Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection

Illingworth et al., Virus Evolution, doi:10.1093/ve/veae001

Jan 2024

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Syrian hamster study showing that short-term treatment with the mutagenic antiviral drugs favipiravir and molnupiravir led to increased genetic variation in SARS-CoV-2 viral populations. Treatment with effective antiviral doses resulted in a gain of 7-10 variants per viral genome compared to untreated controls after only 4 days. The results indicate mutagenic drug treatment can rapidly increase SARS-CoV-2 genetic diversity, which may affect transmission dynamics.

There was a dose-dependent increase in low-frequency mutations that was correlated with reduced viral fitness, suggesting the mutations were deleterious. However, even if the vast majority of mutations caused by these mutagenic drugs are detrimental to the virus, the risk remains that a small fraction could produce dangerous new variants. Just one fitter variant with enhanced pathogenicity or transmissibility could spawn a new wave of infection.

Potential risks include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-14.

Important missing comments or errors? Let us know.

Study covers molnupiravir and favipiravir.

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5. 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.

6. Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.sciencedirect.com, doi.org.

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8. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

9. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

10. Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.asianmedjam.com.

11. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

12. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

13. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

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

Illingworth et al., 4 Jan 2024, peer-reviewed, 9 authors. Contact: christopher.illingworth@glasgow.ac.uk.

This Paper Molnupiravir All

Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection

Christopher J R Illingworth, Jose A Guerra-Assuncao, Samuel Gregg, Oscar Charles, Juanita Pang, Sunando Roy, Rana Abdelnabi, Johan Neyts, Judith Breuer

doi:10.1093/ve/veae001/7511244

Mutagenic antiviral drugs have shown promise against multiple viruses, but concerns have been raised about whether their use might promote the emergence of new and harmful viral variants. Recently, genetic signatures associated with molnupiravir use have been identified in the global SARS-COV-2 population. Here, we examine the consequences of using favipiravir and molnupiravir to treat SARS-CoV-2 infection in a hamster model, comparing viral genome sequence data collected from (i) untreated hamsters, and (ii) from hamsters receiving effective

is expected to tend, under mutation-selection balance, to an equilibrium frequency of x=/s, where  is the mutation rate and s is the magnitude of selection against the allele 53 , according to the equation Furthermore, assuming mutation rates from one allele to the other are equal, the frequency of a neutral allele is expected to tend to a frequency of one half, according to the equation In both of these formulas, the change in the frequency x is proportional to  when x is small. Although positive selection and linkage disequilibrium will affect the evolution of the viral population, we nevertheless sought to fit a linear model to our data. Analysis of variant composition The proportion of low-frequency variation of distinct mutational classes was measured using variants at frequencies of 1% or below. Briefly, the calculation of q was repeated, considering exclusively low-frequency variants, following which the proportion of this sum that is comprised of each of the 12 mutational classes was calculated. In order to explore the potential adaptive evolution of the viral populations, we identified variants which had reached a frequency of 5% or more. To analyse the composition of these variants we calculated πN/πS, defined as Non-synonymous and synonymous variation Where cN and cS were the genome-wide counts of non-synonymous and synonymous variants reaching a frequency of 5% or more, and oN and oS are the number of potential nonsynonymous and synonymous variants that..

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