubMedCrossRefGoogle Scholar
  65. 65.
    Quintero A, Uzcategui N, Loureiro CL, Villegas L, Illarramendi X, Guevara ME, et al. Hepatitis delta virus genotypes I and III circulate associated with hepatitis B virus genotype F in Venezuela. J Med Virol 2001;64:356–359. doi: 10.1002/jmv.1058.PubMedCrossRefGoogle Scholar
  66. 66.
    Devesa M, Pujol FH. Hepatitis B virus genetic diversity in Latin America. Virus Res 2007;127:177–184. doi: 10.1016/j.virusres.2007.01.004.PubMedCrossRefGoogle Scholar
  67. 67.
    Arauz-Ruiz P, Norder H, Robertson BH, Magnius LO. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America. J Gen Virol 2002;83:2059–2073.PubMedGoogle Scholar
  68. 68.
    Kay A, Zoulim F. Hepatitis B virus genetic variability and evolution. Virus Res 2007;127:164–176. doi: 10.1016/j.virusres.2007.02.021.PubMedCrossRefGoogle Scholar
  69. 69.
    Toan NI, Song LH, Kremsner PG, Duy DN, Binh VQ, Koeberlein B, et al. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam. Hepatology 2006;43:1375–1384. doi: 10.1002/hep.21188.PubMedCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2008

Authors and Affiliations

  1. 1.Liver Disease and Hepatitis ProgramAlaska Native Tribal Health Consortium; and Arctic Investigations Program, Centers for Disease Control and PreventionAnchorageUSA

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