{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T02:21:08Z","timestamp":1789438868528,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T00:00:00Z","timestamp":1711843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gilead Sciences"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of \u226494% or &gt;94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of \u22641.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.<\/jats:p>","DOI":"10.3390\/v16040546","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T13:44:52Z","timestamp":1711892692000},"page":"546","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["No Remdesivir Resistance Observed in the Phase 3 Severe and Moderate COVID-19 SIMPLE Trials"],"prefix":"10.3390","volume":"16","author":[{"given":"Charlotte","family":"Hedskog","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3875-5367","authenticated-orcid":false,"given":"Christoph D.","family":"Spinner","sequence":"additional","affiliation":[{"name":"TUM School of Medicine and Health, Department of Clinical Medicine\u2014Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-1911","authenticated-orcid":false,"given":"Ulrike","family":"Protzer","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany"},{"name":"Institute of Virology, Technical University of Munich School of Medicine, 81675 Munich, Germany"},{"name":"Institute of Virology, Helmholtz Munich, 85764 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany"},{"name":"Institute of Virology, Technical University of Munich School of Medicine, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-1602","authenticated-orcid":false,"given":"Chunkyu","family":"Ko","sequence":"additional","affiliation":[{"name":"Institute of Virology, Technical University of Munich School of Medicine, 81675 Munich, Germany"},{"name":"Institute of Virology, Helmholtz Munich, 85764 Munich, Germany"},{"name":"Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8376-8709","authenticated-orcid":false,"given":"Robert L.","family":"Gottlieb","sequence":"additional","affiliation":[{"name":"Center for Advanced Heart and Lung Disease, Department of Internal Medicine, Baylor University Medical Center, Dallas, TX 75246, USA"},{"name":"Baylor Scott & White Research Institute, Dallas, TX 75246, USA"},{"name":"Department of Internal Medicine, Texas A&M Health Science Center, Dallas, TX 75246, USA"},{"name":"Department of Internal Medicine, Burnett School of Medicine at TCU, Fort Worth, TX 76109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhat","family":"Askar","sequence":"additional","affiliation":[{"name":"Center for Advanced Heart and Lung Disease, Department of Internal Medicine, Baylor University Medical Center, Dallas, TX 75246, USA"},{"name":"QU Health and Department of Immunology, College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-2830","authenticated-orcid":false,"given":"Meta","family":"Roestenberg","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center for Infectious Diseases (LUCID), 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-6260","authenticated-orcid":false,"given":"Jutte J. C.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center for Infectious Diseases (LUCID), 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen C.","family":"Carbo","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center for Infectious Diseases (LUCID), 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Martin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Li","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Han","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Foster City, CA 94404, 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Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1476-0815","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Ant\u00f3n","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Medicine Department, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Medicine Department, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2828-3318","authenticated-orcid":false,"given":"Vanessa","family":"Casares","sequence":"additional","affiliation":[{"name":"Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Barcelona Hospital Campus, Medicine Department, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1142-6723","authenticated-orcid":false,"given":"Huldrych F.","family":"G\u00fcnthard","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8057 Zurich, Switzerland"},{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0384-0000","authenticated-orcid":false,"given":"Michael","family":"Huber","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, 8057 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace A.","family":"McComsey","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-717X","authenticated-orcid":false,"given":"Navid","family":"Sadri","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH 44106, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41467-020-20542-0","article-title":"Mechanism of SARS-CoV-2 polymerase stalling by remdesivir","volume":"12","author":"Kokic","year":"2021","journal-title":"Nat. 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