Integrated virologic analysis of resistance to nirmatrelvir/ritonavir in individuals across four phase 2/3 clinical studies for the treatment of COVID-19.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-08-01 Epub Date: 2025-06-30 DOI:10.1016/j.ebiom.2025.105819

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

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引用次数: 0

Abstract

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 M^pro 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 M^pro 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^pro ES were observed: A260T (EPIC-HR [n = 1]), K269R (EPIC-SR [n = 1]). In EPIC-IC, 3 M^pro 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.

Funding: Pfizer Inc.

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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

背景：监测SARS-CoV-2对尼马特利韦/利托那韦（NMV/r）的耐药性对于识别出现和追踪治疗耐药性至关重要。方法：通过EPIC (Evaluation of Protease Inhibition of COVID-19) 2/3期临床研究（-高风险[HR]、-标准风险[SR]、-免疫功能低下[IC]、-再治疗）进行综合病毒学分析，利用新一代测序技术鉴定SARS-CoV-2变体和Mpro或裂解位点紧急取代（ES）。通过GISAID EpiCoV SARS-CoV-2数据库，评估与covid -19相关住院或病毒RNA反弹患者的治疗ES （TES）和ES的体外NMV耐药性、结构分析和全球发病率。研究结果：对1605名NMV/r、1216名安慰剂（PBO）和114名PBO/r治疗的参与者进行了序列评估。EPIC-HR/SR (pooled) (T98I/ r /del [n = 4], E166V [n = 3], W207L/ r /del [n = 4])，裂解（A5328 S/V [n = 7], S6799 A/P/Y [n = 4]）中观察到NMV/r Mpro TES。观察到PBO裂解ES （A5328T [n = 1], S6799F [n = 1]）。在住院NMV/r治疗的参与者（EPIC-HR [n = 10], -SR [n = 5], -IC [n = 2]， -再治疗[n = 0]）中，观察到2个Mpro ES: A260T (EPIC-HR [n = 1]), K269R （EPIC-SR [n = 1]）。在EPIC-IC中，有3个Mpro ES （T98S, A191V, T201I）和2个裂解位点ES （A4136V, S4145N）出现反弹。E166V是唯一与耐药相关的TES (NMV/r: HR [n = 3]；PBO/r: -再治疗[n = 1])，但不包括住院或免疫功能低下的参与者。全球E166V发病率罕见(解释：在EPIC中，nmv耐药突变并不常见。E166V是唯一与耐药相关的替代药物，但未在住院或免疫功能低下的受试者中发现。Nct04960202, nct05011513, nct05438602, nct05567952。融资：辉瑞公司

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来源期刊

EBioMedicine Biochemistry, 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.