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Study Links Molnupiravir to SARS-CoV-2 Virus Mutations

An antiviral drug used to treat COVID-19 patients could be linked to mutations in the virus, new research suggests.

The medication, molnupiravir (Lagevrio, Merck Sharp & Dohme), works by causing mutations in the virus's genetic information, or genome. Many of these mutations will damage or kill the virus, reducing the amount of virus in the body.

Researchers say their findings are helpful in the ongoing assessment of the risks and benefits of molnupiravir treatment. Although the drug is not immediately dangerous to people taking it, the study may have i mportant implications for the future direction of the pandemic.

Molnupiravir was one of the first antivirals available during the COVID-19 pandemic and was widely adopted by many countries. Using global databases to map the virus mutations, the researchers found changes in the virus which looked very different from typical patterns of COVID mutations. According to the findings, published in Nature, the mutations were strongly associated with people who had taken molnupiravir.

Additionally, these mutations increased in 2022, coinciding with the introduction of molnupiravir.

Virus May be Fatally Weakened After Treatment but Not Killed

Christopher Ruis from the department of medicine at the University of Cambridge, said: "Molnupiravir is one of a number of drugs being used to fight COVID-19. It belongs to a class of drugs that can cause the virus to mutate so much that it is fatally weakened. But what we've found is that in some patients this process doesn't kill all the viruses, and some mutated viruses can spread.

"This is important to take into account when assessing the overall benefits and risks of molnupiravir and similar drugs."

The study, by researchers at the Francis Crick Institute, the University of Cambridge, Imperial College London, the University of Liverpool, the University of Cape Town, and the UK Health Security Agency (UKHSA), also found the mutations were more likely in older age groups consistent with the use of the antivirals to treat people who are more at risk.

In England, the researchers analysed treatment data and found that at least 30% of the events involved the use of molnupiravir.

Theo Sanderson, lead author and postdoctoral researcher at the Francis Crick Institute, said: "COVID-19 is still having a major effect on human health, and some people have difficulty clearing the virus, so it's important we develop drugs which aim to cut short the length of infection. But our evidence shows that a specific antiviral drug, molnupiravir, also results in new mutations, increasing the genetic diversity in the surviving viral population.

"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.

"Our work shows that the unprecedented size of post-pandemic sequence datasets, collaboratively built by thousands of researchers and healthcare workers around the world, creates huge power to reveal insights into virus evolution that would not be possible from analysis of data from any individual country."

The causes of mutational events can be traced by looking at their mutational signature – a preference for mutations to occur at particular points in the virus. There was a close match between the signature seen in these mutational events and the signature in clinical trials of molnupiravir, researchers said.

The researchers also saw signs of onward transmission from one person to another, although no established variants of concern are currently linked to this.

Findings of "Critical Value" for Antimicrobial Stewardship

According to the experts, it is also important to consider that chronic COVID infections, which molnupiravir is used for, can themselves result in new mutations. Stephen Griffin, professor of cancer virology at the University of Leeds, said: "This paper is an incredibly important, well-conducted piece of research. The findings are of critical value to our understanding of how the use of this specific antiviral drug could have been better implemented, but also reminds us of more general aspects of good practice and antimicrobial stewardship.

"It is worth noting that the use of this drug is not immediately dangerous to individuals taking it, but these findings have important implications for the future direction of the pandemic."

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