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Merck & Co.’s molnupiravir appears to be speeding evolution of SARS-CoV-2. A widely used COVID-19 drug may be driving the appearance of new SARS-CoV-2 variants, sparking concerns it could prolong and even reinvigorate the pandemic. The drug, molnupiravir, produced by Merck & Co., is designed to kill the virus by inducing mutations in the viral genome. A survey of viral genomes reported in a new preprint, however, suggests some people treated with the drug generate novel viruses that not only remain viable, but spread. “It’s very clear that viable mutant viruses can survive [molnupiravir treatment] and compete [with existing variants],” says virologist William Haseltine, chair of ACCESS Health International, who has repeatedly raised concerns about the drug. “I think we are courting disaster.” But a Merck spokesperson disputes that the drug has led to the emergence of widely circulating variants, and some researchers downplayed the significance of molnupiravir-caused mutations. “Right now, it’s much ado about nothing,” says Raymond Schinazi, a medicinal chemist at the Emory University School of Medicine, noting that with SARS-CoV-2 infecting millions of people worldwide, the virus is naturally mutating at a fast clip. Authorized in the United Kingdom and the United States in late 2021, molnupiravir was the first oral antiviral approved anywhere to fight COVID-19. It has since been authorized in dozens of other countries. In 2022, Merck estimated global sales of the compound at more than $5 billion. Though that is well below the $18.9 billion in 2022 sales for Paxlovid, another oral SARS-CoV-2 antiviral, molnupiravir remains widely popular in certain countries. From the start, however, Haseltine and others worried about the drug’s mechanism, which involves introducing so many mutations into the viral genome that it can no longer reproduce. One concern was that the drug might mutate not just the coronavirus, but the DNA of people receiving it—a side effect that has not been seen so far. Another was that mutated virus would survive and propagate—and perhaps turn out to be more transmissible or virulent than before.
Before the U.S. Food and Drug Administration authorized the drug, a Merck spokesperson called the worry “an interesting hypothetical concern.” Nevertheless, researchers and citizen scientists from around the globe began to scan SARS-CoV-2 genome sequences deposited in the international GISAID database, looking for the kinds of mutations expected to be caused by molnupiravir. Rather than inducing random changes in the virus’ RNA genome, the drug is more likely to cause specific nucleic acid substitutions, with guanine switching to adenine and cytosine to uracil. One virus hunter, Ryan Hisner, a middle school science and math teacher in Monroe, Indiana, started to catalog suspect variants in August 2022 and quickly identified dozens of sequences that showed clusters of those hallmark substitutions. Hisner raised his concerns with researchers on Twitter and ultimately teamed up with Thomas Peacock, a virologist from Imperial College London. With other colleagues, the pair systematically reviewed more than 13 million SARS-CoV-2 sequences in GISAID and analyzed those with clusters of more than 20 mutations. In a preprint posted on 27 January, they report that a large subset showed the hallmark substitutions; all dated from 2022, after molnupiravir began to be widely used. These signature clusters, the researchers found, were up to 100 times more common in countries where molnupiravir was widely used, including the United States, Australia, and the United Kingdom, than in countries such as France and Canada where it was not. Tracking the dates and locations of the sequences showed some of the mutated strains were spreading in the community. “Clearly something is happening here,” Peacock says. Whether the changes will lead to variants that are more pathogenic or transmissible is unclear, the researchers say. “We are not coming to a conclusion about risk,” says team member Theo Sanderson, a geneticist at the Francis Crick Institute. Haseltine, however, likens the danger to keeping a pet lion. “Just because it didn’t bite you yesterday doesn’t mean it won’t bite you today,” he says. The Merck spokesperson says the link between the mutations and the drug is unproved. “There is no evidence that any antiviral agent has contributed to the emergence of circulating variants,” she says.
But the new result comes on the heels of two others that could change the risk-benefit calculus for the drug. In one, researchers in Australia found evidence that molnupiravir treatment may be leading to new variants in immunocompromised patients. Because these patients’ immune systems have trouble clearing the virus, viral variants can accrue large numbers of mutations, possibly causing big leaps in viral behavior that can then be passed to others. (Researchers have speculated that Omicron and other SARS-CoV-2 variants evolved naturally in immunocompromised people.) Repeatedly sequencing SARS-CoV-2 genomes from nine patients, five of whom received the drug and four who did not, the researchers found that molnupiravir-treated individuals harbored an average of 30 new variants each within 10 days of the initial dose, far more than the untreated patients. “Our study demonstrates that this commonly used antiviral can ‘supercharge’ viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic,” the authors wrote in a 22 December 2022 preprint. A second report, which appeared on 28 January in The Lancet, suggests that, at least among people who have been vaccinated against COVID-19, molnupiravir offers limited benefits. The study tracked 26,411 vaccinated participants in the United Kingdom’s PANORAMIC clinical trial, roughly half of whom were given the drug. It did reduce symptom severity and improve patient recovery times, but the researchers found it did not lower the frequency of COVID-19–associated hospitalizations or deaths among high-risk adults. The new U.K. and Australian studies don’t prove molnupiravir is causing the emergence of dangerous new SARS-CoV-2 variants, says Ravindra Gupta, a clinical microbiologist at the University of Cambridge. But he argues the drug’s limited benefit suggests it’s no longer worth the risk. “Taken together, these results do call into question whether molnupiravir should be used.”
