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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

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 SAR...

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Autores principales: Yang, Shangxin, Multani, Ashrit, Garrigues, Jacob M., Oh, Michael S., Hemarajata, Peera, Burleson, Taylor, Green, Nicole M., Oliai, Caspian, Gaynor, Pryce T., Beaird, Omer E., Winston, Drew J., Seet, Christopher S., Schaenman, Joanna M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460003/
https://www.ncbi.nlm.nih.gov/pubmed/37630656
http://dx.doi.org/10.3390/microorganisms11082096
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author Yang, Shangxin
Multani, Ashrit
Garrigues, Jacob M.
Oh, Michael S.
Hemarajata, Peera
Burleson, Taylor
Green, Nicole M.
Oliai, Caspian
Gaynor, Pryce T.
Beaird, Omer E.
Winston, Drew J.
Seet, Christopher S.
Schaenman, Joanna M.
author_facet Yang, Shangxin
Multani, Ashrit
Garrigues, Jacob M.
Oh, Michael S.
Hemarajata, Peera
Burleson, Taylor
Green, Nicole M.
Oliai, Caspian
Gaynor, Pryce T.
Beaird, Omer E.
Winston, Drew J.
Seet, Christopher S.
Schaenman, Joanna M.
author_sort Yang, Shangxin
collection PubMed
description 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.
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spelling pubmed-104600032023-08-27 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 Yang, Shangxin Multani, Ashrit Garrigues, Jacob M. Oh, Michael S. Hemarajata, Peera Burleson, Taylor Green, Nicole M. Oliai, Caspian Gaynor, Pryce T. Beaird, Omer E. Winston, Drew J. Seet, Christopher S. Schaenman, Joanna M. Microorganisms Case Report 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. MDPI 2023-08-16 /pmc/articles/PMC10460003/ /pubmed/37630656 http://dx.doi.org/10.3390/microorganisms11082096 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Case Report
Yang, Shangxin
Multani, Ashrit
Garrigues, Jacob M.
Oh, Michael S.
Hemarajata, Peera
Burleson, Taylor
Green, Nicole M.
Oliai, Caspian
Gaynor, Pryce T.
Beaird, Omer E.
Winston, Drew J.
Seet, Christopher S.
Schaenman, Joanna M.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460003/
https://www.ncbi.nlm.nih.gov/pubmed/37630656
http://dx.doi.org/10.3390/microorganisms11082096
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