Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy.
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.
Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan. chautingy@gmail.com
Chau-Ting
CT
Yeh
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D006514:Hepatitis B Surface Antigens / Q000187:drug effects / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D009705:Nucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors