Mary Lynn Baniecki, Shunjie Guan, Devendra K Rai, Qingyi Yang, Jonathan T Lee, Li Hao, Edward Weinstein, Craig Hyde, Rhonda D Cardin, Holly Soares, Jennifer Hammond
{"title":"四项治疗COVID-19的2/3期临床研究中个体对尼马特利韦/利托那韦耐药的综合病毒学分析","authors":"Mary Lynn Baniecki, Shunjie Guan, Devendra K Rai, Qingyi Yang, Jonathan T Lee, Li Hao, Edward Weinstein, Craig Hyde, Rhonda D Cardin, Holly Soares, Jennifer Hammond","doi":"10.1016/j.ebiom.2025.105819","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 resistance to nirmatrelvir/ritonavir (NMV/r) surveillance is essential to identify emergence and track treatment-resistance.</p><p><strong>Methods: </strong>This integrative virologic analysis across EPIC (Evaluation of Protease Inhibition of COVID-19) phase 2/3 clinical studies (-High Risk [HR], -Standard Risk [SR], -Immunocompromised [IC], -Retreatment) used next-generation sequencing to identify SARS-CoV-2 variants and M<sup>pro</sup> or cleavage site emergent substitutions (ES). Treatment ES (TES) and ES in patients experiencing COVID-19‒related hospitalisation or viral RNA rebound were evaluated for in vitro NMV resistance, structure analysis, and global incidence via GISAID EpiCoV SARS-CoV-2 database.</p><p><strong>Findings: </strong>Sequences were evaluated in 1605 NMV/r, 1216 placebo (PBO), and 114 PBO/r-treated participants. NMV/r M<sup>pro</sup> TES were observed in EPIC-HR/SR (pooled) (T98I/R/del [n = 4], E166V [n = 3], W207L/R/del [n = 4]), cleavage (A5328 S/V [n = 7], S6799 A/P/Y [n = 4]). PBO cleavage ES were observed (A5328T [n = 1], S6799F [n = 1]). Among hospitalised NMV/r-treated participants (EPIC-HR [n = 10], -SR [n = 5], -IC [n = 2], -Retreatment [n = 0]), 2 M<sup>pro</sup> ES were observed: A260T (EPIC-HR [n = 1]), K269R (EPIC-SR [n = 1]). In EPIC-IC, 3 M<sup>pro</sup> ES (T98S, A191V, T201I) and 2 cleavage site ES (A4136V, S4145N) were observed with rebound. E166V was the only TES associated with resistance (NMV/r: HR [n = 3]; PBO/r: -Retreatment [n = 1]), but not in participants experiencing hospitalisation or with immunocompromising conditions. Global E166V incidence was rare (<0.001% in pre- and post-NMV/r emergency use authorization) by GISAID (December 1, 2019-June 30, 2024).</p><p><strong>Interpretation: </strong>In EPIC, NMV-resistance mutations were infrequent. E166V was the only resistance-associated substitution but was not identified in participants experiencing hospitalisation or with immunocompromising conditions. NCT04960202, NCT05011513, NCT05438602, NCT05567952.</p><p><strong>Funding: </strong>Pfizer Inc.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"118 ","pages":"105819"},"PeriodicalIF":10.8000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266373/pdf/","citationCount":"0","resultStr":"{\"title\":\"Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.\",\"authors\":\"Mary Lynn Baniecki, Shunjie Guan, Devendra K Rai, Qingyi Yang, Jonathan T Lee, Li Hao, Edward Weinstein, Craig Hyde, Rhonda D Cardin, Holly Soares, Jennifer Hammond\",\"doi\":\"10.1016/j.ebiom.2025.105819\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>SARS-CoV-2 resistance to nirmatrelvir/ritonavir (NMV/r) surveillance is essential to identify emergence and track treatment-resistance.</p><p><strong>Methods: </strong>This integrative virologic analysis across EPIC (Evaluation of Protease Inhibition of COVID-19) phase 2/3 clinical studies (-High Risk [HR], -Standard Risk [SR], -Immunocompromised [IC], -Retreatment) used next-generation sequencing to identify SARS-CoV-2 variants and M<sup>pro</sup> or cleavage site emergent substitutions (ES). Treatment ES (TES) and ES in patients experiencing COVID-19‒related hospitalisation or viral RNA rebound were evaluated for in vitro NMV resistance, structure analysis, and global incidence via GISAID EpiCoV SARS-CoV-2 database.