COVID drug is driving viral mutations – and now some want to stop using it

A drug widely used to treat COVID-19 could drive the evolution of new SARS-CoV-2 variants.

The drug, molnupiravir, works by introducing a wave of mutations into the viral genome; this helps clear infections. But a study¹ of more than 13 million SARS-CoV-2 sequences has uncovered sequences bearing the fingerprints of molnupiravir. The study authors say the results suggest that treatment with molnupiravir has caused the evolution of viral lineages carrying numerous mutations that, in at least some cases, have the ability to spread to other individuals.

The study was posted to the medRxiv preprint server in January. It has not yet been peer reviewed.

“Whether this should be a concern — that’s an open question,” said Jesse Bloom, an evolutionary virologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Mutations in the SARS-CoV-2 genome may help the virus evade immunity and become more transmissible, but most mutations are likely to harm it.

Molecular mimicry

Molnupiravir was developed by pharmaceutical giant Merck, based in Rahway, New Jersey, and was approved by regulators in the United States and United Kingdom in late 2021, and in Australia in early 2022. A company-sponsored clinical trial found that the drug — a pill taken for five days — reduced hospitalizations and deaths in people at risk of severe COVID-19.

Molnupiravir mimics some of the building blocks of RNA, the genetic material in SARS-CoV-2. The drug peppers the viral genome with mutations that make SARS-CoV-2 less likely to replicate. This results in a marked reduction in SARS-CoV-2 levels in infected human cells and hamsters².

But scientists have raised the possibility that, in rare cases, treatment with molnupiravir may not completely eliminate SARS-CoV-2, leaving some individuals who have taken the drug to continue to transmit the virus.

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Those concerns were largely theoretical until Ryan Hisner, an American schoolteacher who is part of a loose community of SARS-CoV-2 variant spotters, began noticing peculiar patterns in the ranking of data from around the world: a number of genera carried many more mutations. than their closest relatives. Most of the genetic changes were of the type caused by molnupiravir.

The researchers’ global sequence analysis showed that the prevalence of the suspected lineages increased significantly in 2022, the first year of widespread use of molnupiravir. The lineages were also much more common in sequence data from countries where the drug was used — the United States, United Kingdom and Australia — than in data from countries that had not approved it, such as France and Canada.

Where SARS-CoV-2 sequence data included the age of the person sampled, the telltale lineages tended to be from older people, more likely to take molnupiravir. And in Australia, where molnupiravir was pre-placed in care homes, the researchers identified a viral lineage with 25 mutations that had infected at least 20 people, most in their 80s and 90s.

Among the lineages that showed molnupiravir’s influence, a few – including those from Australia – were represented by multiple sequences, indicating that they could spread. “I would say our work rules out the possibility that these viruses could never be transmitted,” said team member Theo Sanderson, a computational biologist at the Francis Crick Institute in London.

Evolutionary Dead Ends?

Evidence linking molnupiravir to the mutation-heavy sequences is “indirect,” Merck said in a statement. “The authors believe these mutations were related to treatment with molnupiravir with no evidence that the viral sequences were isolated from treated patients.”

Bloom thinks the researchers are making a good case that treatment with molnupiravir produces some highly mutated viruses that can spread. But it’s not clear if this could contribute to new variants of the coronavirus, or if it just creates weak viruses that are unlikely to spread far. “SARS-CoV-2 is already generating numerous mutations even without drug treatment,” he adds.

Rustem Ismagilov, a quantitative bioscientist at the California Institute of Technology in Pasadena, says the study underscores the need to quickly measure any risk molnupiravir poses in terms of fueling new variants, and to weigh them against the benefits of the medicine. “If we’re playing Russian Roulette, we’d better know our odds.”

Sarah Otto, an evolutionary biologist at the University of British Columbia in Vancouver, Canada, says the paper is another blow to the continued use of molnupiravir. She notes that a large-scale British study found the drug had no effect on hospitalizations or deaths³. “Given the large-scale risks of this mutagen producing new variants more quickly, including variants that are immune evasive, I encourage public health leaders to call for a global halt to its use,” says Otto.