Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance

Gastroenterology. 2007 Feb;132(2):543-50. doi: 10.1053/j.gastro.2006.12.001. Epub 2006 Dec 3.


Background & aims: Seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is a rare event in chronic hepatitis B patients receiving lamivudine therapy. It is generally believed to be a benevolent sign, implicating clearance of viremia. The aim of this study is to examine the authenticity of this dogma.

Methods: In a 5-year period, 11 patients treated with lamivudine experienced seroclearance of HBsAg. The clinical data were examined. The HBV S gene sequences derived from the patient's serum samples before and after seroclearance of HBsAg were analyzed.

Results: Serum HBV-DNA could be detected by nested polymerase chain reaction (PCR) in all 11 patients, by 1-step PCR in 8, and by Cobas Amplicor HBV-DNA test (>200 copies/mL) in 5. A mutation hot spot, P120A in the S gene, was identified in 6 of the 11 patients. Site-directed mutagenesis experiments indicated that the Ausria-II RIA test failed to detect this mutant. Decreased sensitivity of detection was also observed when other monoclonal antibodies were applied.

Conclusions: Seroclearance of HBsAg during lamivudine therapy may not indicate viral clearance. Specifically, it may be caused by a point mutation in the S gene, which results in detection failure. In such patients, further verification and follow-up using a sensitive HBV-DNA test are advised.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Cell Line
  • DNA, Viral / blood
  • DNA, Viral / genetics
  • Female
  • Hepatitis B Surface Antigens / blood*
  • Hepatitis B Surface Antigens / genetics*
  • Hepatitis B Surface Antigens / immunology
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / immunology
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis B, Chronic / virology*
  • Humans
  • Immunoenzyme Techniques
  • Lamivudine / therapeutic use*
  • Male
  • Middle Aged
  • Mutagenesis, Site-Directed
  • Mutation
  • Polymerase Chain Reaction / methods
  • Predictive Value of Tests
  • Prognosis
  • Protein Precursors / blood
  • Protein Precursors / genetics
  • Radioimmunoassay
  • Reagent Kits, Diagnostic
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Sensitivity and Specificity
  • Time Factors
  • Transfection
  • Treatment Outcome
  • Viremia / drug therapy
  • Viremia / virology


  • DNA, Viral
  • Hepatitis B Surface Antigens
  • Protein Precursors
  • Reagent Kits, Diagnostic
  • Reverse Transcriptase Inhibitors
  • presurface protein 1, hepatitis B surface antigen
  • presurface protein 2, hepatitis B surface antigen
  • Lamivudine