Jonathan M O Rawson, Eric F Donaldson, Julian J O'Rear, Patrick R Harrington
{"title":"FDA 对 2/3 期试验 EPIC-HR 和 EPIC-SR 中 Nirmatrelvir/Ritonavir 耐药性的独立分析。","authors":"Jonathan M O Rawson, Eric F Donaldson, Julian J O'Rear, Patrick R Harrington","doi":"10.1093/cid/ciae615","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":10463,"journal":{"name":"Clinical Infectious Diseases","volume":" ","pages":""},"PeriodicalIF":8.2000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Independent FDA Analyses of Nirmatrelvir/Ritonavir Resistance in the Phase 2/3 Trials EPIC-HR and EPIC-SR.\",\"authors\":\"Jonathan M O Rawson, Eric F Donaldson, Julian J O'Rear, Patrick R Harrington\",\"doi\":\"10.1093/cid/ciae615\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":10463,\"journal\":{\"name\":\"Clinical Infectious Diseases\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":8.2000,\"publicationDate\":\"2024-12-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/cid/ciae615\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/cid/ciae615","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Independent FDA Analyses of Nirmatrelvir/Ritonavir Resistance in the Phase 2/3 Trials EPIC-HR and EPIC-SR.
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.
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Clinical Infectious Diseases (CID) is dedicated to publishing original research, reviews, guidelines, and perspectives with the potential to reshape clinical practice, providing clinicians with valuable insights for patient care. CID comprehensively addresses the clinical presentation, diagnosis, treatment, and prevention of a wide spectrum of infectious diseases. The journal places a high priority on the assessment of current and innovative treatments, microbiology, immunology, and policies, ensuring relevance to patient care in its commitment to advancing the field of infectious diseases.
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