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



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


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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.

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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 66, 257–262 (2021). https://doi.org/10.1007/s10620-020-06125-5

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  • HBsAg
  • Flares
  • Reactivation
  • Hepatitis B
  • HBeAg