{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:02:48Z","timestamp":1792587768568,"version":"4.5.0"},"reference-count":51,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antiviral Therapy"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Data on persistence of NS5A resistance-associated substitutions (RASs) may have implications for resistance testing approaches and selection of initial and retreatment strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Long-term persistence of NS5A RASs in HCV genotype (GT) 1 infected subjects ( n=76) who did not achieve sustained virological response after receiving ledipasvir (LDV) without sofosbuvir (SOF) and were subsequently enrolled in an ongoing 3-year follow-up registry study was investigated by population or deep sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of the 76 subjects enrolled, 67 and 9 subjects had GT1a and GT1b infection, respectively. At pretreatment, NS5A RASs were detected in 14% of subjects (11\/76) by population sequencing, with three subjects having &gt;1 RAS. All RASs that were detected at pretreatment persisted and were observed at the 96 week visit in the follow-up study (FU96). For the remaining subjects with no detectable RASs at pretreatment, RASs were detected in 98% (63\/64) of subjects at virological failure in the parent study and persisted at detectable levels through FU96 in 86% of subjects by deep sequencing (1% cutoff). However, a decline in the quasispecies frequency of most RASs and the number of RASs per subject was observed over time. Phenotypic analysis demonstrated that the majority of NS5A RASs confer similar levels of resistance to LDV and daclatasvir.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The majority of NS5A RASs can persist at detectable levels for &gt;96 weeks post-treatment in subjects who failed treatment with regimens containing an NS5A inhibitor without SOF, suggesting relatively high fitness of NS5A RASs even in the absence of drug pressure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3851\/imp3181","type":"journal-article","created":{"date-parts":[[2017,6,26]],"date-time":"2017-06-26T12:22:12Z","timestamp":1498479732000},"page":"229-238","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":66,"title":["Long-Term Persistence of HCV NS5A Resistance-Associated Substitutions after Treatment with the HCV NS5A Inhibitor, Ledipasvir, without Sofosbuvir"],"prefix":"10.1177","volume":"23","author":[{"given":"David","family":"Wyles","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Denver Health and Hospital Authority, Denver, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Mangia","sequence":"additional","affiliation":[{"name":"Liver Unit, Department of Medical Sciences IRCCS \u2018Casa Sollievo della Sofferenza\u2019, San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Cheng","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Shafran","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schwabe","sequence":"additional","affiliation":[{"name":"Auckland Clinical Studies Ltd, Auckland, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Hedskog","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"McNally","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M","family":"Brainard","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P","family":"Doehle","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evguenia","family":"Svarovskaia","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Miller","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mo","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadas","family":"Dvory-Sobol","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2017,4,1]]},"reference":[{"key":"bibr1-IMP3181","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26141"},{"key":"bibr2-IMP3181","first-page":"161","volume":"2","author":"The Polaris Observatory HCV Collaborators.","year":"2017","journal-title":"Lancet"},{"key":"bibr3-IMP3181","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v13.i17.2406"},{"key":"bibr4-IMP3181","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1213651"},{"key":"bibr5-IMP3181","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.2667"},{"key":"bibr6-IMP3181","volume-title":"Hepatitis C Viruses: Genomes and Molecular Biology","author":"He Y.","year":"2006"},{"key":"bibr7-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.029"},{"key":"bibr8-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00556-10"},{"key":"bibr9-IMP3181","doi-asserted-by":"publisher","DOI":"10.1021\/jm401398x"},{"key":"bibr10-IMP3181","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/S0140-6736(14)61795-5","volume":"385","author":"Lawitz E.","year":"2015","journal-title":"Lancet"},{"key":"bibr11-IMP3181","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1316366"},{"key":"bibr12-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62121-2"},{"key":"bibr13-IMP3181","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306218"},{"key":"bibr14-IMP3181","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306218"},{"key":"bibr15-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61059-X"},{"key":"bibr16-IMP3181","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27113"},{"key":"bibr17-IMP3181","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27053"},{"key":"bibr18-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02193-12"},{"key":"bibr19-IMP3181","doi-asserted-by":"crossref","unstructured":"Cheng G., Peng B., Corsa A. Antiviral activity and resistance profile of the novel HCV NS5A inhibitor GS-5885.\n                      EASL 47th Annual Meeting\n                      . 