Skip to main content
SpringerLink
Log in

Role of viral factors in the natural course and therapy of chronic hepatitis B

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.

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

Similar content being viewed by others

Abbreviations

ALT:

Alanine aminotransferase

BCP:

Basal core promoter

HBeAg:

Hepatitis B e antigen

HCC:

Hepatocellular carcinoma

HBV:

Hepatitis B virus

ULN:

Upper limit of normal

References

  1. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis 2002;2:395–403.

    PubMed  Google Scholar 

  2. Ganem D, Varmus HE. The molecular biology of the hepatitis B viruses. Annu Rev Biochem 1987;56:651–93.

    PubMed  CAS  Google Scholar 

  3. Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000;31:1037–44.

    PubMed  CAS  Google Scholar 

  4. Okamoto H, Imai M, Kametani M, Nakamura T, Mayumi M. Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission. Jpn J Exp Med 1987;57:231–6.

    PubMed  CAS  Google Scholar 

  5. Lau JY, Wright TL. Molecular virology and pathogenesis of hepatitis B. Lancet 1993;342:1335–40.

    PubMed  CAS  Google Scholar 

  6. Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771–4.

    Article  PubMed  CAS  Google Scholar 

  7. Chen DS. Natural history of chronic hepatitis B virus infection: new light on an old story. J Gastroenterol Hepatol 1993;8:470–5.

    PubMed  CAS  Google Scholar 

  8. Kao JH, Chen DS. The natural history of hepatitis B virus infection. In: Lai CL, Locarnini S, editors. Hepatitis B virus. London: International Medical Press Ltd.; 2002. p. 161–72.

    Google Scholar 

  9. Chu CM, Liaw YF. Intrahepatic distribution of hepatitis B surface and core antigens in chronic hepatitis B virus infection. Hepatocyte with cytoplasmic/membranous hepatitis B core antigen as a possible target for immune hepatocytolysis. Gastroenterology 1987;92:220–5.

    PubMed  CAS  Google Scholar 

  10. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al., for the Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology 2007;46:395–401.

    PubMed  Google Scholar 

  11. Liaw YF, Chu CM, Su IJ, Huang 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.

    PubMed  CAS  Google Scholar 

  12. Liaw YF, Yang SS, Chen TJ, Chu CM. Acute exacerbation in hepatitis B e antigen positive chronic type B hepatitis. A clinicopathological study. J Hepatol 1985;1:227–33.

    PubMed  CAS  Google Scholar 

  13. 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;116:829–34.

    PubMed  CAS  Google Scholar 

  14. Chu CM, 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.

    PubMed  Google Scholar 

  15. 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.

    PubMed  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. Chu CM, Liaw YF. Spontaneous relapse of hepatitis in inactive HBsAg carriers. Hepatol Int 2007;1:311–5.

    PubMed  Google Scholar 

  18. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  20. Chu CM, Liaw YF. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B, 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;43:411–7.

    PubMed  CAS  Google Scholar 

  21. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617–24.

    PubMed  CAS  Google Scholar 

  22. Yuen MF. Revisiting the natural history of chronic hepatitis B: impact of new concepts on clinical management. J Gastroenterol Hepatol 2007;22:973–6.

    PubMed  Google Scholar 

  23. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22,707 men in Taiwan. Lancet 1981;2:1129–33.

    PubMed  CAS  Google Scholar 

  24. Lok AS. Chronic hepatitis B. N Engl J Med 2002;346:1682–3.

    PubMed  Google Scholar 

  25. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127 Suppl 1:S35–S50.

    PubMed  Google Scholar 

  26. Kao JH. Hepatitis B virus genotypes and hepatocellular carcinoma in Taiwan. Intervirology 2003;46:400–7.

    PubMed  Google Scholar 

  27. Colombo M. Hepatocellular carcinoma. J Hepatol 1992;15:225–36.

    PubMed  CAS  Google Scholar 

  28. Kao JH, Chen DS. Changing disease burden of hepatocellular carcinoma in the Far East and Southeast Asia. Liver Int 2005:25:696–703.

    PubMed  Google Scholar 

  29. Chen DS. From hepatitis to hepatoma: lessons from type B viral hepatitis. Science 1993;262:369–70.

    PubMed  CAS  Google Scholar 

  30. Kao JH, Chen DS. Overview of hepatitis B and C viruses. In: Goedert JJ, editor. Infectious causes of cancer: targets for intervention. Tottowa: Humana Press Inc.; 2000. p. 313–30.

