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Recurrence of Symptoms Following a 2-Day Symptom Free Period in Patients With COVID-19

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME

Recurrence of symptoms after finishing treatment for COVID-19 with nirmatrelvir-ritonavir (Paxlovid) has become increasingly recognized.13 The biological underpinning of this phenomenon is unclear, and its etiology may be multifactorial, including rapid clearance of nirmatrelvir coupled with delayed immune responses or possible development of drug resistance.13 The contribution of treatment to symptom rebound needs to be differentiated from symptom rebound that might occur during the natural history of COVID-19. In this cohort study, we sought to determine how often COVID-19 symptoms recurred when the disease was untreated.

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: September 12, 2022.

Published: October 27, 2022. doi:10.1001/jamanetworkopen.2022.38867

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Smith DM et al. JAMA Network Open.

Corresponding Author: Davey M. Smith, MD, MAS, Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093-0676 (d13smith@health.ucsd.edu).

Author Contributions: Dr Hughes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Chew and Hughes contributed equally.

Concept and design: Smith, Li, Moser, Currier, Chew, Hughes.

Acquisition, analysis, or interpretation of data: Smith, Moser, Yeh, Chew, Hughes.

Drafting of the manuscript: Smith, Li, Hughes.

Critical revision of the manuscript for important intellectual content: Smith, Moser, Yeh, Currier, Chew, Hughes.

Statistical analysis: Moser, Yeh, Hughes.

Obtained funding: Smith, Currier, Hughes.

Administrative, technical, or material support: Smith, Chew, Hughes.

Supervision: Smith, Li, Chew, Hughes.

Conflict of Interest Disclosures: Dr Smith reported receiving personal fees from consulting work for Linear Therapies, Model Medicines, Kiadis Pharmaceutical, Bayer Pharmaceuticals, Signant Health, Evidera, Fluxergy, Vx Bioscience, and Pharma Holdings outside the submitted work. Dr Li reported receiving grants from Merck outside the submitted work. Dr Currier reported receiving personal fees for advisory board work from Merck and Company outside the submitted work. Dr Chew reported receiving research funding to her institution from Merck Sharp & Dohme, and reported consulting work for Pardes Biosciences; she reported having a patent pending for ACTIV-2 COVID-19 acute and long-term symptom diaries that will be made available at no cost, as they were developed with federal funding. No other disclosures were reported.

Funding/Support: This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under grant Nos. UM1 AI068634, UM1 AI068636, and UM1 AI106701.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The ACTIV-2/A5401 Study Team members appear in the Supplement.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: We thank the study participants, site staff, site investigators, and the entire ACTIV-2/A5401 study team; the AIDS Clinical Trials Group, including Joseph J. Eron, MD, University of North Carolina at Chapel Hill School of Medicine, Eric S. Daar, MD, Lundquist Institute at Harbor-UCLA Medical Center, and David A. Wohl, MD, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine; the Harvard Center for Biostatistics in AIDS Research and ACTG Statistical and Data Analysis Center, including Justin Ritz, MS; the National Institute of Allergy and Infectious Diseases/Division of AIDS, including William Erhardt, MD, Arzhang Cyrus Javan, MD, MPH, DTM&H, and Peter Kim, MD, of the National Institutes of Health; the US Government Response to COVID-19; the Foundation for the National Institutes of Health and the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, including Stacey Adams, PhD; and PPD. All contributors received compensation for activities within ACTIV-2/A5401.

References
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Carlin  AF , Clark  AE , Chaillon  A ,  et al.  Virologic and immunologic characterization of COVID-19 recrudescence after nirmatrelvir/ritonavir treatment.   Clin Infect Dis. Published online June 20, 2022. doi:10.1093/cid/ciac496PubMedGoogle ScholarCrossref
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Charness  ME , Gupta  K , Stack  G ,  et al.  Rebound of SARS-CoV-2 infection after nirmatrelvir-ritonavir treatment.   N Engl J Med. 2022;387:1045-1047. doi:10.1056/NEJMc2206449PubMedGoogle ScholarCrossref
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Boucau  J , Uddin  R , Marino  C ,  et al.  Characterization of virologic rebound following nirmatrelvir-ritonavir treatment for COVID-19.   Clin Infect Dis. Published online June 23, 2022. doi:10.1093/cid/ciac512PubMedGoogle ScholarCrossref
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Chew  KW , Moser  C , Daar  ES ,  et al; ACTIV-2/A5401 Study Team.  Antiviral and clinical activity of bamlanivimab in a randomized trial of non-hospitalized adults with COVID-19.   Nat Commun. 2022;13(1):4931. doi:10.1038/s41467-022-32551-2PubMedGoogle ScholarCrossref
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Viana  R , Moyo  S , Amoako  DG ,  et al.  Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa.   Nature. 2022;603(7902):679-686. doi:10.1038/s41586-022-04411-yPubMedGoogle ScholarCrossref
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Lewis  NM , Duca  LM , Marcenac  P ,  et al.  Characteristics and timing of initial virus shedding in severe acute respiratory syndrome coronavirus 2, Utah, USA.   Emerg Infect Dis. 2021;27(2):352-359. Published online December 4, 2020. doi:10.3201/eid2702.203517PubMedGoogle ScholarCrossref
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