Natural History of Hepatitis B Virus

  • Ryan D. Heath
  • Veysel TahanEmail author


Chronic HBV infection is a worldwide public health issue with an estimated 400 million persons infected. Variations in both epidemiology and genotype have been noted to affect the course and severity of sequelae of the disease; however, general comments can be made regarding the natural history of the disease. The natural history of chronic infection is generally divided into an active, higher replicative phase and a lower replicative phase. An understanding of viral activity in these phases is critical to understanding appropriate surveillance of disease activity as well as indications to begin treatment.


Hepatitis B Natural history Immune Tolerant Inactive Carrier Clearance Reactivation 


  1. 1.
    Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97–107.CrossRefPubMedGoogle Scholar
  2. 2.
    Ganem D, Varmus HE. The molecular biology of the hepatitis B virus. Annu Rev Biochem. 1987;56:651–93.CrossRefPubMedGoogle Scholar
  3. 3.
    Tuttleman JS, Pugh JC, Summer JW. In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus. J Virol. 1986;58:17–25.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Chien YC, Jan CF, Kuo HS, Chen CJ. Nationwide hepatitis B vaccination program in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev. 2006;28:126–35.CrossRefPubMedGoogle Scholar
  5. 5.
    Weasley A, Grytdal S, Gallagher K. Surveillance for acute viral hepatitis - United States 2006. MMWR Surveill Summ. 2008;57:1–24.Google Scholar
  6. 6.
    Botha JF, Ritchie MJ, Dusheilo GM, Mouton HW, Kew MC. Hepatitis B virus carrier state in black children in Ovamboland: role of perinatal and horizontal infection. Lancet. 1984;323:1210–2.CrossRefGoogle Scholar
  7. 7.
    Lin HH, Kao JH, Chang TC, Hsu HY, Chen CS. Secular trend of age-specific prevalence of hepatitis B surface and e antigenemia in pregnant women in Taiwan. J Med Virol. 2003;69:466–70.CrossRefPubMedGoogle Scholar
  8. 8.
    Hadziyannis SJ. Milestones and perspectives in viral hepatitis B. Liver Int. 2011;31(Suppl 1):129–34.CrossRefPubMedGoogle Scholar
  9. 9.
    Cote PJ, Korba BE, Miller RH, Jacob JR, Baldwin BH, Hornbuckle WE. Effects of age and viral determinants on chronicity as an outcome of experimental woodchuck hepatitis virus infection. Hepatology. 2000;31(1):190–200.CrossRefPubMedGoogle Scholar
  10. 10.
    Hadziyannis SJ, Vassilopoulos D. Immunopathogenesis of hepatitis B e antigen negative chronic hepatitis B infection. Antivir Res. 2001;52(2):91–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Yim HJ, Lok AS. Natural history of chronic hepatitis B infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43(Suppl 1):S173–81.CrossRefPubMedGoogle Scholar
  12. 12.
    World Health Organization. Hepatitis B. Fact sheet no 204, updated July 2014. 2014. Accessed 7 Nov 2017.
  13. 13.
    Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in chimpanzees. Proc Natl Acad Sci U S A. 2005;102:17780–5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science. 1999;284:825–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Bertoletti A, Maini M, William R. Role of hepatitis B virus specific cytotoxic T cells in liver damage and viral control. Antivir Res. 2003;60:61–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Thimme R, Wieland S, Steiger C. CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77:68–76.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Visvanathan K, Lewin SR. Immunopathogenesis: role of innate and adaptive immune responses. Semin Liver Dis. 2006;26:104–15.CrossRefPubMedGoogle Scholar
  18. 18.
    Rehermann B. Chronic infections with hepatotoxic viruses: mechanisms of impairment of cellular immune responses. Semin Liver Dis. 2007;27:152–60.CrossRefPubMedGoogle Scholar
  19. 19.
    McMahon BJ, Alward WL, Hall DV. 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;151:599–603.CrossRefPubMedGoogle Scholar
  20. 20.
    Liaw YF. Asia-Pacific pocket guide to hepatitis B. Madison: University of Wisconsin Board of Regents and MDG Development Group; 2006.Google Scholar
  21. 21.
    Hoofnagle JF, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056–75.CrossRefPubMedGoogle Scholar
  22. 22.
    Lok AS, Heathcote EJ, Joofnagle JH. Management of hepatitis B. Gastroenterology. 2001;120:1828–53.CrossRefPubMedGoogle Scholar
  23. 23.
    Bertoletti L, Maini M, Ferrari C. The host-pathogen interaction during HBV infection: immunological controversies. Antivir Ther. 2010;15(Suppl 3):15–24.CrossRefPubMedGoogle Scholar
  24. 24.
    Liaw YF, Tsai SL, Sheen IS, et al. Clinical and virological course of chronic hepatitis B virus infection with hepatitis C and D virus markers. Am J Gastroenterol. 1998;93:354.CrossRefPubMedGoogle Scholar
  25. 25.
    McMahon BJ, Holck P, Bulkow L, Snowball MM. Serologic and clinical outcomes 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med. 2001;135:759–68.CrossRefPubMedGoogle Scholar
  26. 26.