    Google Scholar 

  31. Kao JH, Chen DS. Hepatocellular carcinoma in Taiwan: progress in the past decade 1988–1997. In: Leong ASY, Liew CT, Lau JWY, Johnson PJ, editors. Hepatocellular carcinoma: contemporary diagnosis, investigation and management. London: Arnold; 1999. p. 235–50.

    Google Scholar 

  32. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting liver cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130:678–86.

    PubMed  Google Scholar 

  33. 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;295:65–73.

    PubMed  CAS  Google Scholar 

  34. Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol 2006;101:1797–803.

    PubMed  Google Scholar 

  35. Chen CJ, Iloeje UH, Yang HI. Serum hepatitis B virus DNA as a predictor of the development of cirrhosis and hepatocellular carcinoma. Curr Hepat Rep 2007;6:9–16.

    Article  CAS  Google Scholar 

  36. Tsai FC, Liu CJ, Chen CL, Chen PJ, Lai MY, Kao JH, et al. Lower serum viral loads in young patients with hepatitis-B-virus-related hepatocellular carcinoma. J Viral Hepat 2007;14:153–60.

    PubMed  Google Scholar 

  37. Yeo W, Mo FK, Chan SL, Leung NW, Hui P, Lam WY, et al. Hepatitis B viral load predicts survival of HCC patients undergoing systemic chemotherapy. Hepatology 2007;45:1382–9.

    PubMed  CAS  Google Scholar 

  38. Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular characteristics. J Gastroenterol Hepatol 2002;17:643–50.

    PubMed  CAS  Google Scholar 

  39. Kao JH, Chen DS. HBV genotypes: epidemiology and implications regarding natural history. Curr Hepat Rep 2006;5:5–13.

    Google Scholar 

  40. Kato H, Fujiwara K, Gish RG, Sakugawa H, Yoshizawa H, Sugauchi F, et al. Classifying genotype F of hepatitis B virus into F1 and F2 subtypes. World J Gastroenterol 2005;11:6295–304.

    PubMed  CAS  Google Scholar 

  41. Schaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J Gastroenterol 2007;13:14–21.

    PubMed  CAS  Google Scholar 

  42. Liu CJ, Kao JH. Clinical implications of hepatitis B virus genotype. Hepatol Rev 2006;3:33–40.

    Google Scholar 

  43. Liu CJ, Kao JH, Chen DS. Therapeutic implications of hepatitis B virus genotypes. Liver Int 2005;25:1097–107.

    PubMed  CAS  Google Scholar 

  44. 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;14:147–52.

    PubMed  Google Scholar 

  45. 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.

    PubMed  CAS  Google Scholar 

  46. 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.

    PubMed  CAS  Google Scholar 

  47. Yuen MF, Wong DK, Zheng BJ, Chan CC, Yuen JC, Wong BC, et al. Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion. J Viral Hepat 2007;14:269–75.

    PubMed  Google Scholar 

  48. 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.

    PubMed  CAS  Google Scholar 

  49. Yuen MF, Tanaka Y, Mizokami M, Yuen JC, Wong DK, Yuan HJ, et al. Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study. Carcinogenesis 2004;25:1593–8.

    PubMed  CAS  Google Scholar 

  50. 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;53:1494–8.

    PubMed  Google Scholar 

  51. 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;97:265–72.

    Article  PubMed  CAS  Google Scholar 

  52. Yang HI, Chen PJ, Yeh SH, et al. Risk of hepatocellular carcinoma associated with genotypes and mutants of hepatitis B virus: a community-based prospective cohort study. J Hepatol 2006;44 Suppl 2:27A.

    Google Scholar 

  53. Yuan J, Zhou B, Tanaka Y, Kurbanov F, Orito E, Gong Z, et al. Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications. J Clin Virol 2007;39:87–93.

    PubMed  CAS  Google Scholar 

  54. Orito E, Mizokami M, Sakugawa H, Michitaka K, Ishikawa K, Ichida T, et al. A case–control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Hepatology 2001;33:218–23.

    PubMed  CAS  Google Scholar 

  55. Ding X, Mizokami M, Yao G, Xu B, Orito E, Ueda R, et al. Hepatitis B virus genotype distribution among chronic hepatitis B virus carriers in Shanghai, China. Intervirology 2001;44:43–7.

