Export file:

Format

  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text

Content

  • Citation Only
  • Citation and Abstract

Mathematical investigation of HBeAg seroclearance

Department of Mathematics, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA

Special Issues: Multiscale dynamics of infectious diseases, immune responses and therapeutics

Spontaneous or drug-induced loss of hepatitis B e antigen is considered a beneficial event in the disease progression of chronic hepatitis B virus infections. Mathematical models of within-host interactions are proposed; which provide insight into hepatitis B e antibody formation, its influence on hepatitis B e antigen seroclearance, and reversion of anergic cytotoxic immune responses. They predict that antibody expansion causes immune activation and hepatitis B e antigen seroclearance. Quantification of the time between antibody expansion and hepatitis B e antigen seroclearance in the presence and absence of treatment shows that potent short-term treatment speeds up the time between antibody expansion and hepatitis B e antigen seroclearance. The monthly hepatocyte turnover during this time can be increased or decreased by treatment depending on the amount of core promoter or precore mutated virus produced. The results can inform human interventions.
  Figure/Table
  Supplementary
  Article Metrics

References

1. J. Hou, Z. Liu and F. Gu, Epidemiology and prevention of hepatitis B virus infection, Int. J. Med. Sci., 2 (2005), 50.

2. European Association for the study of the Liver, EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection, J. Hepatol., 67 (2017), 370–398.

3. J. E. Bennett, R. Dolin and M. J. Blaser, Mandell, Douglas and Bennett's Principles and Practice of Infectious Disease, 8th edition, Elsevier Saunders, Philadelphia, 2015.

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

5. D. Milich and T. J. Liang, Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection, Hepatology, 38 (2003), 1075–1086.

6. Y. Han, J. Li, L. Jiang, et al., Regulation of B7-H1 expression on peripheral monocytes and IFN-γ secretion in T lymphocytes by HBeAg, Cell. Immunol., 283 (2013), 25–30.

7. W. R. Kim, S. L. Flamm, A. M. Di Bisceglie, et al., Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease, Hepatology, 47 (2008), 1363–1370.

8. R. Marug'an and S. Garz'on, DNA-guided hepatitis B treatment, viral load is essential, but not sufficient, World J. Gastroenterol., 15 (2009), 423–430.

9. V. Rijckborst and H. L. Janssen, The role of interferon in hepatitis B therapy, Curr. Hepat. Rep., 9 (2010), 231–238.

10. J. Fung, C.-L. Lai, W.-K. Seto, et al., Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B, J. Antimicrob. Chemother., 66 (2011), 2715–2725.

11. European Association for the study of the Liver, EASL clinical practice guidelines: management of chronic hepatitis b virus infection, J. Hepatol., 57 (2012), 167–185.

12. W. Zhang, D. Zhang, X. Dou, et al., Consensus on pegylated interferon alpha in treatment of chronic hepatitis B, J. Clin. Transl. Hepatol., 6 (2018), 1.

13. G. Papatheodoridis, I. Vlachogiannakos, E. Cholongitas, et al., Discontinuation of oral antivirals in chronic hepatitis B: A systematic review, Hepatology, 63 (2016), 1481–1492.

14. A. S. J. Woo, R. Kwok and T. Ahmed, Alpha-interferon treatment in hepatitis B, Ann. Transl. Med., 5 (2017), 159.

15. S. J. Hadziyannis, Update on hepatitis B virus infection: focus on treatment, J. Clin. Transl. Hepatol., 2 (2014), 285.

16. J. Vlachogiannakos and G. V. Papatheodoridis, Hepatitis B: Who and when to treat?, Liver Int., 38 (2018), 71–78.

17. Y.-F. Liaw, HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B, Hepatol. Int., 3 (2009), 425–433.

18. C.-K. Hui, N. Leung, T. W. Shek, et al., Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B chinese patients, Hepatology, 46 (2007), 690–698.

19. H.-I. Yang, S.-N. Lu, Y.-F. Liaw, et al., Hepatitis B e antigen and the risk of hepatocellular carcinoma, N. Engl. J. Med., 347 (2002), 168–174.

20. Y.-S. Hsu, R.-N. Chien, C.-T. Yeh, et al., Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B, Hepatology, 35 (2002), 1522–1527.

21. C.-M. Chu, S.-J. Hung, J. Lin, et al., Natural history of hepatitis be antigen to antibody seroconversion in patients with normal serum aminotransferase levels, Am. J. Med., 116 (2004), 829–834.

22. S.-M. Lin, M.-L. Yu, C.-M. Lee, et al., Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma, J. Hepatol., 46 (2007), 45–52.

23. C.-M. Chu and Y.-F. Liaw, Spontaneous relapse of hepatitis in inactive HBsAg carriers, Hepatol. Int., 1 (2007), 311–315.

24. C.-M. Chu and Y.-F. Liaw, Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion, J. Viral Hepat., 14 (2007), 147–152.

25. C.-M. Chu and Y.-F. Liaw, Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B, Gastroenterology, 133 (2007), 1458–1465.

