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

Mohammed Nooruzzaman, Katherine E. E. Johnson, Ruchi Rani, Eli J. Finkelsztein, Leonardo C. Caserta, Rosy P. Kodiyanplakkal, Wei Wang, Jingmei Hsu, Maria T. Salpietro, Stephanie Banakis, Joshua Albert, Lars F. Westblade, Claudio Zanettini, Luigi Marchionni, Rosemary Soave, Elodie Ghedin (), Diego G. Diel () and Mirella Salvatore ()
Additional contact information
Mohammed Nooruzzaman: Cornell University
Katherine E. E. Johnson: NIH/NIAID/DIR/LPD
Ruchi Rani: Cornell University
Eli J. Finkelsztein: Weill Cornell Medicine
Leonardo C. Caserta: Cornell University
Rosy P. Kodiyanplakkal: Weill Cornell Medicine
Wei Wang: NIH/NIAID/DIR/LPD
Jingmei Hsu: Weill Cornell Medicine
Maria T. Salpietro: Weill Cornell Medicine
Stephanie Banakis: NIH/NIAID/DIR/LPD
Joshua Albert: NIH/NIAID/DIR/LPD
Lars F. Westblade: Weill Cornell Medicine
Claudio Zanettini: Weill Cornell Medicine
Luigi Marchionni: Weill Cornell Medicine
Rosemary Soave: Weill Cornell Medicine
Elodie Ghedin: NIH/NIAID/DIR/LPD
Diego G. Diel: Cornell University
Mirella Salvatore: Weill Cornell Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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 (n = 3) or therapeutic monoclonal antibodies (n = 4). 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 sequentially treated with nirmatrelvir-ritonavir and remdesivir. 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.

Date: 2024
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DOI: 10.1038/s41467-024-51924-3

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