Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. Issue 1 (January 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of infection. Volume 72:Issue 1(2016)
• Page Start: 91
• Page End: 102
• Publication Date: 2016-01
• Subjects: Hepatitis B virus -- Tenofovir disoproxil fumarate -- Susceptibility -- HBV genotype -- Drug resistance; HBV hepatitis B virus -- NAs nucleot(s)ide analogues -- ETV entecavir -- LMV lamivudine -- ADV adefovir dipivoxil -- TDF tenofovir disoproxil fumarate; Infection -- Periodicals; Bacterial Infections -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.905
• DOI: 10.1016/j.jinf.2015.09.038
• Languages: English
• ISSNs: 0163-4453

Abstract

Summary: 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. Highlights: We compared tenofovir disoproxil fumarate (TDF) susceptibilities between HBV genotype A and C. N236T substitution in HBV RT region is significantly associated with TDF susceptibility. Genotypic differences in TDF susceptibility were observed between genotypes A and C in vitro and in vivo .