title: Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.
abstract: Several next-generation nucleoside and nucleotide analogues are currently in clinical development for the treatment of chronic hepatitis B. However, the efficacy of newer agents against lamivudine-resistant hepatitis B virus (HBV) has not been fully explored. To investigate this in vitro, we generated novel stable cell lines expressing HBV encoding the four major patterns of lamivudine resistance mutations (rtL180M+rtM204V, rtV173L+rtL180M+rtM204V, rtM204I and rtL180M+ rtM204I). Using these cell lines, we assessed the susceptibility of all four strains of lamivudine-resistant HBV to eleven nucleoside analogues in various stages of clinical development. Our studies indicate that lamivudine-resistant HBV remain sensitive to acyclic phosphonate nucleotides (adefovir, tenofovir, and alamifovir), have reduced susceptibility to entecavir, and have high-level cross-resistance to all L-nucleosides tested including emtricitabine, telbivudine, clevudine, and torcitabine.
authors.affiliation: Department of Clinical Virology, Gilead Sciences, 333 Lakeside Dr, Foster City, CA, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Alex
authors.initials: A
authors.lastname: Sabogal
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.forename: Shelly
authors.initials: S
authors.lastname: Xiong
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
mesh_terms: D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014162:Transfection
chemical_list: D004279:DNA, Viral; D009705:Nucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine