An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses
, C., The University of Hong Kong, PhD Thesis, Jul 2024
In vitro and hamster study of drug associated SARS-CoV-2 mutations with several drugs including molnupiravir and favipiravir. Next-generation sequencing was used to identify de novo mutational spectra and single base substitution mutational signatures. The study also assessed viral replication kinetics and immune responses using VeroE6-TMPRSS2 and Calu-3 cell models, and compared the pathogenicity of the mutated viruses in vivo in hamsters. Favipiravir showed high increase in nucleotide diversity and was associated with eleveted C>T mutations. Molnupiravir treatment led to elevated C>T and A>G mutations, with some mutated viruses forming significantly larger plaques and inducing stronger proinflammatory responses, raising concerns about the potential emergence of more dangerous strains with use of molnupiravir.
Potential risks of favipiravir include kidney injury1-3, liver injury2-4, and mutagenicity, carcinogenicity, teratogenicity, embryotoxicity, and the creation of dangerous variants5-11.
4 preclinical studies support the efficacy of favipiravir for COVID-19:
Study covers molnupiravir and favipiravir.
1.
Abdulaziz et al., Clinical Features and Prognosis of Acute Kidney Injury in Hospital-Admitted Patients with COVID-19 in Egypt: A Single-Center Experience, Mansoura Medical Journal, doi:10.58775/2735-3990.1433.
2.
Ülger et al., Experimental evaluation of favipiravir (T-705)-induced liver and kidney toxicity in rats, Food and Chemical Toxicology, doi:10.1016/j.fct.2025.115472.
3.
El-Fetouh et al., Experimental Studies on Some Drugs Used in Covid-19 Treatment (Favipiravir and Dexamethasone) in Albino Rats, Journal of Advanced Veterinary Research, 13:10, www.advetresearch.com/index.php/AVR/article/view/1635.
4.
Almutairi et al., Liver Injury in Favipiravir-Treated COVID-19 Patients: Retrospective Single-Center Cohort Study, Tropical Medicine and Infectious Disease, doi:10.3390/tropicalmed8020129.
5.
Zhirnov et al., Favipiravir: the hidden threat of mutagenic action, Journal of microbiology, epidemiology and immunobiology, doi:10.36233/0372-9311-114.
6.
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.
7.
Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.
8.
Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.
9.
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.
10.
Cenikli et al., Does Favipiravir interact with DNA? Design of electrochemical DNA nanobiosensor to investigate the interaction between DNA and Favipiravir used in the treatment of COVID-19, Talanta, doi:10.1016/j.talanta.2025.128084.
11.
Mihaljevic et al., DNA damage in peripheral blood lymphocytes of severely ill COVID-19 patients in relation to inflammatory markers and parameters of hemostasis, Mutagenesis, doi:10.1093/mutage/geac011.
12.
Unal et al., Favipiravir, umifenovir and camostat mesylate: a comparative study against SARS-CoV-2, bioRxiv, doi:10.1101/2022.01.11.475889.
Shum et al., 30 Jul 2024, preprint, 1 author.
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