Study finds remdesivir-resistant version of COVID-19 in kidney transplant recipients

Recent studies have shown that patients with weakened immune systems – which allows the virus responsible for COVID-19 to stay in the body longer, copy itself and continually change – may allow new, slightly different versions to develop. virus (variants) . These people include those who are treated with drugs that suppress the immune system to prevent it from rejecting a newly transplanted organ.

A new study by researchers at NYU Grossman School of Medicine and NYU Long Island School of Medicine shows that two kidney transplant recipients who were treated with immunosuppressive drugs and then had a long COVID-19 infection developed a version of the virus. with a genetic change (mutation) that made him resistant to the antiviral therapy remdesivir.

This treatment is among the first antiviral drugs approved for use in the pandemic and remains an important weapon against the pandemic coronavirus. Remdesivir is particularly important for people who have had a transplant because the more recently developed Paxlovid, a combination of nirmatrelvir and ritonavir, may interfere with immunosuppressants sometimes used for these patients, the study authors explain.

The study results reflect a standard problem in antiviral medicine, in which the rapid, error-prone reproductive process of viruses continuously creates slightly different genetic versions of themselves. Some randomly develop the qualities necessary to resist drug treatment. In the case of SARS-CoV-2, the pandemic virus, remdesivir is thought to work by interfering with the virus’s ability to create copies of itself through the action of a polymerase, a viral enzyme.

According to the results, the two people were initially infected with a version of the coronavirus that did not carry the mutation that confers resistance to remdesivir. However, after treatment with the antiviral agent, the virus developed the V7921 (V7921) RNA-dependent polymerase gene mutation, which has already been shown in the laboratory to make the virus more resistant to remdesivir.

Our findings may help explain how the coronavirus continues to develop resistance to treatment. It is possible that the antiviral treatment itself, combined with the patients’ weakened immune systems, caused the evolution of this concerning mutation. ยป

John I. Hogan, MD, Senior Author, Assistant Professor, Department of Medicine, NYU Langone Health

Despite the availability of vaccines and several drug therapies for COVID-19, experts say people with weakened immune systems, such as transplant patients and people with cancer or untreated HIV, remain at risk. high risk of contracting the disease. The new study, published online Sept. 26 in the journal Clinical infectious diseasesis the first to identify the remdesivir-resistant V7921 mutation in people who have undergone organ transplants and been treated with the antiviral drug, according to Dr. Hogan.

For the investigation, which was funded by NYU Langone, the study team took samples from the nostrils of two people, one in their 50s and the other in their 60s, who had each received a transplant. kidney disease and were using immunosuppressive drugs. Although they had been vaccinated against COVID-19 before the operation, the two developed symptoms of the disease, such as fatigue, cough and fever, which persisted for months.

The study team examined the genetic makeup of viral samples at NYU Langone’s Genome Technology Center by comparing small snippets of the genetic code to identify the mutations found in each strain. According to the researchers, these genetic flags offer similar results to tests used to trace people’s ancestry and for tracking other viral outbreaks, including influenza, HIV and Ebola.

According to the report, the two people were treated for COVID-19 with remdesivir but were readmitted to hospital several weeks later as their symptoms worsened again. They survived their illnesses.

However, when the researchers reanalyzed the viruses, they confirmed the presence of the V7921 mutation, which was not present before the transplant recipients received their remdesivir treatment.

“Our results underscore the importance of continuing to monitor the evolution of the coronavirus over time and of staying alert to genetic mutations that enable the virus to overcome efforts by the medical community to thwart it,” says Adriana Heguy. , PhD, lead study author and genomics. “In the future, physicians may also screen for such mutations before making treatment decisions for their most vulnerable patients,” adds Dr. Heguy, a professor in the Department of Pathology at NYU Langone.

Dr. Heguy adds that the emergence of treatment-resistant mutations may also necessitate the development of additional antiviral therapies or the development of combination drugs to control the infection. Similar approaches to antiviral treatment have led to success in the HIV epidemic.

Dr. Heguy, also director of the Genome Technology Center, says the study authors next plan to further explore the mutations that allow the coronavirus to evade vaccines and therapies. One avenue of interest is the spike protein, a structure used by the virus to latch onto the surface of human cells as a first step in infecting them. Notably, the monoclonal antibody treatments used to treat COVID-19 bind to this same spike protein to prevent the virus from attacking cells or making it more vulnerable to the body’s defenses.

Dr Heguy cautions that as a small case study, the survey offers a limited perspective on viral development.

Source:

Journal reference:

Hogan, J.L. et al. (2022) Remdesivir resistance in transplant recipients with persistent COVID-19. Clinical infectious diseases. doi.org/10.1093/cid/ciac769.

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