Retreatment With Nirmatrelvir/Ritonavir Following Return of COVID-19 Symptoms and SARS-CoV-2 Positivity
Wuyan Zhang, Steven G Terra, Edward Alan Weinstein, Candace Bramson, Heidi Leister-Tebbe, Mary Lynn Baniecki, Shunjie Guan, Alex Agyemang, Simone Antonucci, Wayne Wisemandle, PhD Jennifer Hammond
Clinical Infectious Diseases, doi:10.1093/cid/ciaf548
Background: Rebound of COVID-19 is defined as return of symptoms and/or viral positivity after resolution of the initial infection. While rebound is typically mildly symptomatic and rarely associated with progression to severe disease, the benefit of repeated antiviral treatment has not been investigated.
Methods: This randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of a second 5-day treatment course of nirmatrelvir/ritonavir versus placebo/ritonavir in participants with symptomatic mild to moderate COVID-19 with a positive SARS-CoV-2 rapid antigen test within 14 days of initial nirmatrelvir/ritonavir treatment. The primary efficacy endpoint was the change in viral SARS-CoV-2 RNA level from baseline to Day 5.
Author contributions Jennifer Hammond, Candace Bramson, Mary Lynn Baniecki, Shunjie Guan, Wuyan Zhang, and Wayne Wisemandle designed the research, analyzed the data, critically revised the manuscript for important intellectual content, and approved the final draft. Steve Terra designed the research, critically revised the manuscript for important intellectual content, and approved the final draft. Edward Alan Weinstein, Alex Agyemang, and Simone Antonucci analyzed the data, critically revised the manuscript for important intellectual content, and approved the final draft. Heidi Leister-Tebbe critically revised the manuscript for important intellectual content and approved the final draft.
Data sharing statement Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical- trials/trial-data-and-results for more information. (-1.09, -0.32) (-1.07, -0.33) P value 0.0004 0.0002 LLOQ=lower limit of quantification; LS=least s quares; mITT(1)=modified intention to treat (1); MMRM=mixed model for repeated measures; n=number of participants with nonmissing data in the analysis set and the covariates in the statistical model. a Baseline is defined as the latest measurement between Day -1 and Day 1, but postdose samples that were collected within 1 hour..
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DOI record:
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:sec>\n <jats:title>Background</jats:title>\n <jats:p>Rebound of COVID-19 is defined as return of symptoms and/or viral positivity after resolution of the initial infection. While rebound is typically mildly symptomatic and rarely associated with progression to severe disease, the benefit of repeated antiviral treatment has not been investigated.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Methods</jats:title>\n <jats:p>This randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of a second 5-day treatment course of nirmatrelvir/ritonavir versus placebo/ritonavir in participants with symptomatic mild to moderate COVID-19 with a positive SARS-CoV-2 rapid antigen test within 14 days of initial nirmatrelvir/ritonavir treatment. The primary efficacy endpoint was the change in viral SARS-CoV-2 RNA level from baseline to Day 5.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Results</jats:title>\n <jats:p>The full analysis set included 436 participants assigned to treatment (292, nirmatrelvir/ritonavir; 144, placebo/ritonavir). A second 5-day course of nirmatrelvir/ritonavir resulted in a significant reduction in viral RNA levels at Day 5 compared with placebo/ritonavir (P=0.0004; 95% CI, −1.09, −0.32). The median time to 2 consecutive negative RAT results was 4 versus 5 days, and the median time to sustained alleviation of all targeted signs/symptoms was 8 versus 9 days in the nirmatrelvir/ritonavir and placebo/ritonavir groups, respectively. Retreatment with nirmatrelvir/ritonavir was safe and well tolerated, and there were no occurrences of COVID-19−related hospitalizations or deaths.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Conclusion</jats:title>\n <jats:p>A repeated 5-day course of nirmatrelvir/ritonavir was safe and well tolerated and was associated with a faster decline in viral RNA levels. In this study, there was no clear benefit of retreatment because rebound was transient, mild, and did not lead to severe COVID-19.</jats:p>\n </jats:sec>\n <jats:sec>\n <jats:title>Clinical Trial Registration</jats:title>\n <jats:p>NCT05567952; https://clinicaltrials.gov/study/NCT05567952</jats:p>\n </jats:sec>",
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