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HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B

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Abstract

During the natural history of chronic hepatitis B virus (HBV) infection, the loss of serum hepatitis B e antigen (HBeAg) and the development of anti-HBe antibodies (HBeAg seroconversion) mark a transition from the immune-active phase of disease to the inactive carrier state. This review examines the evidence from natural history and cohort studies on the relationship between HBeAg seroconversion and disease progression. The role of HBeAg seroconversion as an important milestone in the management of HBeAg-positive patients with chronic hepatitis B (CHB), as well as the advantages and disadvantages of administering a finite course of therapy for HBeAg-positive CHB, is also discussed. The evidence from natural history and cohort studies indicates that spontaneous or treatment-induced HBeAg seroconversion is associated with lower rates of disease progression to cirrhosis and hepatocellular carcinoma, a potential of hepatitis B surface antigen seroconversion, and improved survival rates. Updated guidelines developed by major liver associations recommend stopping oral therapy for HBeAg-positive patients who achieve sustained HBeAg seroconversion with polymerase chain reaction-undetectable HBV-DNA on two separate occasions for 6 or more months apart, taking into consideration the individual’s clinical and virologic response to therapy, as well as the severity of liver disease. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogues has important clinical and socioeconomic implications for the management of CHB.

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References

  1. World Health Organization. Hepatitis B fact sheets. Available from: http://www.who.int/mediacentre/factsheets/fs204/en. Accessed 27 Oct 2008

  2. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 1988;61:1942–1956

    Article  PubMed  CAS  Google Scholar 

  3. Lesmana LA, Leung NW, Mahachai V, Phiet PH, Suh DJ, Yao G, et al. Hepatitis B: overview of the burden of disease in the Asia-Pacific region. Liver Int 2006;26:3–10

    Article  Google Scholar 

  4. 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;347:168–174

    Article  PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. 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;130:678–686

    Article  PubMed  Google Scholar 

  7. 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;295:65–67

    Article  PubMed  CAS  Google Scholar 

  8. 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;35:1522–1527

    Article  PubMed  Google Scholar 

  9. 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

    Article  PubMed  CAS  Google Scholar 

  10. 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 Hepatol 2007;14:147–152

    Article  Google Scholar 

  11. Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 2007;133:1458–1465

    Article  PubMed  CAS  Google Scholar 

  12. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long-term follow-up of HBeAg-positive patients treated with interferon Alfa for chronic hepatitis B. N Engl J Med 1996;334:1422–1427

    Article  PubMed  CAS  Google Scholar 

  13. 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;29:971–975

    Article  PubMed  CAS  Google Scholar 

  14. Lin SM, Yu ML, Lee CM, Chien RN, Sheen IS, Chu CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007;46:45–52

    Article  PubMed  CAS  Google Scholar 

  15. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263–283

    Article  PubMed  Google Scholar 

  16. 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: 2008 update. Clin Gastroenterol Hepatol 2008;6:1315–1341

    Article  PubMed  CAS  Google Scholar 

  17. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507–539

    Article  PubMed  CAS  Google Scholar 

  18. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227–242

    Article  PubMed  CAS  Google Scholar 

  19. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology 2003;37:1309–1319

    Article  PubMed  Google Scholar 

  20. 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;351:1521–1531

    Article  PubMed  CAS  Google Scholar 

  21. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206–1217

    Article  PubMed  CAS  Google Scholar 

  22. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007;357:2576–2588

    Article  PubMed  CAS  Google Scholar 

  23. Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437–1444

    Article  PubMed  CAS  Google Scholar 

  24. Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008;48:750–758

    Article  PubMed  CAS  Google Scholar 

  25. Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294–298

    Article  PubMed  CAS  Google Scholar 

  26. 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

    Article  PubMed  CAS  Google Scholar 

  27. Liaw YF. Hepatitis B virus replication and liver disease progression: the impact of antiviral therapy. Antivir Ther 2006;11:669–679

    PubMed  CAS  Google Scholar 

  28. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582–592

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  30. Chang MH, Hsu HY, Hsu HC, Ni YH, Chen JS, Chen DS. The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age. Hepatology 1995;22:1387–1392

    PubMed  CAS  Google Scholar 

  31. Chu CM, Sheen IS, Lin SM, Liaw YF. Sex difference in chronic hepatitis B virus infection: studies of serum HBeAg and alanine aminotransferase levels in 10, 431 asymptomatic Chinese HBsAg carriers. Clin Infect Dis 1993;16:709–713

    PubMed  CAS  Google Scholar 

  32. 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;1:227–233

    Article  PubMed  CAS  Google Scholar 

  33. 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;26:949–955

    Article  PubMed  CAS  Google Scholar 

  34. Hui CK, Leung N, Shek TW, Yao H, Lee WK, Lai JY, et al. Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 2007;46:690–698

    Article  PubMed  Google Scholar 

  35. 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

    Article  PubMed  Google Scholar 

  36. 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

    Article  PubMed  Google Scholar 

  37. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008;48:335–352

    Article  PubMed  CAS  Google Scholar 

  38. Chu CM, Liaw YF. Spontaneous relapse of hepatitis in inactive HBsAg carriers. Hepatol Int 2007;1:311–315

    Article  PubMed  Google Scholar 

  39. You SL, Yang HI, Chen CJ. Seropositivity of hepatitis B e antigen and hepatocellular carcinoma. Ann Med 2004;36:215–224

    Article  PubMed  CAS  Google Scholar 

  40. van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Murad SD, de Man RA, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 2004;39:804–810

    Article  PubMed  CAS  Google Scholar 

  41. Yang PM, Chen DS, Lai MY, Su IJ, Huang GT, Lin JT, et al. Clinicopathologic studies of asymptomatic HBsAg carriers: with special emphasis on carriers older than 40 years. Hepatogastroenterology 1987;34:251–254

    PubMed  CAS  Google Scholar 

  42. Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988;8:493–496

    Article  PubMed  CAS  Google Scholar 

  43. 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;352:2682–2695

    Article  PubMed  CAS  Google Scholar 

  44. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–129

    Article  PubMed  CAS  Google Scholar 

  45. Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 2005;142:240–250

    PubMed  CAS  Google Scholar 

  46. Lau GKK, Piratvisuth T, Luo KX, et al. Durability of response and occurrence of late response to peginterferon alpha-2a (40KD) [PEGASYS] one year post-treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2006;44(Suppl 2):S23–S24. Meeting Abstract: 50

    Article  Google Scholar 

  47. Piratvisuth T, Lau G, Chao YC, et al. Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Hepatol Int 2008;2:102–110

    Article  PubMed  Google Scholar 

  48. Liaw YF. On-treatment outcome prediction and adjustment during chronic hepatitis B therapy: now and future. Antivir Ther 2009;14:13–22

    PubMed  CAS  Google Scholar 

  49. Chien RN, Liaw YF, Atkins M, Asian Hepatitis Lamivudine Trial Group. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Hepatology 1999;30:770–774

    Article  PubMed  CAS  Google Scholar 

  50. Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 2000;32:803–806

    Article  PubMed  CAS  Google Scholar 

  51. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–1010

    Article  PubMed  CAS  Google Scholar 

  52. Hou J, Yin YK, Xu D, Tan D, Niu J, Zhou X, et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: results at 1 year of a randomized, double-blind trial. Hepatology 2008;47:447–454

    Article  PubMed  CAS  Google Scholar 

  53. Wang Y, Hou JL, Chutaputti A. Sustained durability of HBeAg seroconversion in patients with chronic hepatitis B treated with telbivudine or lamivudine. Hepatol Int 2008;2:S165. Abstract no. PP-363

    Google Scholar 

  54. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442–2455

    Article  PubMed  CAS  Google Scholar 

  55. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009;136:486–495

    Article  PubMed  CAS  Google Scholar 

  56. Poynard T, Hou JL, Chutaputti A, Manns M, Naoumov N. Sustained durability of HBeAg seroconversion in chronic hepatitis B. J Hepatol 2008;48:S263–264. Abstract no. 706

    Article  Google Scholar 

  57. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepatol 2004;11:97–107

    Article  CAS  Google Scholar 

  58. Liaw YF. Antiviral therapies of chronic hepatitis B: opportunities and challenges in Asia. J Hepatol 2009. doi:10.1016/j.jhep.2009.04.003

  59. Taiwan Bureau of National Health Insurance. Medical care of liver disease [in Chinese]. [November 11]. Available from: http://www.nhi.gov.tw/06inquire/query8_detail.asp?News_ID=380. Accessed 6 Feb 2009

  60. Sullivan SD, Veenstra DL, Chen PJ, Chang TT, Chuang WL, Tsai C, et al. Cost-effectiveness of peginterferon alpha-2a compared to lamivudine treatment in patients with hepatitis B e antigen positive chronic hepatitis B in Taiwan. J Gastroenterol Hepatol 2007;22:1494–1499

    Article  PubMed  Google Scholar 

  61. Li SC, Ong SC, Lim SG, Yeoh KG, Kwong KS, Lee V, et al. A cost comparison of management of chronic hepatitis B and its associated complications in Hong Kong and Singapore. J Clin Gastroenterol 2004;38(10 Suppl 3):S136–S143

    Article  PubMed  Google Scholar 

  62. Yang BM, Kim CH, Kim JY. Cost of chronic hepatitis B infection in South Korea. J Clin Gastroenterol 2004;38(10 Suppl 3):S153–S157

    Article  PubMed  Google Scholar 

  63. Dan YY, Aung MO, Lim SG. The economics of treating chronic hepatitis B in Asia. Hepatol Int 2008;2:284–295

    Article  PubMed  Google Scholar 

  64. Spackman DE, Veenstra DL. A cost-effectiveness analysis of currently approved treatments for HBeAg-positive chronic hepatitis B. Pharmacoeconomics 2008;26:937–949

    Article  PubMed  Google Scholar 

  65. Takeda A, Jones J, Shepherd J, Davidson P, Price A. A systematic review and economic evaluation of adefovir dipivoxil and pegylated interferon-alpha-2a for the treatment of chronic hepatitis B. J Viral Hepatol 2007;14:75–88

    Article  CAS  Google Scholar 

  66. Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 2003;38:1267–1273

    Article  PubMed  CAS  Google Scholar 

  67. Yoon SK, Jang JW, Kim CW, Bae SH, Choi JY, Choi SW, et al. Long-term results of lamivudine monotherapy in Korean patients with HBeAg-positive chronic hepatitis B: response and relapse rates, and factors related to durability of HBeAg seroconversion. Intervirology 2005;48:341–349

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The author thanks Kathleen Covino, PhD, for her editorial contributions and assistance in the preparation of the manuscript and Ms Su-Chiung Chu for her excellent secretarial assistance.

Conflict of interest statement

The author has been involved in clinical trials and served as a global advisory board member of Roche, BMS, GSK, Novartis, and Gilead Sciences.

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Correspondence to Yun-Fan Liaw.

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Liaw, YF. HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B. Hepatol Int 3, 425–433 (2009). https://doi.org/10.1007/s12072-009-9140-3

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