    Hoofnagle JH, Dusheilo GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med. 1981;94:744–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Lok AS, Lai CL, Wu PC, Leung EK, Lam TS. Spontaneous hepatitis B e antigen to antibody seroconversion and reversion in Chinese patients with chronic hepatitis B infection. Gastroenterology. 1987;92:1839–43.CrossRefPubMedGoogle Scholar
  28. 28.
    Livingston SE, Simonetti JP, BUlkow LR, Homan CE, Snowball MM, Cagle HH. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology. 2007;133:1452–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Liaw YF, Brunetto MR, Hadizyannis S. The natural history of chronic HBV infection and geographical differences. Antivir Ther. 2010;15(Suppl 3):25–33.CrossRefPubMedGoogle Scholar
  30. 30.
    Hui DK, Leung N, Yuen ST, Yuen ST, Zhang HY, Leung KW. Natural history and disease progression in Chinese chronic hepatitis B patients in immune tolerant phase. Hepatology. 2007;46:395–401.CrossRefPubMedGoogle Scholar
  31. 31.
    Andreani T, Serfaty L, Mohand D, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007;5:636.CrossRefPubMedGoogle Scholar
  32. 32.
    Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology. 1988;8:1130.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ. Identification of androgen response elements in the enhancer of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology. 2009;50:1392–402.CrossRefPubMedGoogle Scholar
  34. 34.
    Chen PJ, Yeh SH, Liu WH, Lin CC, Huang HC, Chen CL. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology. 2012;56:632–43.CrossRefPubMedGoogle Scholar
  35. 35.
    Chu CM, Hung SJ, Lin J, Tai DL, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with moral serum aminotransferase levels. Am J Med. 2004;116:829–34.CrossRefPubMedGoogle Scholar
  36. 36.
    McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis. 2005;25(Suppl 1):3–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. J Hepatol. 2011;55(1):183–91.CrossRefPubMedGoogle Scholar
  38. 38.
    Liaw YF, Chu CM, Su IJ, Haung MJ, Lin DY, Chang-Chien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology. 1983;84:216–9.PubMedGoogle Scholar
  39. 39.
    Lok AS, Lai CL. Acute exacerbation in Chinese patients with chronic hepatitis B virus infection. Incidence, predisposing factors and etiology. J Hepatol. 1990;10:29–34.CrossRefPubMedGoogle Scholar
  40. 40.
    Fattovich G, Giustina G, Schalm SW, Hadziyannis S, Sanchez-Tapias J, Almasio P, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21:77–82.PubMedGoogle Scholar
  41. 41.
    Yu MW, Hsu FC, Sheen IS, Chu CM, Lin DY, Chen CJ, et al. Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers. Am J Epidemiol. 1997;145:1039–47.CrossRefPubMedGoogle Scholar
  42. 42.
    de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology. 1992;103:1630–5.CrossRefPubMedGoogle Scholar
  43. 43.
    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31.CrossRefPubMedGoogle Scholar
  44. 44.
    Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999;29:971–5.CrossRefPubMedGoogle Scholar
  45. 45.
    Buster EH, Flink JH, Cakaloglu Y, Simon K, Trojan J, Tabak F. Sustained HBeAg and HBsAg loss after long term follow up of HBeAg positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135(2):459–67.CrossRefPubMedGoogle Scholar
  46. 46.
    Yuen MF, Yuan HJ, Hui CK, Wong DK, Wong WM, Chan AO, et al. A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy. Gut. 2003;52:416–9.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Liaw YF. Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy. J Gastroenterol Hepatol. 2003;18:246–52.CrossRefPubMedGoogle Scholar
  48. 48.
    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;72:363–9.Google Scholar
  49. 49.
    Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology. 2002;122:1756–62.CrossRefPubMedGoogle Scholar
  50. 50.
    Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35:1522–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Brunetto MR, Giarin MM, Oliveri F, Chiaberge E, Baldi M, Alfarano A, et al. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A. 1991;88:4186–90.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2001;34:617–24.CrossRefPubMedGoogle Scholar
  53. 53.
    Davis GL, Hoofnagle JH, Waggoner JG. Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology. 1984;86:230–5.PubMedGoogle Scholar
  54. 54.
    Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, 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;36:263–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Hadziyannis S, Gerber MA, Vissoulis C, Popper H. Cytoplasmic hepatitis B antigen in ground glass hepatocytes of carriers. Arch Pathol. 1973;96(5):327–30.PubMedGoogle Scholar
  56. 56.
    de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med. 1993;118:191–4.CrossRefPubMedGoogle Scholar
  57. 57.
    Martinot-Peignoux M, Boyer N, Colombat M, Akremi R, Pham BN, Ollivier S, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol. 2002;36:543–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Zacharakis GH, Koskinas J, Kotsiou S, Papoutselis M, Tzara F, Vafeiadis N, et al. Natural history of chronic HBV infection: a cohort with with up to 12 years follow-up in North Greece (part of the Interreg I-II/EC-project). J Med Virol. 2005;77:173–9.CrossRefPubMedGoogle Scholar
