title: Entecavir resistance is rare in nucleoside naïve patients with hepatitis B.
abstract: Comprehensive monitoring of genotypic and phenotypic antiviral resistance was performed on 673 entecavir (ETV)-treated nucleoside naïve hepatitis B virus (HBV) patients. ETV reduced HBV DNA levels to undetectable by PCR (<300 copies/mL, <57 IU/mL) in 91% of hepatitis B e antigen (HBeAg)-positive and -negative patients by Week 96. Thirteen percent (n = 88) of the comparator lamivudine (LVD)-treated patients experienced a virologic rebound (> or =1 log increase from nadir by PCR) in the first year, with 74% of these having LVD resistance (LVDr) substitutions evident. In contrast, only 3% (n = 22) of ETV-treated patients exhibited virologic rebound by Week 96. Three ETV rebounds were attributable to LVDr virus present at baseline, with one having a S202G ETV resistance (ETVr) substitution emerge at Week 48. None of the other rebounding patients had emerging genotypic resistance or loss of ETV susceptibility. Genotyping all additional ETV patients with PCR-detectable HBV DNA at Weeks 48, 96, or end of dosing identified seven additional patients with LVDr substitutions, including one with simultaneous emergence of LVDr/ETVr. Generally, ETV patients with LVDr were detectable at baseline (8/10) and most subsequently achieved undetectable HBV DNA levels on ETV therapy (7/10). No other emerging substitutions identified decreased ETV susceptibility. In conclusion, ETVr emergence in ETV-treated nucleoside naïve patients over a 2-year period is rare, occurring in two patients with LVDr variants. These findings suggest that the rapid, sustained suppression of HBV replication, combined with a requirement for multiple substitutions, creates a high genetic barrier to ETVr in nucleoside naïve patients.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492, USA. richard.colonno@bms.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Ronald
authors.initials: R
authors.lastname: Rose
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Baldick
authors.forename: Steven
authors.initials: S
authors.lastname: Levine
authors.forename: Kevin
authors.initials: K
authors.lastname: Pokornowski
authors.forename: Cheng F
authors.initials: CF
authors.lastname: Yu
authors.forename: Ann
authors.initials: A
authors.lastname: Walsh
authors.forename: Jie
authors.initials: J
authors.lastname: Fang
authors.forename: Mayla
authors.initials: M
authors.lastname: Hsu
authors.forename: Charles
authors.initials: C
authors.lastname: Mazzucco
authors.forename: Betsy
authors.initials: B
authors.lastname: Eggers
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhang
authors.forename: Mary
authors.initials: M
authors.lastname: Plym
authors.forename: Kenneth
authors.initials: K
authors.lastname: Klesczewski
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tenney
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis; D024882:Drug Resistance, Viral; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006513:Hepatitis B e Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D009705:Nucleosides; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D009705:Nucleosides; D019259:Lamivudine; C413685:entecavir; D006147:Guanine