Viral and immune factors associated with successful treatment withdrawal in HBeAg-negative chronic hepatitis B patients

J Hepatol. 2021 May;74(5):1064-1074. doi: 10.1016/j.jhep.2020.11.043. Epub 2020 Dec 2.


Background & aims: Factors associated with a successful outcome upon nucleos(t)ide analogue (NA) treatment withdrawal in HBeAg-negative chronic hepatitis B (CHB) patients have yet to be clarified. The objective of this study was to analyse the HBV-specific T cell response, in parallel with peripheral and intrahepatic viral parameters, in patients undergoing NA discontinuation.

Methods: Twenty-seven patients without cirrhosis with HBeAg-negative CHB with complete viral suppression (>3 years) were studied prospectively. Intrahepatic HBV-DNA (iHBV-DNA), intrahepatic HBV-RNA (iHBV-RNA), and covalently closed circular DNA (cccDNA) were quantified at baseline. Additionally, serum markers (HBV-DNA, HBsAg, HBV core-related antigen [HBcrAg] and HBV-RNA) and HBV-specific T cell responses were analysed at baseline and longitudinally throughout follow-up.

Results: After a median follow-up of 34 months, 22/27 patients (82%) remained off-therapy, of whom 8 patients (30% of the total cohort) lost HBsAg. Baseline HBsAg significantly correlated with iHBV-DNA and iHBV-RNA, and these parameters were lower in patients who lost HBsAg. All patients had similar levels of detectable cccDNA regardless of their clinical outcome. Patients achieving functional cure had baseline HBsAg levels ≤1,000 IU/ml. Similarly, an increased frequency of functional HBV-specific CD8+ T cells at baseline was associated with sustained viral control off treatment. These HBV-specific T cell responses persisted, but did not increase, after treatment withdrawal. A similar, but not statistically significant trend, was observed for HBV-specific CD4+ T cell responses.

Conclusions: Decreased cccDNA transcription and low HBsAg levels are associated with HBsAg loss upon NA discontinuation in patients with HBeAg-negative CHB. The presence of functional HBV-specific T cells at baseline are associated with a successful outcome after treatment withdrawal.

Lay summary: Nucleos(t)ide analogue therapy can be discontinued in a high proportion of chronic hepatitis B patients without cirrhosis. The strength of HBV-specific immune T cell responses may contribute to successful viral control after antiviral treatment interruption. Our comprehensive study provides in-depth data on virological and immunological factors than can help guide individualised therapy in patients with chronic hepatitis B.

Keywords: Antiviral therapy discontinuation; Chronic hepatitis B; Covalently closed circular DNA; HBV-RNA; HBV-Specific T cells; HBcrAg; HBsAg; Hepatitis B virus; Immune response; Nucleos(t)ide analogue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / therapeutic use
  • Biomarkers / blood
  • DNA, Circular / isolation & purification
  • DNA, Viral / isolation & purification*
  • Female
  • Hepatitis B Antigens* / analysis
  • Hepatitis B Antigens* / isolation & purification
  • Hepatitis B Surface Antigens / analysis
  • Hepatitis B virus* / genetics
  • Hepatitis B virus* / isolation & purification
  • Hepatitis B, Chronic* / blood
  • Hepatitis B, Chronic* / diagnosis
  • Humans
  • Immunity, Cellular* / drug effects
  • Immunity, Cellular* / immunology
  • Liver* / pathology
  • Liver* / virology
  • Male
  • Middle Aged
  • Nucleosides / therapeutic use*
  • Patient Care Planning
  • Withholding Treatment / statistics & numerical data*


  • Antiviral Agents
  • Biomarkers
  • DNA, Circular
  • DNA, Viral
  • Hepatitis B Antigens
  • Hepatitis B Surface Antigens
  • Nucleosides