Korean J Gastroenterol.  2019 Nov;74(5):245-250. 10.4166/kjg.2019.74.5.245.

Natural History and Treatment Indications of Chronic Hepatitis B

• Sinn DH

• KMID: 2464182
• DOI: http://doi.org/10.4166/kjg.2019.74.5.245

Abstract

HBV is the most common etiology of both liver cirrhosis and hepatocellular carcinoma in Korea. Despite much progress made, the currently available antiviral therapies cannot eradicate or eliminate this virus. Hence, the benefits and risks of antiviral therapy should be carefully evaluated on an individual basis and within the context of the clinical situation. The ultimate goals of treatment are to decrease the mortality from liver disease. The benefits of antiviral therapy come from prevention of progression of liver disease. Understanding the natural history of chronic HBV infection is a key step in the decision making process to treat patients with chronic HBV infection. Generally, chronic hepatitis B patients in the immune tolerant phase and immune inactive phase are not recommended to undergo antiviral treatment, except for those patients in special conditions (e.g., immunosuppression or anticancer chemotherapy). Chronic hepatitis B patients in the immune active phase are recommended for antiviral therapy. For patients with liver cirrhosis, treatment should be considered when serum HBV DNA is detectable regardless of the serum level of ALT.

Keyword

Hepatitis B virus; Natural history; Treatment indication

MeSH Terms

Carcinoma, Hepatocellular
Decision Making
DNA
Hepatitis B virus
Hepatitis B, Chronic*
Hepatitis, Chronic*
Humans
Immunosuppression
Korea
Liver Cirrhosis
Liver Diseases
Mortality
Natural History*
Risk Assessment
DNA

Reference

1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015; 386:1546–1555.

2. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol. 2019; 25:93–159.

3. Calvaruso V, Craxì A. Fibrosis in chronic viral hepatitis. Best Pract Res Clin Gastroenterol. 2011; 25:219–230.

4. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016; 63:261–283.

5. Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007; 46:395–401.

6. Tran TT. Immune tolerant hepatitis B: a clinical dilemma. Gastroenterol Hepatol (N Y). 2011; 7:511–516.

7. 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; 116:829–834.

8. Tsai SL, Chen PJ, Lai MY, et al. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest. 1992; 89:87–96.

9. Lee PI, Chang MH, Lee CY, et al. Changes of serum hepatitis B virus DNA and aminotransferase levels during the course of chronic hepatitis B virus infection in children. Hepatology. 1990; 12(4 Pt 1):657–660.

10. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. Incidence, predisposing factors and etiology. J Hepatol. 1990; 10:29–34.

11. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009; 49(5 Suppl):S45–S55.

12. Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol. 2002; 36:543–546.

13. Zacharakis GH, Koskinas J, Kotsiou S, et al. Natural history of chronic HBV infection: a cohort study 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.

14. de Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med. 1993; 118:191–194.

15. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis. 2003; 23:47–58.

16. 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; 123:1084–1089.

17. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661–662.

18. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002; 35:1522–1527.

19. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants. J Viral Hepat. 2002; 9:52–61.

20. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A. 1994; 91:4077–4081.

21. Okamoto H, Tsuda F, Akahane Y, 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; 68:8102–8110.

22. Croagh CM, Bell SJ, Slavin J, et al. Increasing hepatitis B viral load is associated with risk of significant liver fibrosis in HBeAg-negative but not HBeAg-positive chronic hepatitis B. Liver Int. 2010; 30:1115–1122.

23. Yoo BC, Park JW, Kim HJ, Lee DH, Cha YJ, Park SM. Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea. J Hepatol. 2003; 38:98–103.

24. Raimondo G, Allain JP, Brunetto MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008; 49:652–657.

25. Chu CM, Liaw YF. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology. 2007; 45:1187–1192.

26. Liu J, Yang HI, Lee MH, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology. 2010; 139:474–482.

27. Kim GA, Lee HC, Kim MJ, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol. 2015; 62:1092–1099.

28. Seto WK, Wong DK, Fung J, et al. Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B. Clin Microbiol Infect. 2014; 20:1173–1180.

29. Kim DY, Ahn SH, Lee HW, et al. Clinical course of virologic breakthrough after emergence of YMDD mutations in HBeAg-positive chronic hepatitis B. Intervirology. 2008; 51:293–298.

30. Yip TC, Chan HL, Wong VW, Tse YK, Lam KL, Wong GL. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol. 2017; 67:902–908.

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; 5:636–641.

32. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560–1599.

33. Wong GL. Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend. Clin Mol Hepatol. 2018; 24:108–113.

34. Chan HL, Chan CK, Hui AJ, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014; 146:1240–1248.

35. Wong VW, Hui AJ, Wong GL, et al. Four-year outcomes after cessation of tenofovir in immune-tolerant chronic hepatitis B patients. J Clin Gastroenterol. 2018; 52:347–352.

36. Kim GA, Lim YS, Han S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018; 67:945–952.

37. Sinn DH, Lee JH, Kim K, et al. A novel model for predicting hepatocellular carcinoma development in patients with chronic hepatitis B and normal alanine aminotransferase levels. Gut Liver. 2017; 11:528–534.

38. Kim MN, Kim SU, Kim BK, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology. 2015; 61:1851–1859.

39. Chang Y, Choe WH, Sinn DH, et al. Nucleos(t)ide analogue treatment for patients with hepatitis B virus (HBV) e antigen-positive chronic HBV genotype C infection: a nationwide, multicenter, retrospective study. J Infect Dis. 2017; 216:1407–1414.

40. Lok AS, McMahon BJ, Brown RS Jr, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016; 63:284–306.

41. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017; 112:18–35.

42. Lee JK, Shim JH, Lee HC, et al. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010; 51:1577–1583.

43. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002; 137:1–10.

44. Chung WG, Kim HJ, Choe YG, et al. Clinical impacts of hazardous alcohol use and obesity on the outcome of entecavir therapy in treatment-naïve patients with chronic hepatitis B infection. Clin Mol Hepatol. 2012; 18:195–202.

45. Chao DT, Lim JK, Ayoub WS, Nguyen LH, Nguyen MH. Systematic review with meta-analysis: the proportion of chronic hepatitis B patients with normal alanine transaminase ≤ 40 IU/L and significant hepatic fibrosis. Aliment Pharmacol Ther. 2014; 39:349–358.

46. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009; 49:1017–1044.

47. Korean Association for the Study of the Liver. KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol. 2016; 22:18–75.

48. Song BC, Cho YK, Jwa H, et al. Is it necessary to delay antiviral therapy for 3–6 months to anticipate HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B in endemic areas of HBV genotype C? Clin Mol Hepatol. 2014; 20:355–360.

49. Kim HS, Kim HJ, Shin WG, et al. Predictive factors for early HBeAg seroconversion in acute exacerbation of patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2009; 136:505–512.

50. 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; 295:65–73.

51. Paik N, Sinn DH, Lee JH, et al. Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low-level viremia. Liver Int. 2018; 38:68–75.

52. Nam SW, Jung JJ, Bae SH, et al. Clinical outcomes of delayed clearance of serum HBsAG in patients with chronic HBV infection. Korean J Intern Med. 2007; 22:73–76.

53. Cao Z, Liu Y, Ma L, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha. Hepatology. 2017; 66:1058–1066.

54. de Niet A, Jansen L, Stelma F, et al. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial. Lancet Gastroenterol Hepatol. 2017; 2:576–584.

55. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013; 381:468–475.

56. Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010; 52:886–893.

57. Lee J, Sinn DH, Kim JH, et al. Hepatocellular carcinoma risk of compensated cirrhosis patients with elevated HBV DNA levels according to serum aminotransferase levels. J Korean Med Sci. 2015; 30:1618–1624.

58. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017; 67:370–398.

59. Sinn DH, Lee J, Goo J, et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology. 2015; 62:694–701.

60. Cho YY, Lee JH, Chang Y, et al. Comparison of overall survival between antiviral-induced viral suppression and inactive phase chronic hepatitis B patients. J Viral Hepat. 2018; 25:1161–1171.

61. Suk KT, Baik SK, Yoon JH, et al. Revision and update on clinical practice guideline for liver cirrhosis. Korean J Hepatol. 2012; 18:1–21.

62. Jang JW, Choi JY, Kim YS, et al. Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis. Hepatology. 2015; 61:1809–1820.

63. Shim JH, Lee HC, Kim KM, et al. Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol. 2010; 52:176–182.

64. Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002; 123:719–727.