An antiviral drug used to treat patients with Covid-19 may be causing mutations in the virus and fuelling the evolution of new variants, scientists have said.
Molnupiravir, also sold under the brand name Lagevrio, is designed to mutate the coronavirus to destroy it, but researchers have found evidence that the virus can sometimes survive treatment, leading to mutated versions that occasionally spread to other people.
There is no evidence that molnupiravir has produced more dangerous variants of Covid, but scientists said the mutations have increased the genetic diversity of the virus in the wild and provided more options for future evolution.
“People have some concerns about molnupiravir and in some ways this makes them more concrete,” said Dr Theo Sanderson, the lead author of the study and a postdoctoral researcher at the Francis Crick Institute in London. “We know that these viruses can still be alive after a significant number of mutations, and in some cases they can still be transmissible.”
The findings are important for ongoing assessments of the risks and benefits of molnupiravir and other drugs in development that work in a similar way, the researchers say.
Writing in the journal Nature, the scientists describe several lines of evidence suggesting that molnupiravir can occasionally produce highly mutated but viable forms of the Covid virus. The first clue came when the researchers scoured global databases containing more than 15 million Covid genomes. The scientists found characteristic mutations in viruses from 2022, after the introduction of molnupiravir. As the drug mutates the virus’s RNA, it increases the proportion of specific mutations in certain regions of the genetic code.
The scientists not only identified the signature mutations in Covid viruses from patients, but also found that they were more common in countries where molnupiravir was most commonly used, such as the UK, Australia, the US and Japan. Further analysis showed that the hallmark mutations were more common in Covid viruses taken from older patients, who were more likely to be treated with the drug.
As a final piece of evidence, the scientists selected a number of virus samples in the UK that carried the signature mutations of molnupiravir and asked the UK Health Security Agency which patients had been treated with the drug. Sanderson said: “The number was much higher than you’d expect by chance, which again suggests it’s due to molnupiravir.”
But the implications of the mutations are still unclear, he added. “The signature is very clear, but there aren’t any widely circulating variants that have the signature. At the moment, there’s nothing that’s widely transmitted that’s caused by molnupiravir. Most mutations in the virus would be expected to weaken it rather than make it more dangerous.
One question that scientists are keen to explore is whether drug-induced mutations explain an unusual finding in the Oxford University Panoramic trial, which is investigating the effectiveness of the Covid antivirals. While molnupiravir reduced virus levels in the first week, levels seemed to rise again after two weeks. This could happen if the drug reduces the virus but creates mutated versions that are better able to evade the patient’s immune system.
The Panoramic trial found that molnupiravir did not reduce the risk of hospitalisation or death in vaccinated high-risk patients facing the omicron variant, but it did speed up recovery time.
Professor Chris Butler, a co-investigator on the trial, said: “This could be very useful for speeding up recovery in key populations, for example at times of high pressure on services. Molnupiravir may be very useful in certain contexts, but should definitely not be used as a ‘treat all’ approach.
Stephen Griffin, Professor of Cancer Virology at the University of Leeds, who was not involved in the study or the trial, said: “Does this mean we should stop using molnupiravir? Taking this new evidence together with the evidence from the Panoramic trial, it suggests that we should think about using molnupiravir alone – but it shouldn’t be discarded and could still be valuable if we used it in drug combinations”.
MSD, which makes molnupiravir, said the drug interferes with viral replication and reduces shedding, which in turn reduces the risk of transmission.
The company added: “The authors assume that these mutations are associated with viral spread from molnupiravir-treated patients without documented evidence of such transmission. Instead, the authors rely on circumstantial associations between the region from which the sequence was identified and the timeframe of sequence collection in countries where molnupiravir is available to draw their conclusions.”
