title: Slow response to entecavir treatment in treatment-naive HBV patients is conditioned by immune response rather than by the presence or selection of refractory variants.
abstract: BACKGROUND
  Entecavir is the drug of choice as first-line treatment for treatment-naive HBV patients. As a result of the high genetic barrier to resistance, treatment failure remains rare, but occurs within 3 years of initiation, suggesting that viral genetic characteristics may provide a fast lane to resistance. One of the main concerns is the long time to viral suppression observed in some (even treatment-naive) patients. The reasons for this phenomenon were investigated in a group of chronic hepatitis B treatment-naive patients.
  
  
  METHODS
  Out of 23 treatment-naive patients starting entecavir, the 5 with the best and those with the worst viral load decay curves were selected for the study. Quasispecies analysis was performed for the reverse transcriptase/hepatitis B surface antigen (HBsAg) open reading frame (ORF) by ultra-deep pyrosequencing. For each patient, the analysis was performed at baseline (T0) and when viraemia reached between 15,000 and 200 IU/ml (T1).
  
  
  RESULTS
  The few resistance mutations present at T0 were not selected by treatment; no other resistance mutations or suggestive mutational patterns were selected at T1. Selective pressure analysis indicated that both at T0 and T1 the HBsAg ORF was subjected to a significantly higher pressure in rapid responders, especially in a region rich in cytotoxic T-lymphocyte (CTL) epitopes.
  
  
  CONCLUSIONS
  The results did not provide evidence that a slower response to entecavir is due to the emergence of less sensitive variants. Rather, the lower selective pressure and variability in humoral and CTL epitopes in slow responders suggests that their immune response might be at odds in rapidly clearing infected cells from the liver.
authors.affiliation: National Institute for Infectious Diseases 'Lazzaro Spallanzani' IRCCS, Laboratory of Virology, Rome, Italy.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Solmone
authors.forename: Emanuela
authors.initials: E
authors.lastname: Giombini
authors.forename: Donatella
authors.initials: D
authors.lastname: Vincenti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Rozera
authors.forename: Angela
authors.initials: A
authors.lastname: Testa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Moscetti
authors.forename: Manuela
authors.initials: M
authors.lastname: Catalano
authors.forename: Isabella
authors.initials: I
authors.lastname: Abbate
authors.forename: Maria R
authors.initials: MR
authors.lastname: Capobianchi
authors.forename: Stefano
authors.initials: S
authors.lastname: Menzo
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D005838:Genotype; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008875:Middle Aged; D010802:Phylogeny; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; C413685:entecavir; D006147:Guanine