    PubMed  CAS  Google Scholar 

  56. Chen YL, Chen PJ, Yang HI, Iloeje UH, Su J, et al. Risk of liver cirrhosis associated with genotype and mutants of hepatitis B virus. EASL 2007; Abstract no. 222.

  57. Lin CL, Chen JD, Liu CJ, Lee PH, Chen PJ, Lai MY, et al. Clinicopathological differences between hepatitis B viral genotype B- and C-related resectable hepatocellular carcinoma. J Viral Hepat 2007;14:64–9.

    PubMed  Google Scholar 

  58. Chen JD, Liu CJ, Lee PH, Chen PJ, Lai MY, Kao JH, et al. Hepatitis B genotypes correlate with tumor recurrence after curative resection of hepatocellular carcinoma. Clin Gastroenterol Hepatol 2004;2:64–71.

    PubMed  Google Scholar 

  59. Sugiyama M, Tanaka Y, Kato T, Orito E, Ito K, Acharya SK, et al. Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology 2006;44:915–24.

    PubMed  CAS  Google Scholar 

  60. Wang K, Fan X, Fan Y, Wang B, Han L, Hou Y. Study on the function of circulating plasmacytoid dendritic cells in the immunoactive phase of patients with chronic genotype B and C HBV infection. J Viral Hepat 2007;14:276–82.

    PubMed  CAS  Google Scholar 

  61. Kramvis A, Kew MC, Bukofzer S. Hepatitis B virus precore mutants in serum and liver of Southern African Blacks with hepatocellular carcinoma. J Hepatol 1998;28:132–41.

    PubMed  CAS  Google Scholar 

  62. 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;40:747–55.

    PubMed  Google Scholar 

  63. 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;85:811–20.

    PubMed  CAS  Google Scholar 

  64. Sugauchi F, Orito E, Ichida T, et al. Hepatitis B virus of genotype B with or without recombination with genotype C over the precore region plus the core gene. J Virol 2002;76:5985–92.

    PubMed  CAS  Google Scholar 

  65. Orito E, Sugauchi F, Tanaka Y, Ichida T, Sata M, Tanaka E, et al. Differences of hepatocellular carcinoma patients with hepatitis B virus genotypes of Ba, Bj or C in Japan. Intervirology 2005;48:239–45.

    PubMed  Google Scholar 

  66. Chan HL, Tse CH, Ng EY, Ng EY, Au TC, Yuen L, et al. Epidemiological and virological characteristics of 2 subgroups of hepatitis B virus genotype C. J Infect Dis 2005;191:2022–32.

    PubMed  CAS  Google Scholar 

  67. Tseng TC, Liu CJ, Chen PJ, Lai MY, Lin CL, Kao JH, et al. Subgenotypes of hepatitis B virus genotype C do not correlate with disease progression of chronic hepatitis B in Taiwan. Liver Int 2007;7:983–8.

    Google Scholar 

  68. Wang Z, Tanaka Y, Huang Y, Kurbanov F, Chen J, Zeng G, et al. Clinical and virological characteristics of hepatitis B virus subgenotypes Ba, C1, and C2 in China. J Clin Microbiol 2007;45:1491–6.

    PubMed  CAS  Google Scholar 

  69. Gunther S, Fischer L, Pult I, Sterneck M, Will H. Naturally occurring variants of hepatitis B virus. Adv Virus Res 1999;52:125–37.

    Google Scholar 

  70. Hunt CM, McGill JM, Allen MI, Condreay LD. Clinical relevance of hepatitis B viral mutations. Hepatology 2000;31:1037–44.

    PubMed  CAS  Google Scholar 

  71. Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, et al. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989;2:588–91.

    PubMed  CAS  Google Scholar 

  72. Okamoto H, Yotsumoto S, Akahane Y, Yamanaka T, Miyazaki Y, Sugai 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;64:1298–303.

    PubMed  CAS  Google Scholar 

  73. Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, et al. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol 1994;68:8102–10.

    PubMed  CAS  Google Scholar 

  74. Lin CL, Liao LY, Wang CS, Chen PJ, Lai MY, Chen DS, et al. Basal core promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int 2005;25:564–70.

    PubMed  Google Scholar 

  75. Liu CJ, Chen BF, Chen PJ, Lai MY, Huang WL, Kao JH, et al. Role of hepatitis B viral load and basal core promoter mutation in hepatocellular carcinoma in hepatitis B carriers. J Infect Dis 2006;193:1258–65.

