Scientists detail link between molnupiravir and SARS-CoV-2 mutations

molnupiravir pile

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A new paper suggests scientists are worried about molnupiravir's capacity to trigger SARS-CoV-2 mutations, echoing concerns that were raised even before countries approved it for emergency use in late 2021 as the Omicron variant arrived on the scene.

Writing in Nature yesterday, a team of researchers from the United Kingdom and South Africa described mutations from samples in some patients who were treated with the drug. The team also found evidence that the mutated virus can transmit, though they said no variants of concern carry the mutation.

Persistent concerns about the drug's mechanism

Molnupiravir's antiviral activity stems from its ability to kill the virus by inducing mutations designed to take away its ability to replicate. As regulators weighed the risks and benefits of the drug during the emergency use approval process, they worried about whether the treatment could not only drive the arrival of new SARS-CoV-2 variants, but also trigger mutations in the cells of people who take the drug. Treatment guidelines recommend against using the drug in pregnant women unless no other options are available.

Authors of the Nature study described their findings in a January preprint, and other scientists have also raised concerns about whether the use of molnupiravir could trigger novel variants.

Still, with few oral treatment options available, several countries cleared molnupiravir for emergency use. Though the drug is thought to be less effective than Paxlovid, a recent study found that both drugs reduced COVID deaths and hospitalizations.

Mutation signature matched treatment pattern

For the Nature study, researchers used global sequencing databases to examine when mutations occurred in the SARS-CoV-2 evolution, finding mutations that were different than other mutations and were strongly linked to people who had been treated with molnupiravir. Those mutation events increased in 2022 at the same time countries started using the medication, especially in older people and in countries that frequently used the drug.

The mutational signature they identified closely matched the pattern seen during clinical trials of molnupiravir. Analyzing treatment data, the team found that at least 30% of viruses carrying the molnupiravir mutation signature were linked to use of the drug.

And worryingly, they saw clusters of mutations that suggest onward transmission of the virus.

A red flag about drugs with similar action

Theo Sanderson, PhD, lead author and postdoctoral researcher at the Francis Crick Institute, said in an institute news release that though it's important to develop drugs that help people clear the virus, evidence suggests that molnupiravir can increase genetic diversity of SARS-CoV-2.

"Our findings are useful for ongoing assessment of the risks and benefits of molnupiravir treatment. The possibility of persistent antiviral-induced mutations needs to be taken into account for the development of new drugs which work in a similar way," he said, adding that global collaboration on huge sequencing datasets sheds light on virus evolution that wouldn't be possible by looking at data from any one country.

Ryan Hisner, a study coauthor and graduate student at the University of Cape Town, said that evidence that the drug creates divergent viruses that can not only replicate but also transmit has unknown consequences for public health.

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

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