Recent studies have shown that patients with weakened immune systems—which enable the virus that causes COVID-19 to stay in the body longer, copy itself, and constantly change—may enable them to develop new, slightly different versions of the virus (variants). These patients include those who have been treated with drugs that suppress the immune system to prevent it from rejecting the newly transplanted organ.
A new study, led by researchers at New York University School of Medicine and NYU Long Island School of Medicine, shows that two kidney transplant patients treated with immunosuppressive drugs who later developed a prolonged infection with COVID-19 developed a version of the virus with a genetic change (mutation). ) made her resistant to the antiviral treatment Remsvir.
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 treating transplant recipients because the recently developed Paxlovid (a combination of nirmatrelvir and ritonavir) can interfere with immunosuppressants sometimes used in these patients, the study authors say.
The study findings reflect a standard problem in antiviral medicine, in which the rapid, error-prone process of replication of viruses creates slightly different genetic copies of themselves. Some randomly develop the traits needed 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 make copies of itself through the action of polymerase, a viral enzyme.
According to the results, both patients initially contracted a version of the coronavirus that did not carry the mutation that provides resistance to remdesivir. However, after treatment with the antiviral agent, the virus developed a V7921 RNA polymerase-dependent gene mutation, which was previously shown in laboratory settings to make the virus more resistant to remdesivir.
“Our results may help explain how the coronavirus continues to develop resistance to treatment,” says lead study author John Hogan, assistant professor in the department of medicine at NYU Langone Health. “It is possible that the antiviral therapy itself, along with the patients’ weakened immune systems, may have driven the development of this related mutation.”
Despite the availability of vaccines and many drug treatments for COVID-19, experts say that people with weakened immune systems, such as transplant patients and those with cancer or untreated HIV, remain at high risk of contracting the disease. The new study, published online September 26 in the journal Clinical Infectious Diseases, is the first to identify the remdesivir-resistant V7921 mutation in transplant patients treated with the antiviral drug, according to Hogan.
For the investigation, which was funded by New York University Langone, the study team collected nose samples from two patients in their 50s and 60s who had undergone a kidney transplant and were using immunosuppressive drugs. Despite being vaccinated against COVID-19 before the surgery, they both developed symptoms of illness, such as fatigue, cough and fever, that persisted for several months.
The study team examined the genetic makeup of viral samples at New York University’s Langone Genome Center by comparing small snippets of letter-like genetic code to identify the mutations present in each strain. The researchers say these genetic markers provide results similar to those obtained from tests used to trace people’s ancestors and track other viral outbreaks, including influenza, HIV and Ebola.
According to the report, both patients were treated for COVID-19 with remdesivir but were hospitalized several weeks later where 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 transplant recipients received remdesivir treatment.
“Our findings highlight the importance of continuing to monitor how the coronavirus has changed over time and to continue the search for genetic mutations that allow the virus to outsmart the medical community’s efforts to thwart it,” says study author and genomics expert Adriana Heguy, PhD. “In the future, clinicians may also screen for such mutations before making treatment decisions for their most vulnerable patients,” adds Heggy, a professor in the department of pathology at NYU Langone.
Heggy adds that the emergence of treatment-resistant mutations may also require the development of additional antiviral therapies or the development of combination drugs to control the infection. Similar approaches to antiretroviral therapy have led to success in the HIV epidemic.
Heggy, director of the Center for Genome Technology at NYU Langone, says the study authors’ next plan is to continue exploring mutations that allow the coronavirus’ ability to escape vaccines and treatments. One avenue of interest is the spike protein, a structure the virus uses to attach to the surface of human cells as a first step in infecting them. Notably, the monoclonal antibody therapies used to treat COVID-19 bind to this same thorny protein in order to prevent the virus from attacking cells or making them more vulnerable to the body’s defenses.
Heggy cautions that as a small case study, the investigation offers a limited perspective on viral evolution.
In addition to Hogan and Heggy, other New York University researchers involved in the study were Ralph Doerr, MD, PhD. Dacia DiMartino, Ph.D.; Christian Marier; Sarah Hochman, MD; Sapna Mehta, MD; and Guiqing Wang, MD.
from San Jose News Bulletin https://sjnewsbulletin.com/remdesivir-resistant-version-of-covid-detected-in-transplant-recipients/
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