title: Profile of HBV antiviral resistance mutations with distinct evolutionary pathways against nucleoside/nucleotide analogue treatment among Chinese chronic hepatitis B patients.
abstract: BACKGROUND
  Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs).
  
  
  METHODS
  Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250.
  
  
  RESULTS
  Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively (P<0.01).
  
  
  CONCLUSIONS
  One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.
authors.affiliation: Department of Microbiology, Peking University Health Science Center, Beijing, China.
authors.forename: Jing-Xian
authors.initials: JX
authors.lastname: Yang
authors.forename: Bao-Ming
authors.initials: BM
authors.lastname: Liu
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Li
authors.forename: Chun-Hui
authors.initials: CH
authors.lastname: Yan
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Xie-Wen
authors.initials: XW
authors.lastname: Sun
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Jiao
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Dong
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Hou
authors.forename: Xiernayi
authors.initials: X
authors.lastname: Abuduheilili
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Zhuang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use; D002681:China; D003430:Cross-Sectional Studies; D004279:DNA, Viral / Q000737:chemistry / Q000302:isolation & purification; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D058889:Molecular Typing; D020125:Mutation, Missense; D009705:Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D009705:Nucleosides; D063065:Organophosphonates; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D000077712:Telbivudine; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000225:Adenine; C106812:adefovir dipivoxil; D013936:Thymidine