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November 9, 2021

A breakthrough coronavirus drug works by causing more viral mutations. Is that risky?

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    A prominent virologist recently voiced concerns over Merck's oral antiviral drug for Covid-19, stating it could spur the rise of new, more deadly variants of SARS-CoV-2. Writing for ScienceInsider, Robert Service explains why some experts are worried that the new poll could pose public health risks—while others are not concerned.

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      Merck's new Covid-19 pill

      Last month, Merck and Ridgeback Biotherapeutics released new data from a clinical trial showing that their oral antiviral drug molnupiravir reduced the rate of hospitalization or death by roughly 50% in participants with mild or moderate Covid-19. The drug was most effective when given early in the course of the disease and was effective regardless of whether patients had the delta or other coronavirus variants.

      On Nov. 4, molnupiravir became the first oral antiviral approved to treat Covid-19 when the U.K. Medicines and Healthcare Products Regulatory Agency granted its approval for high-risk individuals. According to Robert Service, the author, an FDA advisory committee will review the drug for possible emergency use authorization in the United States on Nov. 30.

      How molnupiravir might lead to new coronavirus mutations

      Molnupiravir cripples the virus' ability to reproduce by overloading the viral genome with mutations, thereby interrupting viral replication, Service writes. 

      Separately, William Haseltine, a prominent virologist formerly at Harvard University who is known for his HIV research and his work on the human genome project, said the drug could increase the number of coronavirus variants—and create new, more dangerous variants.

      "You are putting a drug into circulation that is a potent mutagen at a time when we are deeply concerned about new variants," Haseltine said Monday in a Forbes blog post. "I can't imagine doing anything more dangerous."

      He added that patients generally stop taking prescribed antibiotics before they complete the entire regimen, a behavior that enables "resistant germs to survive and spread," Service writes. Accordingly, Haseltine voiced concern that if a Covid-19 patient stopped taking the drug before completing the prescribed course, viral mutations could potentially survive and spread.

      "If I were trying to create a new and more dangerous virus in humans, I would feed a subclinical dose [of molnupiravir] to people infected," he said.

      While no other experts have expressed the same level of concern as Haseltine, Service writes, Raymond Schinazi, an infectious disease expert at Emory University agreed that "[t]he possibility [of generating variants] is there."

      Why most experts are not alarmed

      Many virologists told Service that they believe that the largely unfounded concerns over molnupiravir should not prevent individuals who could benefit from the drug from receiving it—although they said they believe the drug's impact on Covid-19 variants should be monitored. 

      According to Daria Hazuda, head of infectious disease discovery for Merck, the company hasn't found any evidence that people who took the drug generated viruses with new, more dangerous mutations. For the individuals who completed the five-day course of molnupiravir, she said "we don't see any infectious virus"—or mutated variants.

      Notably, Hazuda and other experts pointed out that SARS-CoV-2 has produced many variants naturally by replicating in infected people. "There is no shortage of viral variation out there," said Aris Katzourakis, a viral evolution expert at the University of Oxford.

      Separately, Mark Denison, a virologist at Vanderbilt University, said his previous research found that 30 sublethal rounds of molnupiravir, then called EIDD-1931, caused up to 162 mutations in two different coronaviruses—but most of the mutations slowed the virus' growth. "If I take away anything from our work, it is that if the virus tries to adapt, say through resistance [to molnupiravir], it continuously develops deleterious mutations," he said.

      Ultimately, experts noted that the most important question is whether the drug will drive the virus toward transmissibility or virulence. "I find it difficult to imagine," Katzourakis said. "But I can't rule that out."

      For his part, Denison told Service that the most likely outcome is that molnupiravir will not drive the virus to become more deadly or transmissible—but the virus could become more resistant to the drug.

      And at this point, Katzourakis added, "I don't think we are in the position of withholding a life-saving drug for a risk that may or may not happen." (Service, ScienceInsider, 11/7)

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