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Spontaneous Flares of Chronic Hepatitis B Virus in Hepatitis Be Antigen Negative Carriers Who Subsequently Clear Hepatitis B Surface Antigen

Abstract

Background

Acute exacerbations of chronic hepatitis B virus (HBV) infections can occur in HBV-infected, hepatitis e antigen (HBeAg)-negative patients in the absence of recent withdrawal of antiviral or immunosuppressive therapies. Whether these spontaneous “flares” predict subsequent loss of hepatitis B surface antigen (HBsAg) has yet to be determined.

Objectives

To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers.

Methods

A retrospective review of an HBV database identified and followed HBeAg-negative patients for biochemical evidence of flares (ALT > 5× normal) and subsequent HBsAg status. Patients that subsequently cleared HBsAg were matched 1:1 with those who remained HBsAg positive.

Results

Of 1299 HBeAg-negative patients followed for 10.2 ± 6.1 years, 88 (6.8%) developed spontaneous HBV flares. Flares occurred in 14/115 (12.2%) patients who subsequently cleared HBsAg and 4/111 (3.6%) matched patients who remained HBsAg positive (p = 0.025). The severity of flares was similar in the two study cohorts. Following multivariate analyses, only low HBV-DNA levels at baseline identified patients likely to subsequently clear HBsAg.

Conclusions

Although more common in patients who subsequently clear HBsAg, spontaneous HBV flares do not predict subsequent HBsAg clearance.

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References

  1. 1.

    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.

  2. 2.

    Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–1022.

  3. 3.

    Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, ChangChien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology. 1983;84:216–219.

  4. 4.

    Liaw YF, Pao CC, Chu CM, Sheen IS, Huang MJ. Changes of serum hepatitis B virus DNA in two types of clinical events preceding spontaneous hepatitis B e antigen seroconversion in chronic type B hepatitis. Hepatology. 1987;7:1–3.

  5. 5.

    Da Silva LC, Madruga CL, Carrilho FJ, et al. Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection. J Gastroenterol. 1996;31:696–701.

  6. 6.

    Liaw YF. Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy. J Gastroenterol Hepatol. 2003;18:246–252.

  7. 7.

    Coffin CS, Ramji A, Cooper CL, et al. Epidemiologic and clinical features of chronic hepatitis B virus infection in 8 Canadian provinces: a descriptive study by the Canadian HBV Network. CMAJ Open.. 2019;7:E610–E617.

  8. 8.

    Osiowy C, Giles E, Trubnikov M, Choudhri Y, Andonov A. Characterization of acute and chronic hepatitis B virus genotypes in Canada. PLoS ONE. 2015;25:e0136074. https://doi.org/10.1371/journal.pone.0136074.

  9. 9.

    Zhang M, Gong Y, Osiowy C, Minuk GY. Rapid detection of hepatitis B virus mutations using real-time PCR and melting curve analysis. Hepatology. 2002;36:723–728.

  10. 10.

    Feng IC, Koay LB, Sheu MJ, et al. HBcAg-specific CD4+CD25+ regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection. J Biomed Sci. 2007;14:43–57.

  11. 11.

    Tsai SL, Wang SL, Feng IC, et al. Acute exacerbations of chronic hepatitis B are accompanied by decline of core antigen-specific regulatory T-cell frequencies: implications for successful anti-HBV treatments. Hepat Monthly. 2007;7:183–200.

  12. 12.

    Koay LB, Feng IC, Sheu MJ, et al. Hepatitis B virus (HBV) core antigen-specific regulatory T cells confer sustained remission to anti-HBV therapy in chronic hepatitis B with acute exacerbation. Hum Immunol. 2011;72:687–698.

  13. 13.

    Liu J, Yang HI, Lee MH et al. REVEAL-HBV Study Group. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology 2010;139:474–82.

  14. 14.

    Ferreira SC, Chachá SG, Souza FF, et al. Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital. Ann Hepatol. 2014;13:762–770.

  15. 15.

    Chu CM, Liaw YF. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther. 2010;15:133–143.

  16. 16.

    Altinbas A, Yüksel I, Pamukcu M, Ekiz F, Basar O, Yüksel O. Spontaneous HBsAg seroconversion after severe flare of chronic hepatitis B infection. Ann Hepatol. 2010;9:194–197.

  17. 17.

    Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol. 2014;61:1407–1417.

  18. 18.

    Ren X, Xu Z, Liu Y, et al. Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J Viral Hepatol.. 2010;17:887–895.

  19. 19.

    Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: recent advances. J Gastroenterol Hepatol. 2011;26:123–130.

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Acknowledgments

The authors wish to thank Ms R. Vizniak for her prompt and accurate typing of the manuscript.

Funding

No funding to report.

Author information

GYM and NS contributed to study concept and design; DI-F, NS, DM, CO, KK, SW, SC, DP, and GYM were involved in acquisition of data; DI-F, JU and GYM contributed to analysis and interpretation of data; DI-F, GYM, and NS drafted the manuscript; DI-F, NS, DM, CO, KK, SW, SC, and DP were involved in critical revision of the manuscript for intellectual content; JU contributed to statistical analysis; N/A obtained funding; GYM was involved in administrative, technical, material support, and study supervision.

Correspondence to Gerald Y. Minuk.

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Iluz-Freundlich, D., Samad, N., Miles, D. et al. Spontaneous Flares of Chronic Hepatitis B Virus in Hepatitis Be Antigen Negative Carriers Who Subsequently Clear Hepatitis B Surface Antigen. Dig Dis Sci (2020). https://doi.org/10.1007/s10620-020-06125-5

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Keywords

  • HBsAg
  • Flares
  • Reactivation
  • Hepatitis B
  • HBeAg
  • HBV-DNA