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Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant

Yoko Tanino1,2, Keisuke Nishioka1, Chie Yamamoto2

  • 1Department of Infectious Diseases, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Infection and Drug Resistance
|February 13, 2024
PubMed
Abstract

Insights

Dual-drug resistant variants of SARS-CoV-2 emerged rapidly in an immunocompromised patient receiving sotrovimab and remdesivir. These resistant viruses showed increased resistance but a potential fitness cost, highlighting the need for monitoring treatment in vulnerable populations.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • The development of effective treatments for coronavirus disease 2019 (COVID-19) is ongoing.
  • Understanding the characteristics of drug-resistant SARS-CoV-2 is crucial for optimizing therapeutic strategies.

Purpose of the Study:

  • To investigate the emergence of dual-drug resistance to sotrovimab and remdesivir (RDV) in a kidney transplant recipient with COVID-19.
  • To characterize the genetic mutations and in vitro properties of emerging drug-resistant SARS-CoV-2 variants.

Main Methods:

  • Whole-genome sequencing of SARS-CoV-2 from nasopharyngeal swabs at multiple time points during treatment.
  • Comparison of viral genomes to identify mutations associated with drug resistance.
  • In vitro assessment of viral escape ability and growth kinetics for selected isolates.

Main Results:

  • Sotrovimab resistance mutation (S:E340K) emerged by day 12, and RDV resistance mutation (RdRp:V792I) emerged by day 19.
  • A dual-drug resistant variant (S:E340K/RdRp:V791I) became dominant within 23 days, exhibiting significantly higher resistance to both drugs.
  • Dual-resistant variants showed reduced in vitro viral yields compared to wild-type, indicating a potential fitness cost.

Conclusions:

  • Combination therapy with sotrovimab and RDV can rapidly lead to the emergence of dual-drug resistant SARS-CoV-2 in immunocompromised patients.
  • The rapid emergence of resistance underscores the importance of vigilant monitoring for treatment failure and resistance development.
  • Despite a fitness cost, these drug-resistant variants can become dominant, necessitating further research into their clinical implications.
Keywords:
SARS-CoV-2drug resistanceimmunosuppression therapyremdesivirsotrovimab

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