  59. 59.
    Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, et al. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 2008;134:1376–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Chu CM, Hun 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;116(12):829–34.CrossRefPubMedGoogle Scholar
  61. 61.
    Bortolotti F, Guido M, Bartolacci S, Cadrobbi P, Crivellaro C, Noventa F. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology. 2006;43:556–62.CrossRefPubMedGoogle Scholar
  62. 62.
    Manno M, Camma C, Schepis F, Bassi F, Gelmini R, Giannini F, et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology. 2004;127:756–63.CrossRefPubMedGoogle Scholar
  63. 63.
    Kumar M, Chauhan R, Gupta N, et al. Spontaneous increases in alanine aminotransferase levels in asymptomatic chronic hepatitis B virus-infected patients. Gastroenterology. 2009;136:1272.CrossRefPubMedGoogle Scholar
  64. 64.
    Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol. 1977;105:94–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Beasley RP, Hwang LY, Lin CC, Leu ML, Stevens CE, Szmuness W. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis. 1982;146:198–204.CrossRefPubMedGoogle Scholar
  66. 66.
    Shimizu D, Nomura K, Matsumoto Y, Ueda K, Yamaguchi K, Minami M, et al. Hepatitis B virus reactivation in a patient undergoing steroid-free chemotherapy. World J Gastroenterol. 2004;10:2301–2.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: report of a prospective study. Gastroenterology. 1991;100:182–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Chu MC, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology. 2007;45:1187–92.CrossRefPubMedGoogle Scholar
  69. 69.
    Liaw YF, Sheen IS, Chen TJ, Chu CM, Pao CC. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study. Hepatology. 1991;13:627–31.CrossRefPubMedGoogle Scholar
  70. 70.
    Naoumov NV, Schneider R, Grötzinger T, Jung MC, Miska S, Pape GR, et al. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology. 1992;102:538–43.CrossRefPubMedGoogle Scholar
  71. 71.
    Ahn SH, Park YN, Park JY, Chang HY, Lee JM, Shin JE, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol. 2005;42:188–94.CrossRefPubMedGoogle Scholar
  72. 72.
    Arase Y, Ikeda K, Suzuki F, Susuki Y, Saitoh S, Kobayashi M, et al. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med. 2006;119:e9–e15.CrossRefGoogle Scholar
  73. 73.
    Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, et al. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological, histological, and clinical aspects. Hepatology. 2004;39:1694–701.CrossRefPubMedGoogle Scholar
  74. 74.
    Chen YC, Sheen IS, Chu CM, Liaw YF. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology. 2002;123:1084–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Huo TI, Wu JC, Lee PC, Chau GY, Lui WY, Tsay SH, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology. 1998;28:231–6.CrossRefPubMedGoogle Scholar
  76. 76.
    Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV infection? Hepatology. 2004;40:790–2.CrossRefPubMedGoogle Scholar
  77. 77.
    Norder H, Courouce AM, 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;47:289–309.CrossRefPubMedGoogle Scholar
  78. 78.
    Sugauchi F, Orita 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;124:925–32.CrossRefPubMedGoogle Scholar
  79. 79.
    Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology. 2000;118:554–9. Scholar
  80. 80.
    Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, et al. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology. 2004;127:1733–8. Scholar
  81. 81.
    Orito E, Ichida T, Sakugawa H, Sata M, Horiike N, Hino K, et al. Geographic distribution of hepatitis B virus (HBV) genotype in patients with chronic HBV infection in Japan. Hepatology. 2001;34:590–4. Scholar
  82. 82.
    Yu MW, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–72.CrossRefPubMedGoogle Scholar
  83. 83.
    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.CrossRefPubMedGoogle Scholar
  84. 84.
    Yang HI, Yeh SH, Chen PJ, Iloeje UH, Jen CL, Su J, et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:1134–43.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Livingston SE, Simonetti JP, McMahon BJ, Bulkow LR, 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.CrossRefPubMedGoogle Scholar
  86. 86.
    Ni YH, Chang MH, Hsu HY, Tsuei DJ. Longitudinal study on mutation profiles of core promoter and precore regions of the hepatitis B virus genome in children. Pediatr Res. 2004;56:396–9. Scholar
  87. 87.
    Tseng TC, Liu CJ, Yang HC, Chen CL, Yang WT, Tsai CS, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut. 2015;64:292–302. Scholar
  88. 88.
    Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, et al. Role of hepatitis B virus precore/core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis. 2006;194:594–9. Scholar
  89. 89.
    Thakur 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;17:165–70. Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyUniversity of MissouriColumbiaUSA

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