Anti-COVID drug may have led to virus mutations: study

An anti-COVID drug widely used across the world may have caused mutations in the virus, researchers said on Monday, but there was no evidence that the changes had led to more dangerous variants.

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.

Molnupiravir

Pharmaceutical giant Merck's antiviral pill molnupiravir was one of the earliest treatments rolled out during the pandemic to prevent COVID becoming more severe in vulnerable people.

The drug, which is taken orally over a five-day course, works mainly by creating mutations in the virus with the goal of weakening and killing it.

However, a new UK-led study has shown that molnupiravir "can give rise to significantly mutated viruses which remain viable," lead author Theo Sanderson told AFP.

Sanderson, a geneticist at London's Francis Crick Institute, emphasized that there is no evidence that "molnupiravir has to date created more transmissible or more virulent viruses."

None of the variants that have swept the world were due to the drug, he added.

This signature was more commonly found in countries where the drug was widely prescribed, such as the United States, UK, Australia and Japan. But in countries where it was not approved, including Canada and France, it was rarer.

Sales of molnupiravir, sold under the brand name Lagevrio, topped $20 billion last year. However sales fell 82 percent in the second quarter of 2023 compared to the same period last year, according to Merck.

Merck's statement

Merck refuted the study, saying the researchers had relied on "circumstantial associations" between where and when the sequences were taken.

"The authors assume these mutations were associated with viral spread from molnupiravir-treated patients without documented evidence of that transmission," Merck said in a statement sent to AFP.

Sanderson rebuffed this claim, saying the researchers had used "several independent lines of evidence to identify with confidence that molnupiravir drives this mutational signature".

Experts not involved in the study seemed to side with the British researchers

Stephen Griffin, a virologist at the UK's University of Leeds, said it was an "incredibly important, well-conducted piece of research".

Jonathan Ball, a virologist at the University of Nottingham, said the research showed a "strong link" between molnupiravir and the occasional, limited spread of highly mutated genomes.

"What isn't clear is if any of the transmitted viruses contained mutations which would change how they would behave—for example if they were more or less transmissible, more pathogenic or less susceptible to our immunity," he added.

In research published in Nature today, the scientists used global sequencing databases to map mutations in the SARS-CoV-2 virus over time. They analysed a family tree of 15 million SARS-CoV-2 sequences so that at each point in each virus’s evolutionary history they could see which mutations had occurred.

Ryan Hisner, graduate student in bioinformatics at the University of Cape Town, said: “Our findings show that molnupiravir creates genetically divergent viruses capable not only of replicating but transmitting, with unknown consequences for the global public. This should have been of greater concern when molnupiravir was tested in clinical trials, and now that we have this evidence, regulators need to be proactive in monitoring virus sequencing databases for the effects of drugs that work by mutagenesis."

Sanderson, T., Hisner, R., Donovan-Banfield, I. et al. A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature (2023)