    PubMed  CAS  Google Scholar 

  76. 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.

    PubMed  CAS  Google Scholar 

  77. Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 2006;130:1153–68.

    PubMed  CAS  Google Scholar 

  78. Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, et al. Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci USA 2004;101:3575–80.

    PubMed  CAS  Google Scholar 

  79. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS. Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol 2004;72:545–50.

    PubMed  CAS  Google Scholar 

  80. Chu CM, Yeh CT, Chiu CT, Sheen IS, Liaw YF. Precore mutant of hepatitis B virus prevails in acute and chronic infections in an area in which hepatitis B is endemic. J Clin Microbiol 1996;34:1815–8.

    PubMed  CAS  Google Scholar 

  81. 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;124:327–34.

    PubMed  CAS  Google Scholar 

  82. Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma. World J Gastroenterol 2006;12:6620–6.

    PubMed  CAS  Google Scholar 

  83. Sakamoto T, Tanaka Y, Orito E, Co J, Clavio J, Sugauchi F, et al. Novel subtypes (subgenotypes) of hepatitis B virus genotypes B and C among chronic liver disease patients in the Philippines. J Gen Virol 2006;87:1873–82.

    PubMed  CAS  Google Scholar 

  84. Gerken G, Kremsdorf D, Capel F, Petit MA, Dauguet C, Manns MP, et al. Hepatitis B defective virus with rearrangements in the preS gene during chronic HBV infection. Virology 1991;183:555–65.

    PubMed  CAS  Google Scholar 

  85. Fernholz D, Stemler M, Brunetto M, Bonino F, Will H. Replicating and virion secreting hepatitis B mutant virus unable to produce preS2 protein. J Hepatol 1991;13:S102–4.

    PubMed  CAS  Google Scholar 

  86. Xu Z, Yen TSB. Intracellular retension of surface protein by a hepatitis B virus mutant that releases virion particles. J Virol 1996;70:133–40.

    PubMed  CAS  Google Scholar 

  87. Fan YF, Lu CC, Chen WC, Yao WJ, Wang HC, Chang TT, et al. Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection. Hepatology 2001;33:277–86.

    PubMed  CAS  Google Scholar 

  88. Sugauchi F, Ohno T, Orito E, Sakugawa H, Ichida T, Komatsu M, et al. Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease. J Med Virol 2003;70:537–44.

    PubMed  CAS  Google Scholar 

  89. Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000;33:998–1002.

    PubMed  CAS  Google Scholar 

  90. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, et al. Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut 2007 (in press).

  91. Shinkai N, Tanaka Y, Ito K, Mukaide M, Hasegawa I, Asahina Y, et al. Influence of hepatitis B virus X, core promoter mutations on hepatocellular carcinoma among patients with subgenotype C2. J Clin Microbiol 2007 (in press).

  92. Chen CJ, Yang HI, Iloeje UH, Su J, Jen CL, You SL, et al. A risk function nomogram for predicting HCC in patients with chronic hepatitis B: the REVEAL-HBV study. EASL 2007 Abstract no. 475.

  93. Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 2005;25:472–89.

    PubMed  Google Scholar 

  94. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–39.

    PubMed  CAS  Google Scholar 

  95. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol 2006;4:936–62.

    PubMed  CAS  Google Scholar 

  96. Kao JH. Appropriate use of interferon for treatment of chronic hepatitis B. Hepatol Res 2007;37 Suppl 1:S47–54.

    PubMed  CAS  Google Scholar 

  97. Perrillo RP. Therapy of hepatitis B—viral suppression or eradication? Hepatology 2006;43 2 Suppl 1:S182–93.

    PubMed  CAS  Google Scholar 

  98. Cooksley G, Lau GKK, Liaw Y-F, Marcellin P, Chow WC, Thongsawat S, et al. Effect of genotype and other baseline factors on response to PEGInterferon-2a (40 kDa) (Pegasys®) in HBeAg-positive chronic hepatitis B: results from a large, randomized study [Abstract]. J Hepatol 2005;42 Suppl 2:S30.

    Google Scholar 

  99. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, et al. Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 2007;56:699–705.

