Abstract: Clinical Infectious Diseases
MAJOR ARTICLE
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Wuyan Zhang,1 Steven G. Terra,2 Edward Alan Weinstein,3 Candace Bramson,4 Heidi
Leister-Tebbe,4 Mary Lynn Baniecki,5 Shunjie Guan,5 Alex Agyemang,6 Simone
Antonucci,7 Wayne Wisemandle,1 Jennifer Hammond4
Pfizer Research and Development, Pfizer Inc, Lake Forest, IL, USA; 2 Pfizer Research and
Development, Pfizer Inc, Groton, CT, USA; 3 Pfizer Research and Development, Pfizer Inc, New
York, NY, USA; 4 Pfizer Research and Development, Pfizer Inc, Collegeville, PA, USA; 5 Pfizer
Research and Development, Pfizer Inc, Cambridge, MA, USA; 6 Pfizer Research and
Development, Pfizer Ltd, Tadworth, UK; 7 Pfizer Research and Development, Pfizer Italia s.r.l.,
Milan, Italy;
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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.
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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.
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Corresponding author: Jennifer Hammond, PhD, Global Product Development, Pfizer Inc, 500 Arcola
Rd, Collegeville, PA 19426, USA, Email: jennifer.hammond@pfizer.com, Telephone: (860) 501-1065,
Phone: 835-238-4655
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© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of
America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial reproduction and distribution of the work, in any medium, provided the
original work is not altered or transformed in any way, and that the work is properly cited. For
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DOI: 10.1093/cid/ciaf548
Retreatment With Nirmatrelvir/Ritonavir Following Return
of COVID-19 Symptoms and SARS-cov-2 Positivity
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Conclusion: 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.
Clinical Trial Registration: NCT05567952; https://clinicaltrials.gov/study/NCT05567952
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Keywords: COVID-19, nirmatrelvir, ritonavir, retreatment, rebound
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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