title: Increased occurrence of mutant rtI233V of HBV in patients receiving adefovir therapy.
abstract: BACKGROUND
  The study aimed to clarify whether the rtI233V substitution affects adefovir (ADV) resistance.
  
  
  METHODS
  A total of 18,419 patients from Beijing 302 Hospital were investigated. HBV complete reverse transcriptase region of the polymerase was screened by direct sequencing and verified by clonal sequencing if necessary. Replication-competent wild-type and mutant HBV genomic amplicons were transfected into HepG2 cells for phenotypic analysis of viral replication capacity and drug susceptibility.
  
  
  RESULTS
  The rtI233V substitution was detected in 38/5,344 (0.71%) ADV-treated patients and in 8/13,075 patients without receiving ADV (P<0.001). Eight patients with rtI233V ± rtA181V/rtN236T had virological breakthrough in the clinical course of ADV treatment. Phenotypic analysis showed that rtI233V mutants from patient 1 and patient 2 exhibited 1.57-fold and 1.51-fold decreased susceptibility to ADV, respectively, compared to wild-type virus; by contrast, rtN236T and rtI233V+N236T mutants from patient 1 had 6.82-fold and 5.28-fold decreased susceptibility to ADV. rtI233V, rtN236T and rtI233V+N236T mutants had 97.5%, 30.2% and 69.7% of replication capacity compared to wild-type virus in the absence of antivirals and all remained susceptible to lamivudine, entecavir and tenofovir. Viral replication capacity correspondingly decreased after eliminating rtI233V from rtI233V+N236T mutant and was restored after introducing rtI233V into rtN236T mutant. In clinical practice, switching to entecavir rescue therapy suppressed HBV DNA to an undetectable level for both patients.
  
  
  CONCLUSIONS
  rtI233V usually emerged in ADV-treated patients with little impact on ADV susceptibility but it effectively restored replication capacity of the rtN236T mutant, suggesting that rtI233V may partly serve as a compensatory mutation associated with ADV resistance.
authors.affiliation: Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Shaojie
authors.initials: S
authors.lastname: Xin
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Ye
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Chen
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Xu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Haiyan
authors.initials: H
authors.lastname: Ye
authors.forename: Shuquan
authors.initials: S
authors.lastname: Cheng
authors.forename: Dongping
authors.initials: D
authors.lastname: Xu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D003062:Codon; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006509:Hepatitis B / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003062:Codon; D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; C053001:adefovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine