Could a popular COVID-19 antiviral supercharge the pandemic?
Merck & Co.’s molnupiravir appears to be speeding evolution of SARS-CoV-2
1 FEB 20235:40 PMBYROBERT F. SERVICE
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.
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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.”
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medRxiv
Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases
Theo Sanderson, Ryan Hisner, I’ah Donovan-Banfield, Thomas Peacock, Christopher Ruis
doi: https://doi.org/10.1101/2023.01.26.23284998
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus, and many will be lethal. Molnupiravir-induced elevated mutation rates have been shown to decrease viral load in animal models. However, it is possible that some patients treated with molnupiravir might not fully clear SARS-CoV-2 infections, with the potential for onward transmission of molnupiravir-mutated viruses. We set out to systematically investigate global sequencing databases for a signature of molnupiravir mutagenesis. We find that a specific class of long phylogenetic branches appear almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age-groups with widespread usage of the drug. We calculate a mutational spectrum from the AGILE placebo-controlled clinical trial of molnupiravir and show that its signature, with elevated G-to-A and C-to-T rates, largely corresponds to the mutational spectrum seen in these long branches. Our data suggest a signature of molnupiravir mutagenesis can be seen in global sequencing databases, in some cases with onwards transmission.
...
Merck & Co.’s molnupiravir appears to be speeding evolution of SARS-CoV-2
1 FEB 20235:40 PMBYROBERT F. SERVICE
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.
...
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.”
...
---------------
medRxiv
Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases
Theo Sanderson, Ryan Hisner, I’ah Donovan-Banfield, Thomas Peacock, Christopher Ruis
doi: https://doi.org/10.1101/2023.01.26.23284998
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus, and many will be lethal. Molnupiravir-induced elevated mutation rates have been shown to decrease viral load in animal models. However, it is possible that some patients treated with molnupiravir might not fully clear SARS-CoV-2 infections, with the potential for onward transmission of molnupiravir-mutated viruses. We set out to systematically investigate global sequencing databases for a signature of molnupiravir mutagenesis. We find that a specific class of long phylogenetic branches appear almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age-groups with widespread usage of the drug. We calculate a mutational spectrum from the AGILE placebo-controlled clinical trial of molnupiravir and show that its signature, with elevated G-to-A and C-to-T rates, largely corresponds to the mutational spectrum seen in these long branches. Our data suggest a signature of molnupiravir mutagenesis can be seen in global sequencing databases, in some cases with onwards transmission.
...
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