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A218S and C316N were detected in all patients with viral relapse; the percentages of these substitutions in SOF-na\u00efve patients were 64.2% and 55.0%, respectively. Genotype 1b HCV strains with NS5B-C316N mutation were located in the leaves different from those in which HCV strains without such substitutions were present on the phylogenetic tree. Structural modeling revealed that amino acid 218 was located on the surface of the NTP tunnel. Free energy analysis based on molecular dynamics simulations demonstrated that the free energy required to pass through the tunnel was larger for triphosphate SOF than for UTP in NS5B polymerase carrying A218S, but not in wild-type. However, no susceptibility change was observed for these substitutions to SOF in replicon assay. Furthermore, the SVR rate was 100% in patients enrolled the Phase-3 trial. In conclusion, NS5B A218S and C316N were detected in all patients who relapsed following LDV\/SOF in real-world practice. These substitutions did not impact the overall SVR rate after LDV\/SOF, however, further studies are needed to elucidate the impact of these substitutions.<\/jats:p>","DOI":"10.1038\/s41598-018-27291-7","type":"journal-article","created":{"date-parts":[[2018,6,5]],"date-time":"2018-06-05T09:56:56Z","timestamp":1528192616000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Significance of NS5B Substitutions in Genotype 1b Hepatitis C Virus Evaluated by Bioinformatics Analysis"],"prefix":"10.1038","volume":"8","author":[{"given":"Yoshihito","family":"Uchida","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shugo","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Ichi","family":"Kouyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayoko","family":"Naiki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Motoya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayoko","family":"Sugawara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mie","family":"Inao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukinori","family":"Imai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuaki","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoaki","family":"Tomiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Hedskog","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Brainard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Mochida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,6,11]]},"reference":[{"key":"27291_CR1","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1002\/hep.27113","volume":"59","author":"H Kumada","year":"2014","unstructured":"Kumada, H. et al. 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Ltd., Bristol Myers Squibb Co., Gilead Sciences Inc., MSD K.K., Sumitomo Dainippon Pharma Co., Toray Medical Co. Ltd., has received research grants from A2 Healthcare Co., AbbVie GK, Bristol Myers Squibb Co., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., MSD K.K., Sumitomo Dainippon Pharma Co., Toray Medical Co. Ltd. Other authors have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8818"}}