Drug-resistant SARS-CoV-2 variants found in immunocompromised patients
· News-MedicalIndividuals with compromised immunity and persistent COVID-19 infections can harbor drug-resistant variants of the SARS-CoV-2 virus, which have the potential to spread to the general population found researchers at Weill Cornell Medicine, the College of Veterinary Medicine at Cornell University and the National Institutes of Health's (NIH) National Institute of Allergy and Infectious Diseases (NIAID).
In the study, published Sept. 18 in Nature Communications, researchers isolated drug-resistant strains of SARS-CoV-2 from people who had not cleared the virus after two to three months of infection and treatments with antiviral drugs.
One variant showed resistance to antivirals Paxlovid and remdesivir while another strain had mutations associated with a decreased sensitivity to remdesivir and a third antiviral drug, the monoclonal antibody sotrovimab.
Dr. Elodie Ghedin, senior investigator and chief of the Systems Genomics Section in NIAID, is co-senior author. Dr. Mohammed Nooruzzaman, research associate in the Diel Lab at the College of Veterinary Medicine at Cornell University, and Katherine Johnson, senior bioanalyst contractor in NIAID, are co-first authors.
Unique challenges in treating persistent COVID infections
To understand the rise of antiviral drug resistance, the researchers focused on 15 individuals with compromised immune systems who received remdesivir, and in some cases, nirmatrelvir-ritonavir (Paxlovid). They found nine patients had developed virus variants with mutations to the nsp12 protein that is the target of remdesivir and four had viruses with mutations to the nsp5 protein, the target of Paxlovid. These mutations helped the virus persist despite common antiviral treatments.
One person had a virus resistant to both drugs. "For the first time, we isolated virus from a patient's nose 77 days after disease onset that was resistant to Paxlovid and also to remdesivir," Dr. Salvatore said. "It is concerning that some of these patients may have viable virus in their nasal secretions so far into the disease."
Combination therapies may be the answer
The researchers also found that the resistant strain replicated as well as the original SARS-CoV-2 virus in cell culture. Next, using a preclinical model, they tested whether the virus could spread through contact. They discovered this variant was as transmissible as the wildtype virus without the mutations.
It is generally assumed that when a virus acquires drug-resistance mutations, it loses some of its fitness, meaning it may not replicate or transmit from person to person as well—this study shows that isn't the case. The authors will further investigate how mutations associated with therapeutics impact the virus's ability to thrive and spread.
This research highlights the importance of including cohorts of immunocompromised COVID-19 patients when evaluating the efficacy of antivirals. "When the virus has more time to evolve in a host who does not clear the infection early, therapeutic strategies will need to be reassessed," said the authors.
This work was funded in part by NIAID grant R01AI166791-01, by the Division of Intramural Research of the NIAID/NIH and the National Center for Advancing Translational Science of the NIH grant UL1TR002384.
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