Antiviral drug molnupiravir is linked to new mutations in SARS-CoV-2

Molnupiravir, an antiviral drug used to treat patients with COVID-19, appears to drive the mutation and evolution of SARS-CoV-2, with further transmission of some of these new viruses, a new study has shown. However, it is not clear whether these mutated viruses pose an increased risk to patients or can evade the vaccine.

The drug works by disrupting the virus's genome, causing it to develop random mutations as it replicates, weakening the virus to prevent replication and thus allowing the infection to be cleared.

But in research published today in Nature, scientists have shown that in some cases, mutated forms of the virus could be transmitted by patients treated with molnupiravir and spread within the community.

Dr. Christopher Ruis, from the Department of Medicine at the University of Cambridge, said: “Molnupiravir is one of several drugs used to combat COVID-19. It belongs to a class of drugs that can cause the virus to mutate so severely that it…” However, we have found that in some patients this process does not kill all viruses and some mutated viruses can spread. This should be taken into account when evaluating the overall benefits and risks of molnupiravir and similar medications.

Molnupiravir, marketed under the brand name Lagevrio, is approved for the treatment of COVID-19 in several countries, including the UK, US and Japan. It has been used to treat the disease since late 2021.

In the body, molnupiravir is converted into a molecule that destroys the genome of the SARS-CoV-2 virus and introduces some nucleotide mutations in its RNA – randomly turning some Cs into Ts and some Gs into As. These changes mean that as the virus replicates, its offspring become weaker, reducing the virus's ability to replicate and ridding the body of the virus.

However, concerns have been raised that in some cases a number of mutated viruses may not be killed quickly enough and may therefore infect other people, potentially allowing new mutated viruses to spread.

During the COVID-19 pandemic, a number of countries – led by the Cambridge-led COVID-19 Genomics UK Consortium – have sequenced virus samples and deposited the information in databases such as the Global Initiative on Sharing All Influenza Data (GISAID) and the International Nucleotide Sequence Database Collaboration (INSDC). This allowed scientists and health authorities to track the evolution and spread of the virus and, in particular, to keep an eye out for so-called “variants of concern” – versions of the virus with mutations that may make them more transmissible, more deadly or more capable of being more immune to the immune system people, such as the Delta and Omicron variants.

A team of researchers from the UK and South Africa noticed a number of viral genomes that contained large numbers of mutations, particularly where Cs had changed to Ts and Gs had changed to As. While C-to-T mutations are relatively common in SARS-CoV-2 evolution overall, G-to-A mutations occur much less frequently and a higher proportion of G-to-A mutations are associated with treatment Molnupiravir linked.

The team then analyzed a family tree of more than 15 million SARS-CoV-2 sequences in the GISAID and INSDC databases, looking for mutations that had occurred at what point in the virus's evolutionary history. They found that as of 2022, viruses with this mutation signature appeared almost exclusively in countries and age groups where molnupiravir was commonly used to treat COVID-19.

To confirm the link, researchers examined treatment records in England and found that at least one in three viruses that had the mutation signature was linked to molnupiravir use.

Researchers also saw small groups of patients infected with mutated viruses, suggesting that these new viruses were transmitted from one person to another. However, to date, none of the known variants of concern have been associated with molnupiravir use.

Dr. Theo Sanderson, from the Francis Crick Institute, said: “COVID-19 is still having a major impact on human health and some people are struggling to fight the virus. Therefore, it is important that we develop drugs aimed at shortening the duration of infection.” However, our evidence shows that a particular antiviral drug, molnupiravir, also leads to new mutations and increases genetic diversity in the surviving virus population.

“Our results are useful for the ongoing assessment of the risks and benefits of treatment with molnupiravir. The possibility of persistent antiviral mutations must be taken into account when developing new drugs that work in a similar manner.”

The research was funded by Wellcome, Cancer Research UK, the Medical Research Council, the National Institute for Health and Care Research, the Fondation Botnar, the UK Cystic Fibrosis Trust and the Oxford Martin School.