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Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation

Authors :
Shangxin Yang
Ashrit Multani
Jacob M. Garrigues
Michael S. Oh
Peera Hemarajata
Taylor Burleson
Nicole M. Green
Caspian Oliai
Pryce T. Gaynor
Omer E. Beaird
Drew J. Winston
Christopher S. Seet
Joanna M. Schaenman
Source :
Microorganisms, Vol 11, Iss 8, p 2096 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens collected at different treatment time points in two transplant patients with severe COVID-19. In the first patient, an allogeneic hematopoietic stem cell transplant recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed that has not previously been associated with remdesivir resistance. As no in vitro study had been conducted to elucidate the phenotypic effect of nsp12:A449V, its clinical significance is unclear. In the second patient, two other transient RdRp mutations were detected: one in the catalytic subunit (nsp12:V166A) and the other in an accessory subunit important for processivity (nsp7:D67N). This is the first case report for a potential link between the nsp12:V166A mutation and remdesivir resistance in vivo, which had only been previously described by in vitro studies. The nsp7:D67N mutation has not previously been associated with remdesivir resistance, and whether it has a phenotypic effect is unknown. Our study revealed SARS-CoV-2 genetic dynamics during remdesivir treatment in transplant recipients that involved mutations in the RdRp complex (nsp7 and nsp12), which may be the result of selective pressure. These results suggest that close monitoring for potential resistance during the course of remdesivir treatment in highly vulnerable patient populations may be beneficial. Development and utilization of diagnostic RdRp genotyping tests may be a future direction for improving the management of chronic COVID-19.

Details

Language :
English
ISSN :
20762607
Volume :
11
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Microorganisms
Publication Type :
Academic Journal
Accession number :
edsdoj.858597d350c442229ddcb2f17af38224
Document Type :
article
Full Text :
https://doi.org/10.3390/microorganisms11082096