    PubMed  CAS  Google Scholar 

  100. Farci P, Marcellin P, Lu Z-M, Diago M, Lai M-Y, Gurel S, et al. On-treatment predictors of sustained biochemical and virological response in patients with HBeAg-negative chronic hepatitis B (CHB) treated with PEGInterferon-2a (40 kDa) (Pegasys®) [abstract]. J Hepatol 2005;42 Suppl 2:S175.

    Google Scholar 

  101. Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis 2003;36:687–96.

    PubMed  CAS  Google Scholar 

  102. Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 2001;34:785–91.

    PubMed  CAS  Google Scholar 

  103. Ruiz-Sancho A, Sheldon J, Soriano V. Telbivudine: a new option for the treatment of chronic hepatitis B. Expert Opin Biol Ther 2007;7:751–61.

    PubMed  CAS  Google Scholar 

  104. Liu CJ, Kao JH. Hepatitis B genotype: what should the clinician know? Curr Hepat Rep 2007;6:17–23.

    Google Scholar 

  105. Kao JH, Wu NH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes and the response to interferon therapy. J Hepatol 2000;33:998–1002.

    PubMed  CAS  Google Scholar 

  106. Wai CT, Chu CJ, Hussain M, Lok AS. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C. Hepatology 2002;36:1425–30.

    PubMed  CAS  Google Scholar 

  107. Hou J, Schilling R, Janssen HLA. Molecular characteristics of hepatitis B virus genotype A confer a higher response to interferon treatment. J Hepatol 2001;34 Suppl 1:15.

    Google Scholar 

  108. Erhardt A, Blondin D, Hauck K, Sagir A, Kohnle T, Heintges T, et al. Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 2005;54:1009–13.

    PubMed  CAS  Google Scholar 

  109. Liu CJ, Lai MY, Chao YC, Liao LY, Yang SS, Hsiao TJ, et al. Interferon alpha-2b with and without ribavirin in the treatment of hepatitis B e antigen-positive chronic hepatitis B: a randomized study. Hepatology 2006;43:742–9.

    PubMed  CAS  Google Scholar 

  110. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10:298–305.

    PubMed  CAS  Google Scholar 

  111. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al., for the HBV 99-01 Study Group, Rotterdam foundation for liver research. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–9.

    PubMed  CAS  Google Scholar 

  112. Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL, for the HBV 99-01 Study Group. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006;101:297–303.

    PubMed  CAS  Google Scholar 

  113. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682–95.

    PubMed  CAS  Google Scholar 

  114. Zhao H, Kurbanov F, Wan MB, Yin YK, Niu JQ, Hou JL, et al. Genotype B and younger patient age associated with better response to low-dose therapy: a trial with pegylated/nonpegylated interferon-alpha-2b for hepatitis B e antigen-positive patients with chronic hepatitis B in China. Clin Infect Dis 2007;44:541–8.

    PubMed  CAS  Google Scholar 

  115. Hou JL, Schilling R, Janssen HLA, Hansen BE, Heijtink R, Sablon E, et al. Genetic characteristics of hepatitis B virus genotypes as a factor for interferon-induced HBeAg clearance. J Med Virol 2007;79:1055–63.

    PubMed  CAS  Google Scholar 

  116. Lin CL, Kao JH. To genotype or not to genotype: toward an optimal tailoring of treatment of chronic hepatitis B. Clin Infect Dis 2007;44:1665–6.

    PubMed  Google Scholar 

  117. Liu CJ, Chen PJ, Lai MY, Chen TC, Wang HY, Huang WL, et al. Lack of interferon sensitivity-determining region in the genome of hepatitis B virus genotype Ba. Antivir Ther 2004;9:895–903.

    PubMed  CAS  Google Scholar 

  118. Chien RN, Lin CY, Yeh CT, Liaw YF. Hepatitis B virus genotype B is associated with better response to thymosin alpha1 therapy than genotype C. J Viral Hepat 2006;13:845–50.

    PubMed  Google Scholar 

  119. Kao JH, Liu CJ, Chen DS. Hepatitis B viral genotypes and lamivudine resistance. J Hepatol 2002;36:303–4.

    PubMed  Google Scholar 

  120. Yuen MF, Wong DK, Sablon E, Yuan HJ, Sum SM, Hui CK, et al. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine. Antivir Ther 2003;8:531–4.

    PubMed  CAS  Google Scholar 

  121. Chan HL, Wong ML, Hui AY, Chim AM, Tse AM, Hung LC, et al. Hepatitis B virus genotype has no impact on hepatitis B e antigen seroconversion after lamivudine treatment. World J Gastroenterol 2003;9:2695–7.

