Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients

Fountain-Jones et al., medRxiv, doi:10.1101/2022.12.21.22283811

Dec 2022

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Analysis of immunocompromised patients showing rapid creation of new variants with molnupiravir. All patients treated with molnupiravir accrued new mutations in the spike protein of the virus, including non-synonymous mutations that altered the amino acid sequence. Authors note that uncontrolled use may generate new variants with a transmission advantage that prolongs the pandemic and makes other therapeutics less effective.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Hadj Hassine, Huntsman, Swanstrom, Waters, Zibat. Multiple analyses have identifed variants potentially created by molnupiravir Fountain-Jones, Sanderson, twitter.com.

1. Fountain-Jones et al., Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients, medRxiv, doi:10.1101/2022.12.21.22283811.medrxiv.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

4. Sanderson et al., Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases, medRxiv, doi:10.1101/2023.01.26.23284998.medrxiv.org, doi.org.

5. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

6. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

7. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

8. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

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Fountain-Jones et al., 22 Dec 2022, Australia, preprint, 7 authors.

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Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients

Nicholas M Fountain-Jones, Robert Vanhaeften, Jan Williamson, Janelle Maskell, I-Ly J Chua, Michael Charleston, Louise Cooley

doi:10.1101/2022.12.21.22283811

The antiviral Molnupiravir (Lageviro) is widely used across the world to treat SARS-CoV-2 infection. Molnupiravir reduces viral replication by inducing mutations throughout the genome, yet in patients that do not clear the infection, the longer-term impact of the drug on virus evolution is unclear. Here, we used a case-control approach to monitor SARS-CoV-2 genomes through time in nine immunocompromised -patients with five treated with Molnupiravir. Within days of treatment, we detected a large number of low-frequency mutations in patients and that these new mutations could persist and, in some cases, were fixed in the virus population. All patients treated with the drug accrued new mutations in the spike protein of the virus, including non-synonymous mutations that altered the amino acid sequence. Our study demonstrates that this commonly used antiviral can 'supercharge' viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic.

References

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