A Mutagenic Mess?

Molnupiravir is an antiviral medication that induces mutations in the viral genome during replication. Although most of the mutations that arise are deleterious to the virus, there is a risk that patients who are treated with the drug and do not fully clear the infection may contribute to onward transmission of molnupiravir-mutated viruses.

To investigate this further, an international team of researchers have searched SARS-CoV-2 sequencing databases to find traces of mutations associated with the drug (1). After molnupiravir was rolled out in 2022, patterns of molnupiravir-induced mutations emerged in countries where the drug was authorized and in age-groups that were treated with it. “The fact that we can detect this signature in deposited sequences means that, in some cases, molnupiravir treatment can give rise to extensively mutated viruses that remain viable – and clusters of sequences indicated that it can sometimes be transmissible,” says Theo Sanderson, lead researcher on the study.

Going into the study, Sanderon says that the team didn’t expect to be able to see such a strong signature of the drug in the consensus sequences. “I didn’t anticipate that molnupiravir use would lead to sequences with large numbers of mutations that were still viable enough to reach sequencing databases,” he says. “It was also striking that, in some countries, a high proportion of the largest mutational events were due to molnupiravir treatment.”

Sanderson notes there are no clear implications for patients at this point; however, the findings will be “useful for regulators who need to weigh the potential benefits of drugs against their risks.” In terms of guiding development of future mutagenic agents as antivirals, he says, “Our study suggests that agents that work purely through mutation – rather than causing chain termination during replication – may not be ideal as antivirals.”

Scientists have previously argued the potential risks of treating patients with molnupiravir because of its mechanism of action, but recent research suggests the evolutionary safety of the treatment, particularly for patients with low clearance rates (2). Nevertheless, Sanderson’s team is continuing to monitor molnupiravir-induced mutations and their transmissibility.