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Could a popular COVID-19 antiviral supercharge the pandemic? | Science

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Concerns that widely used COVID-19 drugs may be driving the emergence of new SARS-CoV-2 variants that could prolong and even reactivate the pandemic is causing The drug molnupiravir, manufactured by Merck & Co., is designed to kill viruses by mutating the viral genome. However, a survey of the viral genome reported in a new preprint suggests that some people treated with the drug produce new viruses that not only survive but spread.

“It’s very clear that viable mutant viruses can survive. [molnupiravir treatment] and compete [with existing variants]”I think we’re asking for disaster,” said virologist William Haseltine, president of ACCESS Health International, who has repeatedly voiced concerns about the drug. , disputes that the drug has led to the emergence of widely distributed variants, and some researchers downplay the significance of the mutations caused by mornupiravir.Emory University School of Medicine. “Right now, we’re making a fuss about nothing,” said Raymond Skinazi, a medical chemist at We note that viruses mutate rapidly in nature.

Mornupiravir, approved in the UK and US in late 2021, is the first oral antiviral drug approved to combat COVID-19. It has since been licensed in dozens of other countries. In 2022, Merck estimates global sales for this compound at more than $5 billion. This is well below his $18.9 billion 2022 sales for Paxlovid, another oral SARS-CoV-2 antiviral, but molnupiravir remains widely popular in certain countries.

However, from the outset, Haseltine and colleagues were concerned about the drug’s mechanism of introducing so many mutations into the viral genome that it could no longer replicate. It could mutate the DNA of people who were given it. This is a previously unseen side effect. Another is that the mutated virus can survive, multiply, and possibly become more contagious and virulent than before. A spokesperson called the concern an “interesting hypothetical concern.”

Nevertheless, researchers and citizen scientists around the world have begun scanning the SARS-CoV-2 genome sequences registered in the international GISAID database, looking for the type of mutations expected to be caused by molnupiravir. Rather than induce random changes in the viral RNA genome, the drug likely causes specific nucleic acid substitutions, switching guanine to adenine and cytosine to uracil.

Ryan Hisner, one of the virus hunters and a middle school science and math teacher in Monroe, Indiana, began cataloging suspected variants in August 2022, with dozens representing these characteristic clusters of substitutions. quickly identified a sequence of Hisner expressed his concerns to researchers on his Twitter, and eventually he teamed up with Thomas Peacock, a virologist at Imperial College London. The pair, along with other colleagues at GISAID, systematically reviewed over 13 million SARS-CoV-2 sequences, analyzing sequences with clusters of over 20 mutations. In a preprint posted on January 27, they report: A large subset showed characteristic substitutionsboth are from 2022, after molnupiravir began to be widely used.

These distinctive clusters, the researchers found, are up to 100 times more common in countries where molnupiravir is widely used (such as the US, Australia and the UK) than in countries where it is not, such as France and Canada. bottom. Tracking the date and location of the sequences showed that some of the mutant strains had spread to the community. “Clearly something is going on here,” says Peacock.

It is unclear whether this change leads to more pathogenic or contagious variants, researchers said. “We don’t draw conclusions about risk,” says Theo Sanderson, a geneticist and team member at the Francis Crick Institute. But Haseltine likens the danger to having a pet lion. “Just because he didn’t bite yesterday doesn’t mean he won’t bite today,” he says.

A Merck spokeswoman said no link between the mutation and the drug has been proven. However, this new result follows two of her other findings that may change the risk-benefit calculation for this drug.

For one, Australian researchers have found evidence that molnupiravir treatment may lead to new variants in immunocompromised patients. Mutants in can accumulate a large number of mutations, causing large leaps in the behavior of the virus, which can then infect others. We speculate that the variants evolved naturally in immunocompromised people.) We repeatedly sequenced the SARS-CoV-2 genome from 9 patients, 5 of whom were drugged and 4 of whom were not. I didn’t receive it. Each treated patient carried an average of 30 new variants within 10 days of his first dose, far more than untreated patients. This commonly used antiviral drug can ‘supercharge’ viral evolution in immunocompromised patientscould generate new variants and prolong the pandemic,” the authors wrote in a December 22, 2022 preprint.

A second report appeared on January 28 lancetat least among people vaccinated against COVID-19, Mornupiravir benefits are limitedThe study followed 26,411 vaccinated participants in the UK PANORAMIC clinical trial, about half of whom received the drug. Although it reduced the severity of symptoms and improved patient recovery times, researchers found it did not reduce the frequency of COVID-19-related hospitalizations or deaths in high-risk adults.

Ravindra Gupta, a clinical microbiologist at the University of Cambridge, says new British and Australian studies do not prove that molnupiravir is causing the emergence of dangerous new SARS-CoV-2 variants. But he argues that the drug’s limited benefits suggest it’s no longer worth the risk. increase.”

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