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.
To document the percent of patients who experience spontaneous HBV flares and severity of the flares in chronic HBeAg-negative carriers.
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.
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.
Although more common in patients who subsequently clear HBsAg, spontaneous HBV flares do not predict subsequent HBsAg clearance.
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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.
Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009–1022.
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.
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.
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.
Liaw YF. Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy. J Gastroenterol Hepatol. 2003;18:246–252.
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.
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.
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.
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.
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.
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.
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.
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.
Chu CM, Liaw YF. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther. 2010;15:133–143.
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.
Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol. 2014;61:1407–1417.
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.
Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: recent advances. J Gastroenterol Hepatol. 2011;26:123–130.
The authors wish to thank Ms R. Vizniak for her prompt and accurate typing of the manuscript.
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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 66, 257–262 (2021). https://doi.org/10.1007/s10620-020-06125-5
- Hepatitis B