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

A widely used COVID-19 drug could lead to the emergence of new variants of SARS-CoV-2, raising concerns that it could prolong or even revive the pandemic. Merck & Co. The drug named molnupiravir, produced by the company, is designed to kill the virus by causing mutations in the viral genome. However, a study of viral genomes reported in a new preprint suggests that some people treated with the drug produce new viruses that not only stay alive but spread.

“It’s clear that viable mutant viruses can survive. [molnupiravir treatment] and competition [with existing variants]”I think we’re ready for disaster.” But a Merck spokesperson disputes that the drug has caused the emergence of widely circulating variants, and some researchers have downplayed the importance of molnupiravir-induced mutations. “Right now, there’s a lot of noise about nothing,” says Raymond Schinazi, a medicinal chemist at Emory University School of Medicine, noting that the virus naturally mutates at a fast clip as SARS-CoV-2 has infected millions of people worldwide. pulling.

Approved in the UK and United States in late 2021, molnupiravir became the first oral antiviral approved anywhere to fight COVID-19. It has since been authorized in dozens of other countries. In 2022, Merck estimates global sales of the compound at more than $5 billion. While this is well below the $18.9 billion sales of another oral SARS-CoV-2 antiviral, Paxlovid, in 2022, molnupiravir remains quite popular in some countries.

However, from the very beginning, Haseltine and others were concerned about the drug’s mechanism, which involved introducing so many mutations into the viral genome that it could no longer replicate. One of the concerns was that the drug could mutate not only the coronavirus but also the DNA of people who took it; this was an unprecedented side effect. Another was that the mutated virus would survive and spread, perhaps even more contagious or lethal than before. Before the U.S. Food and Drug Administration authorized the drug, a Merck spokesperson described the concern as an “interesting hypothetical concern.”

However, researchers and citizen scientists from around the world have begun scanning the SARS-CoV-2 genome sequences stored in the international GISAID database to look for the types of mutations that molnupiravir is expected to cause. The drug is more likely to cause specific nucleic acid substitutions, with guanine converting to adenine and cytosine to uracil, rather than causing random changes in the virus’s RNA genome.

Ryan Hisner, a virus hunter and a middle school science and math teacher in Monroe, Indiana, began cataloging suspicious variants in August 2022 and quickly identified dozens of sequences showing clusters of these distinctive substitutions. Hisner voiced his concerns with researchers on Twitter and eventually teamed up with Thomas Peacock, a virologist at Imperial College London. The duo, along with other colleagues, systematically examined more than 13 million SARS-CoV-2 sequences in GISAID and analyzed clusters containing more than 20 mutations. In a preprint published Jan. 27, they reported that a large subset showed trait substitutions; all from 2022 after molnupiravir became widely available.

These signature clusters, the researchers found, were up to 100 times more common in countries where molnupiravir was widely used, including the United States, Australia and the United Kingdom, than in countries where it was not used, such as France and Canada. Tracing the dates and locations of the sequences showed that some mutated strains were spreading in the community. “There’s obviously something going on here,” says Peacock.

It’s unclear whether the changes will lead to variants that are more pathogenic or infectious, the researchers say. “We don’t come to a conclusion on risk,” says team member Theo Sanderson, a geneticist at the Francis Crick Institute. However, Haseltine likens the danger to feeding a pet lion. “Just because it didn’t bite you yesterday doesn’t mean it won’t bite you today,” she says.

A spokesperson for Merck says the link between the mutations and the drug has not been proven. “There is no evidence that any antiviral agent contributes to the emergence of circulating variants,” he says. But the new result came just after two other results that could change the drug’s risk-benefit calculation.

In one, researchers in Australia found evidence that molnupiravir treatment can lead to new variants in immunocompromised patients. Because these patients’ immune systems have trouble clearing the virus, viral variants can accumulate large numbers of mutations, possibly causing huge jumps in viral behavior that can then be passed on to others. (The researchers speculated that Omicron and other SARS-CoV-2 variants evolved naturally in immunocompromised individuals.) By repeatedly sequencing the SARS-CoV-2 genomes of nine patients, five who received the drug and four did not, the researchers found that molnupiravir-treated individuals, baseline each harbored an average of 30 new variants within 10 days of dosing; this was much more than in untreated patients. “Our study shows that this widely used antiviral can ‘superload’ viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic,” the authors wrote in a preprint dated Dec. 22, 2022.

A second report, released on January 28, Lancetsuggests that molnupiravir provides limited benefits, at least among people vaccinated against COVID-19. The study followed 26,411 participants who were vaccinated in the PANORAMIC clinical trial in the UK, of which about half were given the drug. It reduced symptom severity and improved patient recovery times, but the researchers found that it did not reduce the frequency of COVID-19-related hospitalizations or deaths among high-risk adults.

Ravindra Gupta, a clinical microbiologist at the University of Cambridge, says new studies in the UK and Australia do not prove that molnupiravir causes dangerous new SARS-CoV-2 variants to emerge. But she argues that the drug’s limited benefit shows it’s no longer worth the risk. “Taken together, these results question whether molnupiravir should be used.”

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