Individuals with weakened immune systems and ongoing COVID-19 infections can carry drug-resistant variants of the SARS-CoV-2 virus, which could pose a risk to the wider community, according to researchers from Weill Cornell Medicine, the College of Veterinary Medicine at Cornell University, and the National Institute of Allergy and Infectious Diseases (NIAID).
A team of researchers from 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) has found that individuals with weak immune systems and ongoing COVID-19 infections can carry drug-resistant strains of the SARS-CoV-2 virus, which might spread to the general population.
A study published on September 18 in Nature Communications documented the isolation of drug-resistant SARS-CoV-2 strains from patients who had not cleared the virus after two to three months of infection and treatment with antiviral medications.
One specific variant demonstrated resistance to the antiviral medications Paxlovid and remdesivir, while another strain exhibited mutations linked to reduced sensitivity to remdesivir and a third antiviral treatment, the monoclonal antibody sotrovimab.
“Emerging mutations could lead to the transmission of these new resistant variants to the general public, which would present fewer effective treatment options,” explained Dr. Mirella Salvatore, one of the study’s co-senior authors and an associate professor of medicine at Weill Cornell Medicine as well as an infectious disease physician at NewYork-Presbyterian/Weill Cornell Medical Center. “We need to develop improved treatments for immunocompromised patients and explore combining different therapies.”
Dr. Elodie Ghedin, a senior investigator and head of the Systems Genomics Section at NIAID, is also a co-senior author of the study. Co-first authors include Dr. Mohammed Nooruzzaman, a research associate at Cornell University’s Diel Lab, and Katherine Johnson, a senior bioanalyst contractor at NIAID.
Challenges in Managing Persistent COVID Infections
While individuals with functional immune systems can typically eliminate SARS-CoV-2 in just a few days, those with compromised immunity might continue to harbor and spread the virus for extended periods, often without exhibiting symptoms. These individuals frequently go through several antiviral treatments over time, leading to the development of drug-resistant variants.
To investigate the emergence of antiviral drug resistance, the researchers examined 15 individuals with compromised immune systems who were treated with remdesivir and, in some cases, nirmatrelvir-ritonavir (Paxlovid). They discovered that nine patients had developed viral variants with mutations in the nsp12 protein targeted by remdesivir, while four harbored viruses with mutations in the nsp5 protein targeted by Paxlovid. These mutations allowed the virus to persist despite standard antiviral treatments.
One patient exhibited a virus resistant to both medications. “For the first time, we isolated a virus from a patient’s nose 77 days after the onset of symptoms that showed resistance to both Paxlovid and remdesivir,” stated Dr. Salvatore. “It is concerning that some of these patients may still have viable virus present in their nasal secretions long after contracting the disease.”
The Potential of Combination Therapies
The researchers found that when they cultured the isolated virus in laboratory cell models, using two drugs together was effective in eliminating the drug-resistant strain. “These findings suggest that combination therapy might provide a more effective treatment option for COVID-19 in highly vulnerable immunocompromised patients,” said Dr. Diego Diel, co-senior author and associate professor of population medicine and diagnostic sciences at the College of Veterinary Medicine at Cornell University.
The resistant strain was found to replicate as effectively as the original SARS-CoV-2 virus in cell cultures. In subsequent preclinical tests, the researchers assessed the variant’s ability to spread through contact and found it was just as transmissible as the wildtype virus, even without the mutations.
Typically, it is believed that when a virus develops drug-resistance mutations, it loses some ability to replicate or spread. This study indicates that is not the case. The authors intend to further explore how mutations related to therapies affect the virus’s capacity to grow and transmit.
This study underscores the necessity of including immunocompromised COVID-19 patients in evaluations of antiviral efficacy. “When a virus is allowed more time to evolve in a host that does not clear the infection quickly, therapeutic strategies will need reevaluation,” concluded the authors.
This research received partial funding from NIAID grant R01AI166791-01, the Division of Intramural Research at NIAID/NIH, and the National Center for Advancing Translational Science at NIH under grant UL1TR002384.
