@article{mbs:/content/journal/jgv/10.1099/jgv.0.001091, author = "Teraoka, Yuji and Uchida, Takuro and Imamura, Michio and Hiraga, Nobuhiko and Osawa, Mitsutaka and Kan, Hiromi and Saito, Yuhei and Tsuge, Masataka and Abe-Chayama, Hiromi and Hayes, C. Nelson and Makokha, Grace Naswa and Aikata, Hiroshi and Miki, Daiki and Ochi, Hidenori and Ishida, Yuji and Tateno, Chise and Chayama, Kazuaki", title = "Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure", journal= "Journal of General Virology", year = "2018", volume = "99", number = "8", pages = "1058-1065", doi = "https://doi.org/10.1099/jgv.0.001091", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.001091", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", keywords = "HCV", keywords = "asunaprevir", keywords = "RAV", keywords = "beclabuvir", keywords = "treatment failures", keywords = "daclatasvir", keywords = "human hepatocyte chimeric mouse", abstract = "Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.", }