18\u201322 April 2012, Barcelona, Spain. Abstract 1172.","DOI":"10.1016\/S0168-8278(12)61184-2"},{"key":"bibr20-IMP3181","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2729"},{"key":"bibr21-IMP3181","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0122844"},{"key":"bibr22-IMP3181","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.24255"},{"key":"bibr23-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02494-12"},{"key":"bibr24-IMP3181","doi-asserted-by":"crossref","unstructured":"Thompson A., Han S., Shiffman M.L. GS-5885 + GS-9451 + peginterferon and ribavirin (PR) for six or twelve weeks achieves high SVR12 rates in treatment-naive genotype 1 IL28B CC patients.\n                      48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013)\n                      . 24\u201328 April 2013, Amsterdam, the Netherlands. Abstract 64.","DOI":"10.1016\/S0168-8278(13)60066-5"},{"key":"bibr25-IMP3181","doi-asserted-by":"crossref","unstructured":"Everson G.T., Di Bisceglie A.M., Vierling J.M. Combination of the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis c infection.\n                      EASL\n                      2013. 24\u201328 April 2013, Amsterdam, the Netherlands. Abstract 13.","DOI":"10.1016\/S0168-8278(13)60015-X"},{"issue":"2","key":"bibr26-IMP3181","first-page":"S355","volume":"58","author":"Marcellin P.","year":"2013","journal-title":"J Hepatol"},{"key":"bibr27-IMP3181","unstructured":"Clinical Trials.gov. GS-5885, GS-9451, tegobuvir and ribavirin in treatment-experienced subjects with chronic genotype 1a or 1b hepatitis C virus (HCV) infection. (Accessed 16 September 2011.) Available from https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01435226."},{"key":"bibr29-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00307-11"},{"key":"bibr30-IMP3181","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5424.110"},{"key":"bibr31-IMP3181","unstructured":"Sarrazin C., Dvory-Sobol H., Svaroskaia E. Baseline and post-baseline resistance analyses of Phase 2\/3 studies of ledipasvir\/sofosbuvir \u00b1 RBV.\n                      65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD)\n                      . 7\u201311 November 2014, Boston MA, USA. Abstract 1926."},{"key":"bibr32-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02294-12"},{"key":"bibr33-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2012.04.024"},{"key":"bibr34-IMP3181","doi-asserted-by":"crossref","unstructured":"Krishnan P., Tripathi R., Schnell G. Long-term follow-up of treatment-emergent resistance-associated variants in NS3, NS5A and NS5B with paritaprevir\/r- ombitasvir- and dasabuvir-based regimens.\n                      EASL 50th Annual Meeting of the European Association for the Study of the Liver\n                      . 22\u201326 April 2015, Vienna, Austria. Abstract 0057.","DOI":"10.1016\/S0168-8278(15)30071-4"},{"key":"bibr35-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(99)80374-2"},{"key":"bibr36-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01319-10"},{"key":"bibr37-IMP3181","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.376822"},{"key":"bibr38-IMP3181","doi-asserted-by":"publisher","DOI":"10.1038\/srep04765"},{"key":"bibr39-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02995-14"},{"key":"bibr40-IMP3181","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04958-14"},{"key":"bibr41-IMP3181","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000035"},{"key":"bibr42-IMP3181","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.04.021"},{"key":"bibr43-IMP3181","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1997.8493"},{"key":"bibr44-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2011.08.015"},{"key":"bibr45-IMP3181","unstructured":"Dvory-Sobol H., Gontcharova V., Miller M.D., Svarovskaia E.S., Mo H. Persistence of resistance-associated mutations after 3 days of monotherapy with NS3 protease inhibitor GS-9451 in genotype 1 hepatitis C virus patients.\n                      63rd Annual Meeting of the American Association for the Study of Liver Diseases\n                      . 9\u201313 November 2012, Boston, MA, USA. Abstract 804."},{"key":"bibr46-IMP3181","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit226"},{"key":"bibr47-IMP3181","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041191"},{"key":"bibr48-IMP3181","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.12405"},{"key":"bibr49-IMP3181","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.06.002"},{"key":"bibr50-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.11.032"},{"key":"bibr51-IMP3181","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61059-X"},{"key":"bibr52-IMP3181","unstructured":"Bourli\u00e8re M., Gordon S.C., Ramji A. Sofosbuvir\/ velpatasvir\/voxilaprevir for 12 weeks as a salvage regimen in NS5A inhibitor-experienced patients with genotype 1\u20136 infection: the Phase 3 POLARIS-1 Study.\n                      The Liver Meeting, AASLD\n                      . 11\u201315 November 2016, Boston, MA, USA. Abstract 194."}],"container-title":["Antiviral Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3181","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3181","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T12:52:26Z","timestamp":1777380746000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3851\/IMP3181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,1]]},"references-count":51,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,4]]}},"alternative-id":["10.3851\/IMP3181"],"URL":"https:\/\/doi.org\/10.3851\/imp3181","relation":{},"ISSN":["1359-6535","2040-2058"],"issn-type":[{"value":"1359-6535","type":"print"},{"value":"2040-2058","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,1]]}}}