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SARS-CoV-2 Mutational Signature Associated With Mutagenic Antiviral Drug

NEW YORK – A team from the UK and South Africa has identified a mutational signature in SARS-CoV-2 sequences that appears to stem from exposure to the antiviral molnupiravir — a drug known for introducing rampant mutations in the genome as the virus replicates.

Molnupiravir "belongs to a class of drugs that can cause the virus to mutate so much that it is fatally weakened," senior and co-corresponding author Christopher Ruis, a researcher at the University of Cambridge, said in a statement.

"[W]hat we've found is that in some patients, this process doesn't kill all the viruses, and some mutated viruses can spread," Ruis explained. "This is important to take into account when assessing the overall benefits and risks of molnupiravir and similar drugs."

As they reported in Nature on Monday, the researchers used longitudinal genomic data, nucleotide transversion or transition patterns, and phylogenetic analyses to assess some 15 million SARS-CoV-2 sequences available in GISAID and other databases from around the world, comparing isolates from individuals who were or were not treated with molnupiravir.

The drug was approved in the UK and the US in late 2021 and is sold under the brand name Lagevrio, but it is not approved in Europe. Researchers had previously voiced their concern about its mutagenic effect on the virus, which could potentially result in new variants of concern.

The current study team tracked down a mutational signature marked by the introduction of new mutations well beyond the level linked to typical SARS-CoV-2 mutation patterns. They noted an uptick in the signature in 2022, particularly in isolates from older individuals from places where molnupiravir began to be used more routinely for high-risk COVID-19 cases.

"These results are very specific to a specific antiviral drug, molnupiravir, which works by inducing mutations in the virus," first and co-corresponding author Theo Sanderson, a postdoctoral researcher at the Francis Crick Institute, said in an email. "Our results show that molnupiravir treatment can sometimes result in viruses carrying significant numbers of mutations that are in some cases still fit enough to survive in the patient, and in some cases to be transmitted."

While the team's analyses highlighted apparent transmission clusters involving highly mutated viruses linked to treatment with the antiviral, the large sequence collection did not point to the presence of SARS-CoV-2 variants of concern stemming from a molnupiravir-associated mutational signature.

"Our findings show that molnupiravir creates genetically divergent viruses capable not only of replicating but transmitting, with unknown consequences for the global public," coauthor Ryan Hisner, a graduate student in bioinformatics at the University of Cape Town, said in a statement.

"This should have been of greater concern when molnupiravir was tested in clinical trials," Hisner suggested, "and now that we have this evidence, regulators need to be more proactive in monitoring virus sequencing databases for the effects of drugs that work by mutagenesis."