{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T06:45:46Z","timestamp":1789368346043,"version":"build-2803163510"},"reference-count":42,"publisher":"SAGE Publications","issue":"7","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"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":[[2016,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Use of direct-acting antiviral drugs (DAAs) that target HCV may be hampered by the rapid selection of viral strains that harbour drug resistance-associated variants (RAVs). These RAVs are often associated with a fitness cost and tend to occur on low-frequency strains within treatment-naive subjects. To address the clinical relevance of low frequency RAVs in the setting of DAAs, this study utilized a Primer ID ultra-deep sequencing approach to mitigate PCR errors and bias to accurately quantify viral sequences in subjects that failed DAA treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Subjects were enrolled in the follow-up study P05063, and had previous treatment with boceprevir and all had detectable RAVs at virological failure (VF) based on Sanger-based population sequencing. Twelve subjects had three time points available: baseline, VF and follow-up (median 830.5 days). Viral RNA was amplified using unique primer identifiers (Primer IDs) and sequenced using 454 ultra-deep sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The sequencing strategy used in this study improved the detection of clinically relevant low frequency strains bearing RAVs compared to population sequencing and showed that these strains can persist for up to 2 years post-treatment failure. Strains carrying multiple RAVs were common in breakthrough viruses. Putative compensatory mutations were identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The Primer ID ultra-deep sequencing approach identifies RAVs that can reduce drug sensitivity at levels below the detection threshold for population sequencing. The approach also removes PCR errors and biases, suggesting this sequencing strategy should become the standard approach by which to perform temporal quasispecies studies and resistance screening. ClinicalTrials.gov NCT00689390.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3851\/imp3056","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T10:42:26Z","timestamp":1464086546000},"page":"567-577","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":8,"title":["Primer ID Ultra-Deep Sequencing Reveals Dynamics of drug Resistance-Associated Variants in Breakthrough Hepatitis C Viruses: Relevance to Treatment Outcome and Resistance Screening"],"prefix":"10.1177","volume":"21","author":[{"given":"Richard","family":"Barnard","sequence":"first","affiliation":[{"name":"Antiviral Research, Merck and Co., West Point, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abha","family":"Chopra","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"James","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Blinco","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W","family":"Watson","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra B","family":"Jabara","sequence":"additional","affiliation":[{"name":"Department of Biology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"name":"Present address: 10X Genomics, Inc., Pleasanton, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Hazuda","sequence":"additional","affiliation":[{"name":"Antiviral Research, Merck and Co., West Point, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley M","family":"Lemon","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mallal","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"},{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA"},{"name":"Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana","family":"Gaudieri","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia"},{"name":"Department of Medicine, Division of Infectious Disease, Vanderbilt University, Nashville, TN, USA"},{"name":"School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,10,1]]},"reference":[{"key":"bibr1-IMP3056","doi-asserted-by":"publisher","DOI":"10.2174\/1871526514666141014145612"},{"key":"bibr2-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1100829"},{"key":"bibr3-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306218"},{"key":"bibr4-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402355"},{"key":"bibr5-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402454"},{"key":"bibr6-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402869"},{"key":"bibr7-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1010494"},{"key":"bibr8-IMP3056","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1012912"},{"key":"bibr9-IMP3056","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.206"},{"key":"bibr10-IMP3056","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i4.1421"},{"key":"bibr11-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.09.011"},{"key":"bibr12-IMP3056","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5386.103"},{"key":"bibr13-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2012.08.004"},{"key":"bibr14-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2013.12.003"},{"key":"bibr15-IMP3056","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22773"},{"key":"bibr16-IMP3056","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3000544"},{"key":"bibr17-IMP3056","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.10.056"},{"key":"bibr18-IMP3056","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22549"},{"key":"bibr19-IMP3056","doi-asserted-by":"publisher","DOI":"10.1086\/591141"},{"key":"bibr20-IMP3056","unstructured":"Lenz O., Fevery B., Verbinnen T. Resistance analyses of HCV isolates from patients treated with simeprevir in Phase 2b\/3 studies.\n                      64rd Annual Meeting of the American Association for the Study of Liver Diseases\n                      . 1\u20135 November 2013, Washington, DC, USA. Abstract 1101."},{"key":"bibr21-IMP3056","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2821"},{"key":"bibr22-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2013.06.029"},{"key":"bibr23-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2014.10.010"},{"key":"bibr24-IMP3056","unstructured":"Sherman K.E., Sulkowski M.S., Zoulim F. Follow-up of SVR durability and viral resistance in patients with chronic hepatitis c treated with telaprevir-based regimens: interim analysis of the EXTEND study.\n                      62th Annual Meeting of the American Association for the Study of Liver Diseases\n                      . 6\u20139 November 2011, San Francisco, CA, USA."},{"key":"bibr25-IMP3056","doi-asserted-by":"publisher","DOI":"10.1038\/nm992"},{"key":"bibr26-IMP3056","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.05.010"},{"key":"bibr27-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2009.05.008"},{"key":"bibr28-IMP3056","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23192"},{"key":"bibr29-IMP3056","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2005.12.003"},{"key":"bibr30-IMP3056","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1110064108"},{"key":"bibr31-IMP3056","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03466-14"},{"key":"bibr32-IMP3056","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mst197"},{"key":"bibr33-IMP3056","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bti079"},{"key":"bibr34-IMP3056","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0130420"},{"key":"bibr35-IMP3056","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i12.3480"},{"key":"bibr36-IMP3056","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23101"},{"key":"bibr37-IMP3056","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134395"},{"key":"bibr38-IMP3056","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn085"},{"key":"bibr39-IMP3056","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005683"},{"key":"bibr40-IMP3056","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801774105"},{"key":"bibr41-IMP3056","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00912-06"},{"key":"bibr42-IMP3056","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1177\/135965350501000409","volume":"10","author":"John M.","year":"2005","journal-title":"Antivir Ther"}],"container-title":["Antiviral Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3056","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3851\/IMP3056","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T12:52:03Z","timestamp":1777380723000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.3851\/IMP3056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,1]]},"references-count":42,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["10.3851\/IMP3056"],"URL":"https:\/\/doi.org\/10.3851\/imp3056","relation":{},"ISSN":["1359-6535","2040-2058"],"issn-type":[{"value":"1359-6535","type":"print"},{"value":"2040-2058","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,1]]}}}