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In vitro resistance studies were performed to characterize NS5A changes that might confer reduced velpatasvir susceptibility in vivo. Resistance selection studies using HCV replicon cells for subtypes 1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a identified NS5A resistance\u2010associated substitutions (RASs) at nine positions, most often 28M\/S\/T, 31F\/I\/M\/P\/V and 93D\/H\/N\/S. In subtype 1a, RASs were selected at positions 31 and\/or 93, while in subtype 1b, replicons with two or more RASs at positions 31, 54 or 93 were selected. Y93H was selected in subtypes 1a, 1b, 2a, 3a and 4a. In subtype 5a or 6a, L31P or P32L\/Q was selected, respectively. Velpatasvir susceptibility of 358 replicons from genotypes 1 to 6 containing one or more NS5A\u00a0RASs was also evaluated. The majority (63%) of subtypes 1a and 1b single RAS\u2010containing replicons retained susceptibility to velpatasvir (&lt;2.5\u2010fold change in EC<jats:sub>50<\/jats:sub>). High levels of resistance to velpatasvir were observed for six single mutants in subtype 1a, including M28G, A92K, Y93H\/N\/R\/W and for one mutant, A92K, in subtype 1b. Most single mutants in subtypes 2a, 2b, 3a, 4a and 5a displayed low levels of reduced velpatasvir susceptibility. High\u2010level resistance was observed for C92T and Y93H\/N in subtype 2b, Y93H\/S in 3a, and L31V and P32A\/L\/Q\/R in 6a, and several double mutants in these subtypes. Overall, velpatasvir maintained activity against most common RASs that are known to confer resistance to first\u2010generation NS5A inhibitors.<\/jats:p>","DOI":"10.1111\/jvh.13116","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T15:50:48Z","timestamp":1555948248000},"page":"991-1001","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["In vitro resistance profile of hepatitis C virus NS5A inhibitor velpatasvir in genotypes 1 to 6"],"prefix":"10.1111","volume":"26","author":[{"given":"Hadas","family":"Dvory\u2010Sobol","sequence":"first","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Han","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Lu","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Yu","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudolf K.","family":"Beran","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guofeng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ross","family":"Martin","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evguenia","family":"Svarovskaia","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences Foster City California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26141"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(16)30181-9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy401"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v13.i36.4808"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26744"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840190538"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v7.i6.831"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27950"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756283X15587481"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2147\/HMER.S55864"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00328-07"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508175200"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.7.3480-3488.2004"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003359"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.6b00143"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.21.13473-13482.2005"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902693106"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00616-10"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01319-10"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.07.019"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03293-14"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.12.015"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24594"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02524-15"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1512610"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1512612"},{"key":"e_1_2_8_28_1","first-page":"991","article-title":"Protocol For the ASTRAL\u20101 trial (NCT02201940). 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