Molnupiravir, a drug used to treat Covid-19, appears to be driving the evolution of the SARS-CoV-2 coronavirus, according to an analysis of the 15m viruses sequenced worldwide so far, according to a study in Nature. A spokesperson for Merck, which makes molnupiravir, said the study relies on circumstantial associations.
The researchers found around 900 viruses with distinctive patterns of mutation that probably arose in people being treated with the drug molnupiravir. While in at least a few cases these viruses appear to have spread from the person being treated to others, none of the variants of concern have any of these patterns, said Theo Sanderson of the Francis Crick Institute, London.
Molnupiravir works by inducing so many mutations in RNA viruses – such as SARS-CoV-2 – as they replicate in a person, that the viruses lose the ability to replicate and die out.
But before the viruses are eliminated from the body, there is a risk of them spreading to others.
A few biologists think the risk of these mutagenic drugs generating potentially dangerous new variants outweighs their benefits, reports New Scientist.
Animal studies suggest molnupiravir might also cause DNA mutations in those taking it, which is why it isn’t given during pregnancy, or if a potential recipient is trying to conceive or is breastfeeding.
Despite these concerns, regulatory agencies in many countries, including the US and UK, have approved molnupiravir for treating Covid-19.
Sanderson and his colleagues, who carried out the analysis, said several lines of evidence support their conclusions. For starters, molnupiravir induces distinct types of mutation in the genomes of RNA viruses.
In countries that began using the drug in 2022, there was a rise in the number of viruses with these distinctive changes. “These sequences were more likely to be observed in countries that use molnupiravir, and particularly in those that use the most molnupiravir,” said Sanderson.
What’s more, the team was able to check if the viruses sequenced in the UK came from people treated with the drug. They found that 31% of variants with the distinctive pattern came from treated people, whereas just 0.04% of the overall sequenced viruses came from treated individuals.
It is expected that molnupiravir will mutate the viruses in those being treated. The issue is whether those mutated viruses spread to other people. In most cases, the team couldn’t establish this.
However, they did identify a few clusters, including one in Australia where there seemed to have been spread from person to person.
“We provide some cases where that’s very clear,” Sanderson said.
Whether this could create dangerous new variants is unclear. “Our data don’t say how likely that is, but it’s clearly something that needs consideration.”
“I think the most interesting question is: does treatment generate more new mutations in the population than non-treatment?” said Martin Nowak at Harvard University.
In a study published last month, he and his colleagues estimated the answer was no.
A spokesperson for Merck, which makes molnupiravir, said the study relies on circumstantial associations. “The authors assume these mutations were associated with viral spread from molnupiravir-treated patients without documented evidence of that transmission… Furthermore, these sequences were uncommon and were associated with sporadic cases.”
The Merck spokesperson pointed to a review by the US Food and Drug Administration (FDA) of Sanderson’s initial findings earlier this year.
“While it is plausible that [molnupiravir] use could contribute to mutational patterns in SARS-CoV-2 sequences, there are some uncertainties…” an FDA memorandum states. “A causal relationship… has not yet been established.”
The memorandum also points out that the risk of treatments triggering the evolution of new variants isn’t limited to mutagenic drugs.
Conventional drugs and antibodies put pressure on viruses to evolve to evade the treatment. The study “does not change the review team’s overall risk assessment”, the memorandum concluded.
Study 1 details
A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes
Theo Sanderson, Ryan Hisner, Christopher Ruis, et al.
Published in Nature on 25 September 2023
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, and so molnupiravir-induced elevated mutation rates reduce viral load. However, if some patients treated with molnupiravir do not fully clear SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. 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. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onwards transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.
Study 2 details
Evolutionary safety of lethal mutagenesis driven by antiviral treatment
Gabriela Lobinska, Yitzhak Pilpel, Martin Nowak.
Published in PLOS Biology on 8 August 2023
Abstract
Nucleoside analogs are a major class of antiviral drugs. Some act by increasing the viral mutation rate causing lethal mutagenesis of the virus. Their mutagenic capacity, however, may lead to an evolutionary safety concern. We define evolutionary safety as a probabilistic assurance that the treatment will not generate an increased number of mutants. We develop a mathematical framework to estimate the total mutant load produced with and without mutagenic treatment. We predict rates of appearance of such virus mutants as a function of the timing of treatment and the immune competence of patients, employing realistic assumptions about the vulnerability of the viral genome and its potential to generate viable mutants. We focus on the case study of Molnupiravir, which is an FDA-approved treatment against Coronavirus Disease-2019 (COVID-19). We estimate that Molnupiravir is narrowly evolutionarily safe, subject to the current estimate of parameters. Evolutionary safety can be improved by restricting treatment with this drug to individuals with a low immunological clearance rate and, in future, by designing treatments that lead to a greater increase in mutation rate. We report a simple mathematical rule to determine the fold increase in mutation rate required to obtain evolutionary safety that is also applicable to other pathogen-treatment combinations.
FDA review of molnupiravir
See more from MedicalBrief archives:
Merck’s COVID pill narrowly wins FDA panel’s ‘yes’ vote
Molnupiravir demonstrates benefits against COVID – 3 studies at ECCMID conference
Reduction in infectious SAR-CoV-2 with molnupiravir — Small US study