title: Mechanisms of hepatitis B virus resistance development.
abstract: Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional 'right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA. The selection of resistance occurs at different rates for each NA, and is affected by the high mutational rate of HBV and the ability of the drug to suppress viral replication. Some mutations or combinations of mutations may be associated with multidrug resistance, limiting treatment options. In contrast to most other viruses, resistance in HBV is confounded by the overlapping surface gene, the major NA-resistant mutations also altering the surface proteins in most cases, potentially altering virus secretion and neutralization, which may pose a public health threat in the future.
authors.affiliation: Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory (VIDRL), North Melbourne, Vic., Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Warner
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D000068679:Emtricitabine; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D063065:Organophosphonates / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000077712:Telbivudine; D000068698:Tenofovir; D013936:Thymidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D000077712:Telbivudine; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D000068679:Emtricitabine; D000225:Adenine; D013936:Thymidine