The Journal of infection · 2015
Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones.
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Murakami Eisuke, Tsuge Masataka, Hiraga Nobuhiko, Kan Hiromi, Uchida Takuro, Masaki Keiichi, Nakahara Takashi, Ono Atsushi, Miki Daiki, Kawaoka Tomokazu, Abe Hiromi, Imamura Michio, Aikata Hiroshi, Ochi Hidenori, Hayes C Nelson, Akita Tomoyuki, Tanaka Junko, Chayama Kazuaki
Аннотация
BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones.
METHODS: HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo.
RESULTS: TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023).
CONCLUSIONS: The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.
METHODS: HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo.
RESULTS: TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023).
CONCLUSIONS: The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.