26. H. Dakin, C. Fidler and C. Harper, Mixed treatment comparison meta-analysis evaluating the relative efficacy of nucleos(t)ides for treatment of nucleos(t)ide-naive patients with chronic hepatitis B, Value Health, 13 (2010), 934–945.

27. A. Wiens, L. Lenzi, R. Venson, et al., Comparative efficacy of oral nucleoside or nucleotide analog monotherapy used in chronic hepatitis B: a mixed-treatment comparison meta-analysis, Pharmacotherapy, 33 (2013), 144–151.

28. T. Xing, H. Xu, L. Cao, et al., HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term nucleos(t)ide analog treatment: a systematic review and network meta-analysis, PLoS One, 12 (2017), e0169444.

29. M. Yuen, H. Yuan, C. Hui, et al., A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy, Gut, 52 (2003), 416–419.

30. M. Nowak, S. Bonhoeffer, A. Hill, et al., Viral dynamics in hepatitis B virus infection, Proc. Natl. Acad. Sci. U.S.A., 93 (1996), 4398–4402.

31. S. Ciupe, R. Ribeiro, P. Nelson, et al., The role of cells refractory to productive infection in acute hepatitis B viral dynamics, Proc. Natl. Acad. Sci. U.S.A., 104 (2007), 5050–5055.

32. A. Goyal, R. M. Ribeiro and A. S. Perelson, The role of infected cell proliferation in the clearance of acute HBV infection in humans, Viruses, 9 (2017), 350.

33. A. Neumann, N. Lam, H. Dahari, et al., Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-α therapy, Science, 282 (1998), 103–107.

34. Y. Ji, W. Li, L. Min, et al., A mathematical model for anti-HBV infection treatment with lamivudine and curative effect prediction, in Control and Automation, 2007. ICCA 2007. IEEE International Conference on, IEEE, 2007, 2485–2488.

35. S. Gourley, Y. Kuang and J. Nagy, Dynamics of a delay differential model of hepatitis B virus, J. Biol. Dyn., 2 (2008), 140–153.

36. S. Eikenberry, S. Hews, J. Nagy, et al., The dynamics of a delay model of HBV infection with logistic hepatocyte growth, Math. Biosci. Eng., 6 (2009), 283–299.

37. H. Dahari, E. Shudo, R. M. Ribeiro, et al., Modeling complex decay profiles of hepatitis B virus during antiviral therapy, Hepatology, 49 (2009), 32–38.

38. S. R. Lewin, R. M. Ribeiro, T. Walters, et al., Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed, Hepatology, 34 (2001), 1012–1020.

39. A. U. Neumann, S. Phillips, I. Levine, et al., Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells, Hepatology, 52 (2010), 875–885.

40. J. Forde, S. Ciupe, A. Cintron-Arias, et al., Optimal control of drug therapy in a hepatitis B model, Appl. Sci, 6 (2016), 219.

41. A. Carracedo Rodriguez, M. Chung and S. Ciupe, Understanding the complex patterns observed during hepatitis B virus therapy, Viruses, 9 (2017), 117.

42. A. Goyal and J. M. Murray, Modelling the impact of cell-to-cell transmission in hepatitis B virus, PLoS One, 11 (2016), e0161978.

43. J. M. Murray and A. Goyal, In silico single cell dynamics of hepatitis B virus infection and clearance, J. Theor. Biol., 366 (2015), 91–102.

44. A. Goyal and R. Chauhan, The dynamics of integration, viral suppression and cell-cell transmission in the development of occult hepatitis B virus infection, J. Theor. Biol., 455 (2018), 269–280.

45. S. Ciupe, R. Ribeiro, P. Nelson, et al., Modeling the mechanisms of acute hepatitis B virus infection, J. Theor. Biol., 247 (2007), 23–35.

46. C. Long, H. Qi and S. Huang, Mathematical modeling of cytotoxic lymphocyte-mediated immune response to hepatitis B virus infection, J. Biomed. Biotechnol., 2008 (2008), 743690.

47. H. Kim, H. Kwon, T. Jang, et al., Mathematical modeling of triphasic viral dynamics in patients with HBeAg-positive chronic hepatitis B showing response to 24-week clevudine therapy, PLoS One, 7 (2012), e50377.

48. N. Yousfi, K. Hattaf and A. Tridane, Modeling the adaptive immune response in HBV infection, J. Math. Biol., 63 (2011), 933–957.

49. S. Ciupe, R. Ribeiro and A. Perelson, Antibody response during hepatitis B viral infection, PLoS Comput. Biol., 10 (2014), e1003730.

50. S. Ciupe and S. Hews, Mathematical models of e-antigen mediated immune tolerance and activation following prenatal HBV infection, PLoS One, 7 (2012), e39591.

51. J. Rozga, Hepatocyte proliferation in health and in liver failure, Med. Sci. Monit., 8 (2002), RA32–RA38.

52. L. Allweiss and M. Dandri, The role of cccDNA in HBV maintenance, Viruses, 9 (2017), 156.

53. D. R. Milich, M. K. Chen, J. L. Hughes, et al., The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence, J. Immunol., 160 (1998), 2013–2021.

