title: Similar evolution of hepatitis B virus quasispecies in patients with incomplete adefovir response receiving tenofovir/emtricitabine combination or tenofovir monotherapy.
abstract: OBJECTIVE
  Adefovir (ADV) resistance mutations induce low-level cross-resistance to tenofovir in vitro. Our aim was to compare viral kinetics, nucleos(t)ide analog resistance mutations, and quasispecies (QS) evolution during therapy with tenofovir disoproxil fumarate (TDF) or emtricitabine + TDF (FTC/TDF) in selected patients with incomplete ADV responses.
  
  
  METHODS
  Patients with chronic hepatitis B and incomplete response to ADV were randomized in a double-blind trial of TDF vs. FTC/TDF. Extensive analysis of QS evolution was performed in 17 patients through 48 weeks of treatment.
  
  
  RESULTS
  At week 24, 48% of patients (9/17) achieved HBV DNA undetectability (<69 IU/ml) with no difference between treatment groups. ADV and/or LAM resistance mutations were detected in all 17 patients at baseline and in 5/6 analyzable patients at week 48. A total of 1224 reverse transcriptase clones were analyzed. Clonal analysis revealed no significant difference at baseline in QS complexity or diversity between treatment groups. There was a trend in both treatment groups for an increase in QS complexity at week 12, followed by a decrease in complexity and diversity by week 48. Analysis of individual patients showed no consistent selection/accumulation of specific viral resistance patterns during treatment, but at week 48, mutations at rtA181 persisted in 4 patients.
  
  
  CONCLUSIONS
  TDF or FTC/TDF demonstrated strong viral suppression in patients with an incomplete response to ADV and no significant selective pressure on pre-existing ADV or LAM resistant strains. TDF monotherapy and FTC/TDF combination therapy had a comparable impact on QS evolution.
authors.affiliation: Inserm, U1052, UMR CNRS 5268, Centre de Recherche en Cancérologie de Lyon, F-69003 Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lavocat
authors.forename: Paul
authors.initials: P
authors.lastname: Dény
authors.forename: Christian
authors.initials: C
authors.lastname: Pichoud
authors.forename: Nasser
authors.initials: N
authors.lastname: Al Hawajri
authors.forename: Kathryn
authors.initials: K
authors.lastname: Kitrinos
authors.forename: Katyna
authors.initials: K
authors.lastname: Borroto-Esoda
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D019143:Evolution, Molecular; D005260:Female; D005838:Genotype; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007700:Kinetics; D019259:Lamivudine / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000008:administration & dosage*; D010802:Phylogeny; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D000068698:Tenofovir; D013997:Time Factors; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D003841:Deoxycytidine; D019259:Lamivudine; C053001:adefovir; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D000068679:Emtricitabine; D000225:Adenine
keywords: ADV; Antivirals; Drug resistance; FTC; HBV; Hepatitis B virus; LAM; NA; PCR; QS; Quasispecies; TDF; VL; Viral genome heterogeneity; WT; adefovir; emtricitabine; hepatitis B virus; lamivudine; nucleos(t)ides analogues; quasispecies; reverse transcriptase chain reaction; tenofovir disoproxil fumarate; viral load; wild type