Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.
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.
Yang
Huiling
H
Department of Clinical Virology, Gilead Sciences, 333 Lakeside Dr, Foster City, CA, USA.
Qi
Xiaoping
X
Sabogal
Alex
A
Miller
Michael
M
Xiong
Shelly
S
Delaney
William E
WE
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
D004279:DNA, Viral; D009705:Nucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine