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, which is also sold under the brand name Lagevrio, is designed to mutate coronavirus to destruction, but researchers found evidence that the virus can sometimes survive the treatment, leading to mutated versions that occasionally spread to other people.
There is no evidence molnupiravir has produced more dangerous variants of Covid, but scientists said the mutations increased the genetic diversity of the virus in the wild and provided more options for future evolution.
“People have some concerns about molnupiravir and to some sense this makes those more concrete,” said Dr Theo Sanderson, the lead author on the study and a postdoctoral researcher at the Francis Crick Institute in London. “We know these viruses can still be alive following a significant number of mutations and they can still be transmissible in some cases.”
The findings are important for continuing 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 numerous strands of evidence that suggest molnupiravir can occasionally produce highly mutated but viable forms of the Covid virus. The first sign emerged when the researchers scoured global databases that containing more than 15m Covid genomes. The scientists found hallmark mutations in viruses from 2022, after molnupiravir was introduced. When the drug mutates the virus’s RNA, it increases the proportion of specific mutations at certain regions of the genetic code.
As well as spotting signature mutations in Covid viruses obtained from patients, the scientists found that these were more common in countries that used the most molnupiravir, such as the UK, Australia, the US and Japan. Further analyses found the hallmark mutations were more common in Covid virus taken from older patients who awere more likely to be treated with the drug.
As a final piece of evidence, the scientists picked out a number of viral samples in England that bore the signature mutations of molnupiravir and asked the UK Health Security Agency which patients had been treated with the drug. Sanderson said: “That number was much higher than you’d expect by chance, which again suggests it’s due to molnupiravir.”
But the implications of the mutations were 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 transmitted very widely that’s due to molnupiravir.” Most mutations in the virus would be expected to weaken it rather than make it more dangerous.
One question scientists are keen to explore is whether drug-induced mutations explain an unusual finding in Oxford University’s Panoramic trial, which is investigating the effectiveness of Covid antivirals. While molnupiravir reduced levels of virus in the first week, levels appeared to rise again at two weeks. This could happen if the drug drives virus down but creates mutated versions that are better at evading patients’ immune defences.
The Panoramic trial found molnupiravir did not reduce the risk of hospitalisation or death among vaccinated, high-risk patients faced with the Omicron variant, but it did speed up recovery time.
Prof Chris Butler, a co-investigator on the trial, said it “may be very useful in speeding recovery among key workers, for example, during 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, and was not part of the study or the trial, said: “Does this mean we should stop using molnupiravir? Taking this new evidence together with evidence from the Panoramic trial, there is the suggestion that we should think about whether molnupiravir should be used on its own – but it shouldn’t be discarded and could still be valuable if we were to use it in drug combinations.”
MSD, the manufacturer of molnupiravir, said the drug impaired viral replication and reduced shedding, which in turn reduced the risk of transmission.
The company added: “The authors assume these mutations were associated with viral spread from molnupiravir-treated patients without documented evidence of that transmission,. Instead, the authors rely on circumstantial associations between the region from which the sequence was identified and timeframe of sequence collection in countries where molnupiravir is available to draw their conclusions.”