54. M. Oprea and A. S. Perelson, Exploring the mechanisms of primary antibody responses to t cell-dependent antigens, J. Theor. Biol., 181 (1996), 215–235.

55. J. S. Dooley, A. Lok, A. K. Burroughs, et al., Sherlock's diseases of the liver and biliary system, John Wiley & Sons, 2011.

56. A.-K. Sohlenius-Sternbeck, Determination of the hepatocellularity number for human, dog, rabbit, rat and mouse livers from protein concentration measurements, Toxicol. In Vitro, 20 (2006), 1582–1586.

57. J. Murray, R. Purcell and S. Wieland, The half-life of hepatitis B virions, Hepatology, 44 (2006), 1117–1121.

58. S. A. Whalley, J. M. Murray, D. Brown, et al., Kinetics of acute hepatitis B virus infection in humans, J. Exp. Med., 193 (2001), 847–854.

59. R. Ahmed and D. Gray, Immunological memory and protective immunity: understanding their relation, Science, 272 (1996), 54–60.

60. S. E. Brown, C. R. Howard, A. J. Zuckerman, et al., Determination of the affinity of antibodies to hepatitis B surface antigen in human sera, J. Immunol. Methods, 72 (1984), 41–48.

61. S. Stein, J. Ware and R. Woods, Serum immunoglobulins: Methods for the determination of normal values in international units, J. Immunol. Methods, 16 (1977), 371–384.

62. T. Igarashi, C. Brown, A. Azadegan, et al., Human immunodeficiency virus type 1 neutralizing antibodies accelerate clearance of cell–free virions from blood plasma, Nat. Med., 5 (1999), 211.

63. G. D. Tomaras, N. L. Yates, P. Liu, et al., Initial B-cell responses to transmitted human immunodeficiency virus type 1: Virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma Anti-gp41 antibodies with ineffective control of initial viremia, J. Virol., 82 (2008), 12449–12463.

64. P. T. Kennedy, E. Sandalova, J. Jo, et al., Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B, Gastroenterology, 143 (2012), 637–645.

65. S. Cai, Z. Li, T. Yu, et al., Serum hepatitis B core antibody levels predict HBeAg seroconversion in chronic hepatitis B patients with high viral load treated with nucleos(t)ide analogs, Infect. Drug Resist., 11 (2018), 469.

66. H. Okamoto, F. Tsuda, Y. Akahane, 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., 68 (1994), 8102–8110.

67. W. Carman, S. Hadziyannis, M. McGarvey, et al., Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection, Lancet, 334 (1989), 588–591.

68. S. F. Baqai, J. Proudfoot, H. Y. Debbie, et al., High rate of core promoter and precore mutations in patients with chronic hepatitis B, Hepatol. Int., 9 (2015), 209–217.

69. N. Kamijo, A. Matsumoto, T. Umemura, et al., Mutations of pre-core and basal core promoter before and after hepatitis B e antigen seroconversion, World J. Gastroenterol., 21 (2015), 541.

70. H. Okamoto, S. Yotsumoto, Y. Akahane, 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., 64 (1990), 1298–1303.

71. J.-H. Kao, P.-J. Chen and D.-S. Chen, Recent advances in the research of hepatitis B virus-related hepatocellular carcinoma: epidemiologic and molecular biological aspects, Adv. Cancer Res., 108 (2010), 21–72.

72. E.-C. Shin, P. S. Sung and S.-H. Park, Immune responses and immunopathology in acute and chronic viral hepatitis, Nat. Rev. Immunol., 16 (2016), 509–523.

73. C. Ferrari, HBV and the immune response, Liver Int., 35 (2015), 121–128.

74. D. He, G. Yan and Y. Wang, Serum levels of interleukin-12 in various clinical states with hepatitis B virus infection, Cell. Immunol., 272 (2012), 162–165.

75. S. M. Ciupe, Modeling the dynamics of hepatitis B infection, immunity, and drug therapy, Immunol. Rev., 285 (2018), 38–54.

76. M. Dandri, J. M. Murray, M. Lutgehetmann, et al., Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia, Hepatology, 48 (2008), 1079–1086.

77. R. M. Ribeiro, G. Germanidis, K. A. Powers, et al., Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections, J. Infect. Dis., 202 (2010), 1309–1318.

78. W. Mason, S. Litwin, C. Xu, et al., Hepatocyte turnover in transient and chronic hepadnavirus infections, J. Viral Hepat., 14 (2007), 22–28.

79. L. G. Guidotti, R. Rochford, J. Chung, et al., Viral clearance without destruction of infected cells during acute hbv infection, Science, 284 (1999), 825–829.

80. E. Rodr´ ıguez-I˜ nigo, L. Mariscal, J. Bartolomé, et al., Distribution of hepatitis B virus in the liver of chronic hepatitis C patients with occult hepatitis B virus infection, J. Med. Virol., 70 (2003), 571–580.

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved