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Clinical, Virologic, and Immunologic Evaluation of Symptomatic Coronavirus Disease 2019 Rebound Following Nirmatrelvir/Ritonavir Treatment

  1. Author:
    Epling, Brian P [ORCID]
    Rocco, Joseph M
    Boswell, Kristin L
    Laidlaw, Elizabeth
    Galindo, Frances
    Kellogg,Anela
    Das, Sanchita
    Roder, Allison
    Ghedin, Elodie
    Kreitman, Allie
    Dewar,Robin
    Kelly, Sophie E M
    Kalish, Heather
    Rehman, Tauseef
    Highbarger,Jeroen
    Rupert,Adam
    Kocher, Gregory
    Holbrook, Michael R
    Lisco, Andrea
    Manion, Maura
    Koup, Richard A
    Sereti, Irini [ORCID]

  2. Author Address

    Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland, USA., Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA., Systems Genomics Section, Laboratory of Parasitic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA., Virus Isolation and Serology Laboratory, Frederick National Laboratory, Frederick, Maryland, USA., Trans-NIH Shared Resource on Biomedical Engineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA., AIDS Monitoring Laboratory, Frederick National Laboratory, Frederick, Maryland, USA., Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland, USA.,
    1. Year: 2022
    2. Date: Oct 06
    3. Epub Date: 2022 10 06
  2. Journal: Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America
  4. Type of Article: Article
  1. Abstract:

    Nirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion. Six individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti-receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed. High levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2-specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8. Nirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses. Clinical trials registration. NCT04401436. Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.

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External Sources

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  2. DOI: 10.1093/cid/ciac663
  3. PMID: 36200701
  4. PII : 6749408

Library Notes

  1. Fiscal Year: FY2022-2023
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