Natural history of hepatitis B virus infection


  • Birth in highly endemic regions such as sub-Saharan Africa and East Asia is a risk factor for developing chronic hepatitis B (CHB) infection (1). The primary mode of transmission in such cases is vertical (i.e. mother to child).
  • The risk of developing CHB is highest in those who acquire hepatitis B virus (HBV) infection perinatally and lowest in those who acquire the infection in adulthood.
  • The natural history of HBV infection depends on complex interactions between host, virus and environment.
  • There are four phases of CHB, and the host immune response in each phase determines the outcome of infection and the severity of liver injury.
  • Liver damage is caused by the host immune response rather than the HBV itself.
  • Complications of CHB include cirrhosis with hepatocellular failure and hepatocellular carcinoma. All complications can be minimised with effective antiviral therapy.

Print as PDF

  1. World Health Organization (WHO). Global policy report on the prevention and control of viral hepatitis. Geneva: WHO; 2013.
  2. Australasian Society for HIV Medicine (ASHM). Antenatal testing and blood-borne viruses (BBVs). 2011. Update March 2015.
  3. Takegoshi K, Zhang W. Hepatitis B virus infections in families in which the mothers are negative but the fathers are positive for HBsAg. Hepatol Res 2006;36:75–7.
  4. Tajiri H, Tanaka Y, Kagimoto S, Murakami J, Tokuhara D, Mizokami M. Molecular evidence of father-to-child transmission of hepatitis B virus. J Medl Virol 2007;79:922–6.
  5. Komatsu H, Inui A, Sogo T, Hiejima E, Kudo N, Fujisawa T. Source of transmission in children with chronic hepatitis B infection after the implementation of a strategy for prevention in those at high risk. Hepatol Res 2009;39:569–76.
  6. Ko YC, Li SC, Yen YY, Yeh SM, Hsieh CC. Horizontal transmission of hepatitis B virus from siblings and intramuscular injection among preschool children in a familial cohort. Am J Epidemiol 1991;133:1015–23.
  7. Villeneuve JP. The natural history of chronic hepatitis B virus infection. J Clini Virol 2005;34:S139–S42.
  8. Edmunds WJ, Medley GF, Nokes DJ, Hall AJ, Whittle HC. The influence of age on the development of the hepatitis B carrier state. Proc Biol Sci 1993;253:197–201.
  9. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–2.
  10. Beasley RP, Hwang LY, Lin CC, Leu ML, Stevens CE, Szmuness W, et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis 1982;146:198–204.
  11. Edith Cowan University. Hepatitis Education Project. 2014; Available at: (last accessed 21 June 2018).
  12. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–39.
  13. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-98.
  14. Livingston SE, Simonetti JP, Bulkow LR, 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;133:1452–7.
  15. McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med 2001;135:759–68.
  16. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34(4 Pt 1):617–24.
  17. 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.
  18. Chu CM, Chen YC, Tai DI, Liaw YF. Clin Gastroenterol Hepatol 2010;8:535.
  19. 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.
  20. Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012;142:1140–9.
  21. Chu CJ, Hussain M, Lok AS. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 2002;36:1408–15.
  22. Yuen MF, Tanaka Y, Ng IO, Mizokami M, Yuen JC, Wong DK, et al. Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core-promoter and precore mutations. J Viral Hepat 2005;12:513–8.
  23. Fattovich G. Natural history of hepatitis B. Journal of Hepatology 2003;39:S50–S58.
  24. Raimondo G, Caccamo G, Filomia R, Pollicino T. Occult HBV infection. Sem Immunopathol. 2013;35:39–52.
  25. Yang R, Song G, Guan W, Wang Q, Liu Y, Wei L. The Lumipulse G HBsAg- Quant assay for screening and quantification of the hepatitis B surface J Virol Methods 2016;228:39–47.
  26. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46:160–70.
  27. Gupta S, Govindarajan S, Fong TL, Redeker AG. Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 1990;12:562–8.
  28. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016;63:261-83.
  29. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006;43:209–20.
  30. World Health Organization (WHO). Hepatitis B fact sheet. Updated 5 July 2017. Geneva: WHO, 2017.
  31. 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. Hepatology 1995;21(1):77–82.
  32. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA 2006;295(1):65–73.
  33. Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–74.
  34. Schiff ER. Prevention of mortality from hepatitis B and hepatitis C. Lancet 2006;368:896–7.
  35. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271–85.
  36. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23:47–58.
  37. Parker C, Tong S, Dempsey K, Condon J, Sharma S, Chen J, et al. Hepatocellular carcinoma in Australia’s Northern Territory – high incidence and poor outcomes. Med J Aust 2014;201:470-4.
  38. El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol. 2001;96(8):2462–7.
  39. Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS. Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 2005;42:218–24.
  40. Loomba R, Liu J, Yang HI, Lee MH, Lu SN, Wang LY, et al. Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma. Clin Gastroenterol Hepatol 2013; 11:1636-45.
  41. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005;9:191–211, v.
  42. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49:S45–S55.
  43. Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carci- noma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol 2016;22:319–26.
  44. Papatheodoridis G, Dalekos G, Sypsa V, Yurdaydin C, Buti M, Goulis J, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol 2016;64:800–6.
  45. Brouwer W, Hansen B, Raffetti E, Donato F, Fattovich G. The PAGE-B score stratifies chronic hepatitis B patients with compensated cirrhosis at high risk of hepatocellular carcinoma development with good accuracy. Hepatology 2015;62 (Suppl):93A–207A.
  46. Brouwer W, van der Meer A, Boonstra A, Plompen E, Pas S, de Knegt R, et al. The PAGE-B score accurately predicts clinical outcome and outperforms other biomarkers over 15 years of follow-up in a diverse cohort of chronic hepatitis B patients. Hepatology 2015;62 (Suppl):93A–207A.
  47. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678–86.
  48. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Alimentary Pharmacol Ther 2008;28:1067–77.
  49. Kim CH, Um SH, Seo YS, Jung JY, Kim JD, Yim HJ, et al. Prognosis of hepatitis B-related liver cirrhosis in the era of oral nucleos(t)ide analog antiviral agents. J Gastroenterol Hepatol 2012;27:1589–95.
  50. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017;66:153–94.
  51. De Monte A, Courjon J, Anty R, Cua E, Naqvi A, Mondain V, et al. Direct- acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge. J Clin Virol 2016;78:27–30.
  52. Ende AR, Kim NH, Yeh MM, Harper J, Landis CS. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report. J Med Case Rep 2015;9:164.
  53. Collins JM, Raphael KL, Terry C, Cartwright EJ, Pillai A, Anania FA, et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis 2015;61:1304–1306.
  54. Wang C, Ji D, Chen J, Shao Q, Li B, Liu J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol 2017;15:132–136.
  55. Raimondo G, Pollicino T, Squadrito G. What is the clinical impact of occult hepatitis B virus infection? Lancet 2005;365:638–40.