{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T01:12:56Z","timestamp":1785805976006,"version":"3.56.0"},"reference-count":46,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Gilead Sciences"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2025,2,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and 14) were eligible for analysis if their viral load was above the lower limit of quantification for the RT-qPCR assay (2228 copies\/mL). The SARS-CoV-2 genome was sequenced for all remdesivir participants and 50% of placebo participants (baseline, Days 3, 7, and 14) and for participants who progressed to COVID-19-related hospitalization or all-cause death (all time points). Emergent substitutions in Nsp12 and other replication complex proteins were phenotyped using site-directed mutagenesis in a SARS-CoV-2 subgenomic replicon system. Overall, emergent Nsp12 substitutions were detected in 8\/115 (7.0%) remdesivir participants and 7\/129 (5.4%) placebo participants (1 substitution overlap between groups). Based on a structural analysis, none of the emergent Nsp12 substitutions were in direct contact with the incoming nucleoside triphosphate substrate, the RNA, or the RNA template 5\u2032 overhang. One substitution (A376V) showed reduced susceptibility to remdesivir (12.6-fold change in remdesivir half-maximal concentration [EC\n              <jats:sub>50<\/jats:sub>\n              ]); it also showed reduced fitness when introduced in the SARS-CoV-2 replicon and virus\n              <jats:italic>in vitro<\/jats:italic>\n              . Other substitutions had &lt;1.1-fold change in remdesivir EC\n              <jats:sub>50<\/jats:sub>\n              . None of the emergent substitutions in Nsp8, Nsp10, Nsp13, or Nsp14 (remdesivir, 10\/115 [8.7%]; placebo, 10\/129 [7.8%]) showed reduced remdesivir susceptibility. In conclusion, emergent substitutions in the SARS-CoV-2 RdRp complex with reduced remdesivir susceptibility were uncommon, indicating a high barrier to remdesivir resistance.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>CLINICAL TRIALS<\/jats:title>\n              <jats:p>\n                This study is registered with\n                <jats:related-object xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"pre-results\" document-id=\"NCT04501952\" document-id-type=\"clinical-trial-number\" source-id=\"http:\/\/clinicaltrials.gov\/\" source-id-type=\"registry-nameov\" source-type=\"clinical-trials-registry\" xlink:href=\"https:\/\/clinicaltrials.gov\/show\/NCT04501952\">\n                  <jats:ext-link ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\/\" xlink:type=\"simple\">ClinicalTrials.gov<\/jats:ext-link>\n                  as\n                  <jats:ext-link ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04501952\" xlink:type=\"simple\">NCT04501952<\/jats:ext-link>\n                <\/jats:related-object>\n                .\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/aac.01238-24","type":"journal-article","created":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T14:06:00Z","timestamp":1734617160000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["SARS-CoV-2 resistance analyses from the Phase 3 PINETREE study of remdesivir treatment in nonhospitalized participants"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9124-4652","authenticated-orcid":true,"given":"Lauren","family":"Rodriguez","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hery W.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta","place":["Edmonton, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Li","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross","family":"Martin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Han","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simin","family":"Xu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Moshiri","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Peinovich","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Camus","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason K.","family":"Perry","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Hyland","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle P.","family":"Porter","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazin","family":"Abdelghany","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"G\u00f6tte","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta","place":["Edmonton, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Hedskog","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.","place":["Foster City, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep43395"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal3653"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2019.104541"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17180"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12985-022-01951-7"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36561-6"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.1061142"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-022-01254-1"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.13854"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2022.05.002"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2120219"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jiac.2021.06.010"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05514-2"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad270"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/v16040546"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2021.105033"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05664-3"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.013679"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104793"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2021.105153"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-03996-w"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00222-22"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo0718"},{"key":"e_1_3_5_25_2","volume-title":"35th International Conference on Antiviral Research","author":"Du Pont V","year":"2022","unstructured":"Du Pont V, Stevens L, Pruijssers A, George A, Hughes T, Xie X, Shi PY, Porter D, Cihlar T, Denison M, Bilello J. 2022. Characterization of the susceptibility of specific SARS-CoV-2 nsp12 substitutions to remdesivir using a coronavirus reverse genetic system, Poster 160V. 35th International Conference on Antiviral Research. Seattle, WA"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00198-22"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009929"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29104-y"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2023.105609"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofad500.614"},{"key":"e_1_3_5_31_2","volume-title":"Conference on Retroviruses and Opportunistic Infections","author":"Rodriguez L","year":"2023","unstructured":"Rodriguez L, Hsiang TY, Li J, Han D, Moshiri J, Lu X, Martin R, Riola NC, Pitts J, Perry JK, Bilello JP, Gale Jr M, Porter DP, Hedskog C. 2023. Remdesivir retains potent antiviral activity against SARS-CoV-2 variants of concern, Poster 562. Conference on Retroviruses and Opportunistic Infections; Seattle, WA"},{"key":"e_1_3_5_32_2","unstructured":"VEKLURY. 2022. VEKLURY (remdesivir) [prescribing information]. Gilead Sciences Inc."},{"key":"e_1_3_5_33_2","unstructured":"VEKLURY. 2022. VEKLURY 100 mg powder for concentrate for solution for infusion. Summary of product characteristics. Gilead Sciences Ltd."},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.16349"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2116846"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-13380-1"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-024-01655-4"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.033"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.AC120.015720"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00750"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40121-023-00789-y"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0239403"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.3390\/v12101164"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19055-7"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104974"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00491-8"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01238-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01238-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T15:05:38Z","timestamp":1739459138000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01238-24"}},"subtitle":[],"editor":[{"given":"Jared A.","family":"Silverman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":46,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2,13]]}},"alternative-id":["10.1128\/aac.01238-24"],"URL":"https:\/\/doi.org\/10.1128\/aac.01238-24","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,13]]},"assertion":[{"value":"2024-08-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01238-24"}}