Molnupiravir, an antiviral COVID-19 pill created by Merck, has been linked with new mutations of the virus that have been observed worldwide, according to a new study published in the Nature science journal on Monday.
The drug, known commercially as Lagevrio, was one of the first authorized antiviral treatments made available during the pandemic. Pfizer's Paxlovid has also been approved for use in the treatment of COVID-19.
According to a new study, the Merck antiviral drug can make the coronavirus change its genetic code. This might make it easier to fight the virus, but it could also let it spread to others.
The findings may raise questions about the usefulness of the drug.
The study shows that when doctors use molnupiravir to treat COVID-19 patients, it can cause mutations within the virus's genetic material as it reproduces, resulting in random mutations that damage and destroy virus proteins, thus reducing its viral load, or the amount of virus, in the body.
However, the study has discovered that among patients treated with molnupiravir, there have been cases where the coronavirus has not been eliminated, resulting in mutations of the virus that have spread to other people.
Theo Sanderson, the lead author of the study and a researcher at the Francis Crick Institute in London, offered insights into the study in a post on X.
"Molnupiravir creates mutations because of its chemistry," he wrote. "Its structure is like that of a base of RNA, but can exist in two forms. One looks like a C and so binds to G, but it can then switch to another form that binds to A. This means it causes mainly G-to-A and C-to-T mutations."
Researchers from the United Kingdom and South Africa looked at available data from patients, including medical records, who had been treated with molnupiravir and those who had not.
Having looked at 15 million sequenced virus genomes from global databases, they found that certain mutations of the coronavirus were observed as having "increased dramatically" mostly in 2022 "immediately after the roll-out of molnupiravir."
They also saw these changes more in certain places and among certain age groups where many people were taking the drug.
The study found that one specific type of mutation, rarely seen in natural SARS-CoV-2 evolution, was associated with the use of the Merck drug. This specific mutation was found at high rates among senior citizens in Australia, where retirement homes had stocked molnupiravir.
"Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, 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," the study states.
Mr. Sanderson said that the researchers think the evidence "is very strong" that the observed mutational events are due to the use of molnupiravir, highlighting the study's confidence in linking the drug to specific mutations observed in the virus.
In Australia, the drug was approved by regulators for use in people over 50, particularly those in aged care facilities, and indigenous people over 30. It was also approved for anyone over 18 who had been reinfected after having previously been hospitalized for COVID-19.
Mr. Sanderson addressed concerns about whether the use of molnupiravir as a COVID-19 treatment might promote the emergence of new variants of the virus. "Since molnupiravir was first proposed as a treatment for COVID-19, some people have asked whether it could make the evolution of variants of concern more likely," he wrote.
"In some sense our data makes these concerns more concrete because it makes clear that treatment can result in viruses with significant numbers of molnupiravir-induced mutations that can: (A) still be viable, rising to dominance in the host, and (B) in some cases be transmissible," he continued.
However, he also acknowledged the complexity of quantifying the precise impact of molnupiravir treatment on the risk of variant development. He noted that, to date, no variant with a known advantage over other variants had exhibited the specific signature associated with molnupiravir-induced mutations.
Nonetheless, Mr. Sanderson emphasized that "only a small proportion of infections have been treated with molnupiravir."
He noted that the types of mutations observed as being caused by molnupiravir are "quite different" to those often seen in coronavirus evolution. "So use of the drug might result in the virus exploring a broader range of its genotypic landscape than it otherwise would," he wrote.
The study also warns that mutations caused by the Merck drug "could also potentially allow infections to persist for longer by creating a more varied target for the immune system.”
Merck has questioned the study's findings and methodology in statements to multiple media outlets.
The company noted that the researchers made an assumption that these mutations were linked to the spread of the virus from individuals treated with Molnupiravir. However, Merck pointed out that there was no documented evidence to confirm this assumption.
“Instead, the authors rely on circumstantial associations between the region from which the sequence was identified and timeframe of sequence collection in countries where molnupiravir is available to draw their conclusions,” the company stated.
Furthermore, Merck stated that the sequences with the identified mutations were uncommon and appeared to be associated with isolated cases rather than widespread occurrences.
“As noted by the authors, there are limitations to the analyses conducted in this study, which are described in more detail in the manuscript,” the company's statement added. “These data must be considered in the context of all available clinical and non-clinical molnupiravir data.”
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