De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report

Shiv Gandhi (), Jonathan Klein, Alexander J. Robertson, Mario A. Peña-Hernández, Michelle J. Lin, Pavitra Roychoudhury, Peiwen Lu, John Fournier, David Ferguson, Shah A. K. Mohamed Bakhash, M. Catherine Muenker, Ariktha Srivathsan, Elsio A. Wunder, Nicholas Kerantzas, Wenshuai Wang, Brett Lindenbach, Anna Pyle, Craig B. Wilen, Onyema Ogbuagu, Alexander L. Greninger, Akiko Iwasaki, Wade L. Schulz and Albert I. Ko ()
Additional contact information
Shiv Gandhi: Yale University School of Medicine
Jonathan Klein: Yale University School of Medicine
Alexander J. Robertson: Yale School of Public Health
Mario A. Peña-Hernández: Yale University School of Medicine
Michelle J. Lin: University of Washington School of Medicine
Pavitra Roychoudhury: University of Washington School of Medicine
Peiwen Lu: Yale University School of Medicine
John Fournier: Yale University School of Medicine
David Ferguson: Yale New Haven Hospital
Shah A. K. Mohamed Bakhash: University of Washington School of Medicine
M. Catherine Muenker: Yale School of Public Health
Ariktha Srivathsan: Yale School of Public Health
Elsio A. Wunder: Yale School of Public Health
Nicholas Kerantzas: Yale School of Medicine
Wenshuai Wang: Cellular and Developmental Biology, Yale University
Brett Lindenbach: Yale School of Medicine
Anna Pyle: Cellular and Developmental Biology, Yale University
Craig B. Wilen: Yale University School of Medicine
Onyema Ogbuagu: Yale University School of Medicine
Alexander L. Greninger: University of Washington School of Medicine
Akiko Iwasaki: Yale University School of Medicine
Wade L. Schulz: Yale New Haven Hospital
Albert I. Ko: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-8

Abstract: Abstract SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Date: 2022
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DOI: 10.1038/s41467-022-29104-y

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