Researchers have discovered a link between the antiviral drug molnupiravir and specific mutations of the SARS-CoV-2 virus. While molenpiravir is used to induce mutations that weaken the virus, studies have found different patterns of mutations in people who have taken the drug. These variants are particularly prevalent in older populations and in areas where more monogravir is used.
A study has found a link between the antiviral drug monogravir and different SARS-CoV-2 variants, underscoring the need for careful evaluation during drug development.
Researchers from 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) have discovered a link between an antiviral drug called molnupiravir, used to treat COVID-19 infections, and the mutation patterns of the SARS-CoV-2 virus.
The principle of action of monogravir is to induce mutations in the genetic information or genome of the virus during the virus replication process. Many of these mutations destroy or kill the virus, thereby reducing the viral load in the body. It was one of the first antiviral drugs to hit the market during the COVID-19 pandemic and was widely adopted in many countries.
In research published today (September 25) in the journal Nature, scientists used global sequencing databases to map the mutations of the SARS-CoV-2 virus over time. They analyzed a family tree consisting of 15 million SARS-CoV-2 viral sequences, allowing them to see which mutations occurred at each stage in the evolutionary history of each virus.
Unusual mutation patterns
Although the virus is mutating all the time, researchers in global sequencing databases have discovered mutation events that are completely different from the typical patterns of COVID-19 mutations, and these mutation events are closely related to individuals who have taken morenpivir.
These mutations increased in 2022, coinciding with the introduction of monogravir. These mutations are also more likely to appear in older people, consistent with the use of antiviral drugs to treat high-risk groups and with countries known to have higher rates of molnupiravir use. In the UK, researchers analyzed treatment data and found that at least 30% of events were related to the use of monogravir.
Comparison of the global sequencing database with known datasets of patients treated with monogravir showed identical mutation patterns (C to T and G to A mutations). Image credit: Theo Sanderson, Nature (2023).
The cause of a mutation event can be traced by observing its "mutation signature": a preference for mutations to occur at specific sequences in the genome. The researchers found that the characteristics emerging from these mutational events closely matched those seen in clinical trials of molnupiravir.
The researchers also found some small clusters of variants, suggesting the variant can be passed from one person to another, although no variants of concern have been found to be linked to the trait.
Impact and expert insights
It is difficult to understand the impact of molnupiravir treatment on the risk of new variants and any impact it may have on public health. It is also important to consider that chronic COVID-19 infection, which molnupiravir is used to treat, can itself lead to new variants.
"COVID-19 is still having a major impact on human health, and some people have difficulty clearing the virus, so we must develop drugs aimed at shortening the duration of infection," said Theo Sanderson, first author of the paper and a postdoctoral researcher at the Francis Crick Institute. "But our evidence shows that one particular antiviral drug - molnupiravir - can also cause new mutations and increase the genetic diversity of the surviving virus population."
"Our findings contribute to the ongoing assessment of the risks and benefits of molnupiravir treatment. The possibility of persistence of antiviral-induced variants needs to be taken into account when developing new drugs that work in a similar way. Our work shows that the unprecedented scale of post-pandemic sequence datasets, built collaboratively by thousands of researchers and healthcare workers around the world, has enormous power to reveal truths about viral evolution that would not be possible by analyzing data from any one country."
Christopher Ruiz, from the Department of Medicine at the University of Cambridge, said: "Monoravir is one of a number of drugs used to fight COVID-19. It belongs to a class of drugs that can cause the virus to mutate severely, making it fatally weakened. But we found that in some patients, this process did not kill all the virus and some mutated viruses spread. This must be taken into account when assessing the overall benefits and risks of molnupiravir and similar drugs."