Molnupiravir: Covid-19 drug may be creating new variants with distinctive mutations

The covid-19 drug molnupiravir works to stop the SARS-CoV-2 virus from growing and spreading, but can introduce mutations that may get passed on

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A drug used to treat covid-19 appears to be driving the evolution of the SARS-CoV-2 coronavirus, according to an analysis of the 15 million viruses sequenced around the world so far. The analysis found around 900 viruses with distinctive patterns of mutation that probably arose in people being treated with the drug molnupiravir. In at least a few cases, these viruses appear to have spread from the person being treated to others, but no variants of concern have any of these patterns.

“The signal is pretty clear and there aren’t variants of concern that have those signals,” says Theo Sanderson at the Francis Crick Institute in London.

Molnupiravir works by inducing so many mutations in RNA viruses, such as SARS-CoV-2, as they replicate in a person’s body that the viruses lose the ability to replicate and die out. But before the viruses are eliminated from a person’s body, there is a risk of them spreading to others.

A few biologists think the risk of these mutagenic drugs generating potentially dangerous new variants outweighs their benefits. Animal studies suggest molnupiravir might also cause DNA mutations in those taking it, which is why it isn’t given during pregnancy, or if a potential recipient is trying to get pregnant or is breastfeeding.

Despite these concerns, regulatory agencies in many countries, including the US and UK, have approved molnupiravir for treating covid-19.

Sanderson, who carried out the analysis with his colleagues, says there are several lines of evidence supporting their conclusions. For starters, molnupiravir induces distinct types of mutation in the genomes of RNA viruses.

In countries that began using the drug in 2022, there was a rise in the number of viruses with these distinctive changes. “These sequences were much more likely to be observed in countries that use molnupiravir and particularly in the countries that use the most molnupiravir,” says Sanderson.

What’s more, the team was able to check if the viruses sequenced in the UK came from people treated with the drug. They found that 31 per cent of variants with the distinctive pattern came from treated people, whereas just 0.04 per cent of the overall sequenced viruses came from treated individuals.

It is expected that molnupiravir will mutate the viruses in those being treated. The issue is whether those mutated viruses spread to other people. In most cases, the team couldn’t establish this. However, the researchers did identify a few clusters, including one in Australia, where there seemed to have been spread from person to person. “We provide some cases where that’s very clear,” says Sanderson.

Whether this could create dangerous new variants is unclear, he says. “Our data doesn’t say how likely that is, but it’s clearly something that needs consideration.”

“I think the most interesting question is: does treatment generate more new mutations in the population than non-treatment?” says Martin Nowak at Harvard University. In a study published last month, he and his colleagues estimated that the answer to this question is no.

A spokesperson for Merck, which makes molnupiravir, says that the study relies on circumstantial associations. “The authors assume these mutations were associated with viral spread from molnupiravir-treated patients without documented evidence of that transmission… Furthermore, these sequences were uncommon and were associated with sporadic cases.”

The Merck spokesperson pointed to a review by the US Food and Drug Administration (FDA) of Sanderson’s initial findings earlier this year. “While it is plausible that [molnupiravir] use could contribute to mutational patterns in SARS-CoV-2 sequences, there are some uncertainties…” an FDA memorandum states. “A causal relationship… has not yet been established.”

The memorandum also points out that the risk of treatments triggering the evolution of new variants isn’t limited to mutagenic drugs. Conventional drugs and antibodies put pressure on viruses to evolve to evade the treatment. The study “does not change the review team’s overall risk assessment”, the memorandum concludes.


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