COVID drug molnupiravir appears to be driving SARS-CoV-2 to mutate and evolve

Molnupiravir, an antiviral drug used to treat patients with COVID-19, appears to be driving SARS-CoV-2 to mutate and evolve, with a few of these recent viruses being transmitted onwards, a brand new study has shown. It will not be clear, nonetheless, whether these mutated viruses pose an increased risk to patients or are in a position to evade the vaccine.

The drug works by disrupting the virus’s genome, causing it to develop random mutations because it replicates, weakening the virus to stop replication, thereby enabling clearance of infection.

But in research published today in Nature, scientists have shown that in some cases, mutated types of the virus have been in a position to be transmitted from patients treated with molnupiravir and spread inside the community.

Molnupiravir is considered one of a variety of drugs getting used to fight COVID-19. It belongs to a category of medicine that could cause the virus to mutate a lot that it’s fatally weakened. But what we have found is that in some patients, this process doesn’t kill all of the viruses, and a few mutated viruses can spread. This is very important to have in mind when assessing the general advantages and risks of molnupiravir and similar drugs.”

Dr Christopher Ruis, Department of Medicine, University of Cambridge

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

Within the body, molnupiravir is converted right into a molecule that disrupts the genome of the SARS-CoV-2 virus, introducing some nucleotide mutations in its RNA – randomly changing some Cs to Ts and a few Gs to As. These changes mean that because the virus replicates, its progeny get weaker, reducing how quickly the virus is in a position to replicate and ridding the body of the virus.

Nonetheless, concern has been expressed that in some cases, a variety of mutated viruses will not be killed off quickly enough and so are in a position to infect other individuals, potentially allowing recent mutated viruses to spread.

Through the COVID-19 pandemic, a variety of countries – spearheaded by the Cambridge-led COVID-19 Genomics UK Consortium – sequenced virus samples, depositing the knowledge in databases equivalent to the Global Initiative on Sharing All Influenza Data (GISAID) and the International Nucleotide Sequence Database Collaboration (INSDC). This allowed scientists and public health agencies to trace the evolution and spread of the virus, and particularly to look out for so-called ‘variants of concern’ – versions of the virus with mutations that may make them more transmissible, more lethal, or in a position to evade the immune system of vaccinated individuals, equivalent to the Delta and Omicron variants.

A team of researchers from the UK and South Africa noticed a variety of viral genomes that contained numerous mutations, particularly where Cs had modified to Ts and Gs to As. While C-to-T mutations are relatively common overall in SARS-CoV-2 evolution, G-to-A mutations occur much less regularly, and a better proportion of G-to-A mutations is related to molnupiravir treatment.

The team then analyzed a family tree of greater than 15 million SARS-CoV-2 sequences within the GISAID and INSDC databases searching for which mutations had occurred at each point within the virus’s evolutionary history. They found that viruses with this signature of mutations had begun to emerge almost exclusively from 2022 onwards and in countries and age groups where molnupiravir was being widely used to treat COVID-19.

To substantiate the link, the researchers examined treatment records in England and located that a minimum of one in three of viruses showing the mutational signature involved the usage of molnupiravir.

The researchers also saw small clusters of patients infected with mutated viruses, which suggests that these recent viruses were being passed from one person to a different. Nonetheless, not one of the known variants of concern has to date been linked to the usage of molnupiravir.

Dr Theo Sanderson from the Francis Crick Institute, said: “COVID-19 remains to be having a significant effect on human health, and a few people have difficulty clearing the virus, so it is vital we develop drugs which aim to chop short the length of infection. But our evidence shows that a selected antiviral drug, molnupiravir, also ends in recent mutations, increasing the genetic diversity within the surviving viral population.

“Our findings are useful for ongoing assessment of the risks and advantages of molnupiravir treatment. The potential for persistent antiviral-induced mutations must be taken under consideration for the event of recent drugs which work in an analogous way.”

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