</p><p><strong>Findings: </strong>Sequences were evaluated in 1605 NMV/r, 1216 placebo (PBO), and 114 PBO/r-treated participants. NMV/r M<sup>pro</sup> TES were observed in EPIC-HR/SR (pooled) (T98I/R/del [n = 4], E166V [n = 3], W207L/R/del [n = 4]), cleavage (A5328 S/V [n = 7], S6799 A/P/Y [n = 4]). PBO cleavage ES were observed (A5328T [n = 1], S6799F [n = 1]). Among hospitalised NMV/r-treated participants (EPIC-HR [n = 10], -SR [n = 5], -IC [n = 2], -Retreatment [n = 0]), 2 M<sup>pro</sup> ES were observed: A260T (EPIC-HR [n = 1]), K269R (EPIC-SR [n = 1]). In EPIC-IC, 3 M<sup>pro</sup> ES (T98S, A191V, T201I) and 2 cleavage site ES (A4136V, S4145N) were observed with rebound. E166V was the only TES associated with resistance (NMV/r: HR [n = 3]; PBO/r: -Retreatment [n = 1]), but not in participants experiencing hospitalisation or with immunocompromising conditions. Global E166V incidence was rare (<0.001% in pre- and post-NMV/r emergency use authorization) by GISAID (December 1, 2019-June 30, 2024).</p><p><strong>Interpretation: </strong>In EPIC, NMV-resistance mutations were infrequent. E166V was the only resistance-associated substitution but was not identified in participants experiencing hospitalisation or with immunocompromising conditions. NCT04960202, NCT05011513, NCT05438602, NCT05567952.</p><p><strong>Funding: </strong>Pfizer Inc.</p>\",\"PeriodicalId\":11494,\"journal\":{\"name\":\"EBioMedicine\",\"volume\":\"118 \",\"pages\":\"105819\"},\"PeriodicalIF\":10.8000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266373/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EBioMedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ebiom.2025.105819\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/30 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2025.105819","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.
Background: SARS-CoV-2 resistance to nirmatrelvir/ritonavir (NMV/r) surveillance is essential to identify emergence and track treatment-resistance.
Methods: This integrative virologic analysis across EPIC (Evaluation of Protease Inhibition of COVID-19) phase 2/3 clinical studies (-High Risk [HR], -Standard Risk [SR], -Immunocompromised [IC], -Retreatment) used next-generation sequencing to identify SARS-CoV-2 variants and Mpro or cleavage site emergent substitutions (ES). Treatment ES (TES) and ES in patients experiencing COVID-19‒related hospitalisation or viral RNA rebound were evaluated for in vitro NMV resistance, structure analysis, and global incidence via GISAID EpiCoV SARS-CoV-2 database.
Findings: Sequences were evaluated in 1605 NMV/r, 1216 placebo (PBO), and 114 PBO/r-treated participants. NMV/r Mpro TES were observed in EPIC-HR/SR (pooled) (T98I/R/del [n = 4], E166V [n = 3], W207L/R/del [n = 4]), cleavage (A5328 S/V [n = 7], S6799 A/P/Y [n = 4]). PBO cleavage ES were observed (A5328T [n = 1], S6799F [n = 1]). Among hospitalised NMV/r-treated participants (EPIC-HR [n = 10], -SR [n = 5], -IC [n = 2], -Retreatment [n = 0]), 2 Mpro ES were observed: A260T (EPIC-HR [n = 1]), K269R (EPIC-SR [n = 1]). In EPIC-IC, 3 Mpro ES (T98S, A191V, T201I) and 2 cleavage site ES (A4136V, S4145N) were observed with rebound. E166V was the only TES associated with resistance (NMV/r: HR [n = 3]; PBO/r: -Retreatment [n = 1]), but not in participants experiencing hospitalisation or with immunocompromising conditions. Global E166V incidence was rare (<0.001% in pre- and post-NMV/r emergency use authorization) by GISAID (December 1, 2019-June 30, 2024).
Interpretation: In EPIC, NMV-resistance mutations were infrequent. E166V was the only resistance-associated substitution but was not identified in participants experiencing hospitalisation or with immunocompromising conditions. NCT04960202, NCT05011513, NCT05438602, NCT05567952.
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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