The use of antiviral drugs that kill viruses by inducing lots of mutations should be restricted because of potential dangers highlighted by new research, some researchers say. Computer modelling suggests these drugs could result in viruses acquiring changes they wouldn’t otherwise and in a way that lab testing will miss.
All organisms continually mutate and most of these mutations are detrimental. Harmful mutations are normally eliminated from populations by natural selection, but if mutation rates are high enough, natural selection cannot eliminate mutations fast enough to prevent them building up to lethal levels and killing entire populations.
Mutagenic drugs are designed to raise mutation levels in viruses or cancer cells and produce such a “mutational meltdown”. Several mutagenic drugs are in use, including molnupiravir, which is used to treat covid-19. The drugs consist of molecules that mimic the building blocks of RNA and get added to the RNA genomes of viruses when they replicate, inducing mutations.
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Using the model, at the University of Bern in Switzerland and her colleagues assessed several potential ways for viruses to evolve resistance to these drugs. The most surprising finding is that changes that make viruses more susceptible to the effects of harmful mutations could, in very rare cases, help them escape meltdown.
This can happen because a higher susceptibility to harmful mutations makes natural selection more effective at removing harmful mutations. But this susceptibility must evolve very early on, or a virus population will already have accumulated enough harmful mutations to drive it extinct.
The model suggests this would be so rare that the escape mechanism would be unlikely to be seen in lab testing and human trials before a drug is approved, but it could occur if a drug is given to millions of people.
If this happened while a person was being treated, the risk wouldn’t just affect them. A virus that survives treatment with a mutagenic drug could acquire a lot more mutations than it would otherwise, potentially leading to the evolution of more dangerous variants that could spread widely if they infected other people.
“Such complex mutations could outrun the human immune system or have other effects that are advantageous to the virus,” says Bank.
The risks will be even higher if people miss doses or fail to complete drug courses, she says. “I would suggest that mutagenic drugs should only be administered in hospitals and doctors’ practices such that doses and administration intervals are monitored.
“As regularly happens with antibiotic treatments, patients are likely to forget to take the drug or to stop treatment prematurely when they feel better, if they are allowed to administer it by themselves,” she says.
at global health think tank ACCESS Health International thinks the study’s conclusions are accurate, but confirming it will require experimental observations, he says.
Haseltine has previously raised concerns about the safety of mutagenic drugs and thinks the risks outweigh the benefits. “They should not be used for transmissible viruses,” he says. “It’s a substantial danger.”
But Haseltine acknowledges he is in a minority in this regard. “Few share my views,” he says.
at the University of North Carolina at Chapel Hill doesn’t see the use of mutagenic drugs as a major risk. “I tend to be less concerned about that,” says Swanstrom. “The virus [that causes covid-19] seems to be doing a pretty good job of that on its own.”
“History has shown that insights made solely from computational modelling experiments require careful evaluation and interpretation when compared to findings from studies conducted in living systems,” said a spokesperson for Merck, the manufacturer of molnupiravir.
Swanstrom says there is another potential issue with mutagenic drugs. Because RNA building blocks can get turned into DNA building blocks, the drugs could, in theory, induce mutations in the cells of people being treated. Swanstrom’s team , but this process hasn’t been shown to pose any dangers to animals or people.
“We just don’t know what that means long-term for people,” he says. It might be no more dangerous than getting an X-ray, says Swanstrom.
Because of this theoretical risk, molnupiravir is . However, in an article earlier this year, Swanstrom suggested that the to people who really need it and who are aged over 50, to minimise any risk of cancer or of harmful mutations being passed to children. There should also be a registry of those who have received the drug, he says.
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