New research has found that the antiviral drug molnupiravir (Lagevrio) that has been used in the treatment of COVID-19 may increase the risk of the SARS-CoV-2 coronavirus evolving and developing new variants that are transmitted to the population, although it has not been determined if these mutated viruses are more dangerous to patients, or if they have the ability to evade vaccines.
The study was carried out by scientists from the University of Cambridge, the Francis Crick Institute, Imperial College London, the University of Liverpool, the University of Cape Town and the UK Health Security Agency (UKHSA), and its results have been published. published in the journal Nature.
The mechanism of action of this drug is to alter the genome of the virus, which causes it to develop random mutations as it replicates and this weakens the virus with the aim of preventing replication and allowing the infection to be eliminated. However, the study results show that, in some cases, mutated forms of the virus have been able to be transmitted from patients treated with molnupiravir and spread within the community.
“Molnupiravir is one of several drugs used to combat COVID-19. It belongs to a class of drugs that can cause the virus to mutate so much that it is fatally weakened. But what we have found is that, in some patients, this process does not kill all viruses and some mutated viruses can spread. “It is important to take this into account when assessing the overall benefits and risks of molnupiravir and similar medicines,” said Dr Christopher Ruis, from the Department of Medicine at the University of Cambridge.
Viruses with this mutation signature had begun to emerge almost exclusively starting in 2022 and in countries and age groups where molnupiravir was widely used to treat COVID-19.
Molnupiravir has been used to treat COVID-19 since late 2021 and is approved in several countries, including the United Kingdom, the United States and Japan. The EMA (European Medicines Agency), however, decided not to recommend the marketing of this drug because it considered that its benefits had not been demonstrated.
A drug that alters the coronavirus genome
In the patient’s body, molnupiravir becomes a molecule that alters the SARS-CoV-2 genome, introducing some nucleotide mutations in its RNA, randomly changing some Cs into Ts and some Gs into As. These changes mean that, As it replicates, the virus weakens and this decreases its ability to replicate and favors the elimination of the virus from the body. However, there is a possibility that mutated viruses are not eliminated quickly enough and could be transmitted to other individuals, allowing them to spread.
During the COVID-19 pandemic, several countries, led by the Cambridge-led COVID-19 Genomics UK Consortium, sequenced virus samples and stored the information in databases, allowing scientists and public health agencies to track the evolution and spread of the virus and look for the so-called “variants of concern”: versions of the virus with mutations that could make them more transmissible, more lethal or capable of evading the immune system of vaccinated people, such as the delta and omicron variants.
A group of scientists from the United Kingdom and South Africa looked at a series of viral genomes with a large number of mutations, specifically where Cs had changed to Ts and Gs to As. Although mutations from C to T are relatively common in the evolution of SARS- CoV-2, G to A mutations are much less frequent and a higher proportion of G to A mutations are associated with molnupiravir treatment.
The team then analyzed a family tree of more than 15 million SARS-CoV-2 sequences recorded in databases to identify mutations that had occurred at each point in the virus’s evolutionary history. They found that viruses with this mutation signature had begun to emerge almost exclusively starting in 2022 and in countries and age groups where molnupiravir was widely used to treat COVID-19.
To confirm the link, researchers examined treatment records in England and found that at least one in three viruses showing the mutational signature involved the use of molnupiravir. Additionally, they observed small groups of patients infected with mutated viruses, suggesting that these new viruses were transmitted from one person to another. However, so far none of the known variants of concern have been linked to the use of molnupiravir.
“COVID-19 continues to have a significant effect on human health and some people are having difficulty clearing the virus, so it is important that we develop medicines that aim to shorten the duration of infection. But our evidence shows that a specific antiviral drug, molnupiravir, also produces new mutations, increasing genetic diversity in the surviving viral population,” said Dr Theo Sanderson, from the Francis Crick Institute.
“Our findings are useful for the continued evaluation of the risks and benefits of molnupiravir treatment. It is necessary to take into account the possibility of persistent mutations induced by antivirals for the development of new drugs that work in a similar way,” concludes the expert.
