Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

  1. Mohammed Nooruzzaman
  2. Katherine E.E. Johnson
  3. Ruchi Rani
  4. Eli J. Finkelsztein
  5. Leonardo C. Caserta
  6. Rosy P. Kodiyanplakkal
  7. Wei Wang
  8. Jingmei Hsu
  9. Maria T. Salpietro
  10. Stephanie Banakis
  11. Joshua Albert
  12. Lars Westblade
  13. Claudio Zanettini
  14. Luigi Marchionni
  15. Rosemary Soave
  16. Elodie Ghedin
  17. Diego G. Diel
  18. Mirella Salvatore

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Abstract

We investigated the impact of antiviral treatment on the emergence of SARS-CoV-2 resistance during persistent infections in immunocompromised patients (n=15). All patients received remdesivir and some also received nirmatrelvir-ritonavir or monoclonal antibodies. Sequence analysis showed that nine patients carried viruses with mutations in the nsp12 (RNA dependent RNA polymerase), while four had viruses with nsp5 (3C protease) mutations. Infectious SARS-CoV-2 with a double mutation in nsp5 (T169I) and nsp12 (V792I) was recovered from respiratory secretions 77 days after initial COVID-19 diagnosis from a patient treated with remdesivir and nirmatrelvir-ritonavir. In vitro characterization confirmed its decreased sensitivity to remdesivir and nirmatrelvir, which was overcome by combined antiviral treatment. Studies in golden Syrian hamsters demonstrated efficient transmission to contact animals. This study documents the isolation of SARS-CoV-2 carrying resistance mutations to both nirmatrelvir and remdesivir from a patient and demonstrates its transmissibility in vivo .

Article activity feed

  1. Rapid Reviews Infectious Diseases

    Jishnu Das

    Review 2: "Emergence of Transmissible SARS-CoV-2 Variants with Decreased Sensitivity to Antivirals in Immunocompromised Patients with Persistent Infections"

    The reviewers agree that the study is well designed and provides reliable evidence. They make very minor comments regarding potential questions to pursue in order to better characterize the results.

  2. Rapid Reviews Infectious Diseases

    David Ussery

    Review 1: "Emergence of Transmissible SARS-CoV-2 Variants with Decreased Sensitivity to Antivirals in Immunocompromised Patients with Persistent Infections"

    The reviewers agree that the study is well designed and provides reliable evidence. They make very minor comments regarding potential questions to pursue in order to better characterize the results.

  4. Version published to 10.1101/2024.06.14.24308523v1 on medRxiv