Rawson Jonathan M O, Donaldson Eric F, O'Rear Julian J, Harrington Patrick R
Division of Antivirals, Office of Infectious Diseases, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
Clin Infect Dis. 2025 Jun 4;80(5):1005-1012. doi: 10.1093/cid/ciae615.
PAXLOVID consists of nirmatrelvir, an inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro), copackaged with ritonavir, a pharmacokinetic enhancer. Nirmatrelvir/ritonavir received emergency use authorization in the United States in 2021 and was approved in 2023. However, there is limited published information on SARS-CoV-2 clinical resistance to nirmatrelvir/ritonavir.
To investigate SARS-CoV-2 resistance development to nirmatrelvir/ritonavir in treated patients, we analyzed baseline and matching post-baseline SARS-CoV-2 next-generation sequencing data from 1862 participants (912 nirmatrelvir/ritonavir, 950 placebo) in Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) and Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR), which were Phase 2/3, randomized, double-blind, placebo-controlled trials in participants with mild-to-moderate coronavirus disease 2019 (COVID-19). Potential resistance-associated substitutions (RAS) were defined as those that were enriched in nirmatrelvir/ritonavir-treated participants or occurred at Mpro positions of interest, defined using nonclinical data. SARS-CoV-2 sequence databases were analyzed to characterize temporal frequencies of nirmatrelvir/ritonavir RAS in circulating viruses.
In EPIC-HR, nirmatrelvir/ritonavir RAS included Mpro T21I (n = 1), E166V (n = 3), A173T (n = 1), and T304I (n = 1), with E166V being the clearest RAS observed. In EPIC-SR, no RAS were detected. Nirmatrelvir/ritonavir RAS were not associated with hospitalization or death. Analyses of SARS-CoV-2 sequence databases did not reveal concerning increases in the frequencies of nirmatrelvir/ritonavir RAS over time.
In clinical trials, emergence of SARS-CoV-2 resistance to nirmatrelvir/ritonavir was infrequent (<0.3%-1.1%). Surveillance data currently indicate a low frequency of circulating SARS-CoV-2 variants with nirmatrelvir/ritonavir RAS. Collectively, these results provide the most comprehensive analysis of SARS-CoV-2 resistance to nirmatrelvir/ritonavir in the clinical setting to date. Viral sequences should continue to be closely monitored to identify the potential emergence of nirmatrelvir/ritonavir-resistant variants.
帕罗韦德由奈玛特韦（一种严重急性呼吸综合征冠状病毒2 [SARS-CoV-2] 主要蛋白酶 [Mpro] 抑制剂）与利托那韦（一种药代动力学增强剂）共同包装而成。奈玛特韦/利托那韦于2021年在美国获得紧急使用授权，并于2023年获得批准。然而，关于SARS-CoV-2对奈玛特韦/利托那韦的临床耐药性，已发表的信息有限。
为了研究接受治疗的患者中SARS-CoV-2对奈玛特韦/利托那韦耐药性的发展情况，我们分析了1862名参与者（912名接受奈玛特韦/利托那韦治疗，950名接受安慰剂治疗）的基线及匹配的基线后SARS-CoV-2下一代测序数据，这些数据来自高危患者中COVID-19蛋白酶抑制评估（EPIC-HR）和标准风险患者中COVID-19蛋白酶抑制评估（EPIC-SR），这两项是针对轻度至中度2019冠状病毒病（COVID-19）患者的2/3期随机、双盲、安慰剂对照试验。潜在的耐药相关替代突变（RAS）被定义为在接受奈玛特韦/利托那韦治疗的参与者中富集或出现在使用非临床数据定义的Mpro感兴趣位置的突变。对SARS-CoV-2序列数据库进行分析，以表征循环病毒中奈玛特韦/利托那韦RAS的时间频率。
在EPIC-HR中，奈玛特韦/利托那韦RAS包括Mpro T21I（n = 1）、E166V（n = 3）、A173T（n = 1）和T304I（n = 1），其中E166V是观察到的最明显的RAS。在EPIC-SR中，未检测到RAS。奈玛特韦/利托那韦RAS与住院或死亡无关。对SARS-CoV-2序列数据库的分析未发现奈玛特韦/利托那韦RAS的频率随时间有令人担忧的增加。
在临床试验中，SARS-CoV-2对奈玛特韦/利托那韦产生耐药性的情况很少见（<0.3%-1.1%）。监测数据目前表明，携带奈玛特韦/利托那韦RAS的循环SARS-CoV-2变体频率较低。总体而言，这些结果提供了迄今为止在临床环境中对SARS-CoV-2对奈玛特韦/利托那韦耐药性的最全面分析。应继续密切监测病毒序列，以识别奈玛特韦/利托那韦耐药变体的潜在出现。
