Background PAXLOVID consists of nirmatrelvir, an inhibitor of 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. Methods 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 1,862 participants (912 nirmatrelvir/ritonavir, 950 placebo) in EPIC-HR and EPIC-SR, which were Phase 2/3, randomized, double-blind, placebo-controlled trials in participants with mild-to-moderate 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. Results 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. Conclusions 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.

中文翻译：

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FDA 在 2/3 期试验 EPIC-HR 和 EPIC-SR 中对奈马曲韦/利托那韦耐药性的独立分析


背景 PAXLOVID 由 SARS-CoV-2 主要蛋白酶 （Mpro） 抑制剂 nirmatrelvir 与药代动力学增强剂利托那韦共同包装。奈马曲韦/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 nirmatrelvir/ritonavir 的临床耐药性的已发表信息有限。方法 为了研究接受治疗的患者对奈马曲韦/利托那韦的 SARS-CoV-2 耐药性发展，我们分析了 EPIC-HR 和 EPIC-SR 中 1,862 名参与者（912 名奈马曲韦/利托那韦，950 名安慰剂）的基线和匹配的基线后 SARS-CoV-2 下一代测序数据，这是 2/3 期、随机、双盲、安慰剂对照试验轻度至中度 COVID-19 参与者。潜在耐药相关替代 （RAS） 定义为在 nirmatrelvir/ritonavir 治疗的参与者中富集或发生在感兴趣的 Mpro 位置的替代，使用非临床数据定义。分析 SARS-CoV-2 序列数据库以表征 nirmatrelvir/ritonavir RAS 在循环病毒中的时间频率。结果 在 EPIC-HR 中，奈马曲韦/利托那韦 RAS 包括 Mpro T21I （n=1）、E166V （n=3）、A173T （n=1） 和 T304I （n=1），其中 E166V 是观察到的最清晰的 RAS。在 EPIC-SR 中，未检测到 RAS。奈马曲韦/利托那韦 RAS 与住院或死亡无关。对 SARS-CoV-2 序列数据库的分析并未揭示 nirmatrelvir/ritonavir RAS 频率随时间增加的问题。结论 在临床试验中，SARS-CoV-2 对奈马曲韦/利托那韦耐药的出现很少 （<0.3%-1.1%）。目前的监测数据表明，奈马曲韦/利托那韦 RAS 的 SARS-CoV-2 变体传播频率较低。 总的来说，这些结果提供了迄今为止临床环境中 SARS-CoV-2 对 nirmatrelvir/ritonavir 耐药性的最全面分析。应继续密切监测病毒序列，以确定可能出现的 nirmatrelvir/ritonavir 耐药变体。