Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy

Antivir Ther. 2010;15(3 Pt B):471-5. doi: 10.3851/IMP1552.


Structurally modified nucleotide/nucleoside analogues can exert potent inhibitory effect on HBV polymerase activities. Some of these agents have been approved for the treatment of chronic hepatitis B. Because of a high risk of reactivation upon drug withdrawal, continuous long-term therapy is recommended to maintain maximal viral suppression. Consequently, drug resistance has developed in a significant proportion of patients. During long-term therapy, mutations occur not only in the polymerase gene but also in the S gene, resulting in the emergence of surface protein mutants. Two types of surface protein mutants are recognized. The first type arises as a result of amino acid substitutions caused by primary and compensatory resistance mutations in the polymerase gene, which concomitantly generate S gene mutations owing to overlapping S and polymerase genes. The second type occurs because of prolonged viral suppression leading to seroclearance of HBV surface antigen, where vaccine-escape-like mutants might be selected. The second type of mutants does not possess primary resistance mutations in the polymerase gene. Some drug-related S gene mutations are nonsense mutations, leading to truncation of the surface proteins. Among them, the rtA181T/sW172* mutant has a dominant negative secretion effect as well as an increased oncogenic potential. The clinical consequences of infection by these S gene mutants demand further clarification. Judicious selection of the antiviral agents and vigilant monitoring of viral mutants during the course of therapy are advised.

Publication types

  • Review

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Drug Resistance, Viral
  • Hepatitis B Surface Antigens / drug effects
  • Hepatitis B Surface Antigens / genetics*
  • Hepatitis B virus / drug effects
  • Hepatitis B virus / genetics
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis B, Chronic / virology
  • Humans
  • Mice
  • Mutation*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Nucleosides / therapeutic use*
  • Nucleotides / chemistry
  • Nucleotides / pharmacology
  • Nucleotides / therapeutic use*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Reverse Transcriptase Inhibitors / therapeutic use


  • Antiviral Agents
  • Hepatitis B Surface Antigens
  • Nucleosides
  • Nucleotides
  • Reverse Transcriptase Inhibitors