    PubMed  CAS  Google Scholar 

  122. Buti M, Cotrina M, Valdes A, Jardi R, Rodriguez-Frias F, Esteban R. Is hepatitis B virus subtype testing useful in predicting virological response and resistance to lamivudine? J Hepatol 2002;36:445–6.

    PubMed  Google Scholar 

  123. Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003;38:1267–73.

    PubMed  CAS  Google Scholar 

  124. Zollner B, Petersen J, Puchhammer-Stockl E, Kletzmayr J, Sterneck M, Fischer L, et al. Viral features of lamivudine resistant hepatitis B genotypes A and D. Hepatology 2004;39:42–50.

    PubMed  Google Scholar 

  125. Pan XP, Li LJ, Du WB, Li MW, Cao HC, Sheng JF. Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C. J Viral Hepatitis 2007 (in press).

  126. Westland C, Delaney W IV, Yang H, Chen SS, Marcellin P, Hadziyannis S, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 2003;125:107–16.

    PubMed  CAS  Google Scholar 

  127. Lurie Y, Manns MP, Gish RG, Chang TT, Yurdaydin C, Lai CL, et al. The efficacy of entecavir is similar regardless of disease-related baseline subgroups in treatment of nucleoside-naive, HBeAg(+) and HBeAg(−) patients with chronic hepatitis B. J Hepatol 2005;42 Suppl 2:184.

    Google Scholar 

  128. Rivkin A. Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B. Drugs Today (Barc) 2007;43:201–20.

    CAS  Google Scholar 

  129. Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 2006;44:283–90.

    PubMed  CAS  Google Scholar 

  130. Brunetto MR, Oliveri F, Colombatto P, Capalbo M, Barbera C, Bonino F. Treatment of chronic anti-HBe-positive hepatitis B with interferon-alpha. J Hepatol 1995;22:42–4.

    PubMed  CAS  Google Scholar 

  131. Lin CL, Liao LY, Liu CJ, Chen PJ, Lai MY, Kao JH, et al. Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B. J Gastroenterol 2002;37:283–7.

    PubMed  Google Scholar 

  132. Liu CJ, Chen PJ, Lai MY, Lin FY, Wang T, Kao JH, et al. Viral factors correlate with hepatitis B e antigen seroconversion in patients with chronic hepatitis B. Liver Int 2006;26:949–55.

    PubMed  CAS  Google Scholar 

  133. Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 1997;26:1621–5.

    PubMed  CAS  Google Scholar 

  134. Erhardt A, Reineke U, Blondin D, Gerlich WH, Adams O, Heintges T, et al. Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 2000;31:716–25.

    PubMed  CAS  Google Scholar 

  135. Lok AS-F, Hussain M, Cursano C, MargottiI M, Gramenzi A, Grazi GL, et al. Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen negative patients receiving lamivudine therapy. Hepatology 2000;32:1145–53.

    PubMed  CAS  Google Scholar 

  136. Lin CL, Liao LY, Wang CS, Chen PJ, Lai MY, Chen DS, et al. Evolution of hepatitis B virus precore/basal core promoter gene in HBeAg-positive chronic hepatitis B patients receiving lamivudine therapy. Liver Int 2004;24:9–15.

    PubMed  CAS  Google Scholar 

  137. Thompson AJ, Ayres A, Yuen L, Bartholomeusz A, Bowden DS, Iser DM, et al. Lamivudine resistance in patients with chronic hepatitis B: role of clinical and virological factors. J Gastroenterol Hepatol 2007;22:1078–85.

    PubMed  CAS  Google Scholar 

  138. Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 2007;46:254–65.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hepatitis Research Center, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, 100, Taiwan

    Jia-Horng Kao

  2. Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Jia-Horng Kao

  3. Department of Medical Research, Graduate Institute of Clinical Medicine, National Taiwan University Hospital, Taipei, Taiwan

    Jia-Horng Kao

Authors
  1. Jia-Horng Kao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jia-Horng Kao.

Additional information

Communicated by Shiv Kumar Sarin, M.D.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kao, JH. Role of viral factors in the natural course and therapy of chronic hepatitis B. Hepatol Int 1, 415–430 (2007). https://doi.org/10.1007/s12072-007-9033-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-007-9033-2

Keywords

Search

Navigation