Efficacy of Molnupiravir in reducing the risk of severe outcome in patients with SARS-CoV-2 infection: a real-life full-matched case-control study (SAVALO Study).

Gentile et al., medRxiv, doi:10.1101/2024.09.09.24313305, SAVALO

Sep 2024

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PSM retrospective case-control study with 1,382 SARS-CoV-2 positive outpatients in Italy, showing lower risk for a composite outcome of hospitalization, ICU admission, or death with molnupiravir, but no significant difference for mortality or hospitalization.

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.

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risk of death, 4.2% lower, OR 0.96, p = 0.79, treatment 146, control 1,236, case control OR, propensity score matching.

risk of hospitalization, 25.6% lower, OR 0.74, p = 0.74, treatment 146, control 1,236, case control OR, propensity score matching.

hospitalization, ICU, mortality, 64.7% lower, OR 0.35, p = 0.01, treatment 146, control 1,236, case control OR, propensity score matching.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

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

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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.

Gentile et al., 9 Sep 2024, retrospective, Italy, preprint, 19 authors, study period 1 January, 2022 - 31 December, 2022, SAVALO trial. Contact: riccardo.scotto@unina.it, ri.scotto@gmail.com.

This Paper Molnupiravir All

Efficacy of Molnupiravir in reducing the risk of severe outcome in patients with SARS-CoV-2 infection: a real-life full-matched case-control study (SAVALO Study).

Ivan Gentile, M.D Riccardo Scotto, Maria Michela Scirocco, Francesco Di Brizzi, Federica Cuccurullo, Maria Silvitelli, Luigi Ametrano, Francesco Antimo Alfe', Daria Pietroluongo, Irene Irace, Mariarosaria Chiariello, Noemi De Felice, Simone Severino, Giulio Viceconte, Nicola Schiano Moriello, Alberto Enrico Maraolo, Antonio Riccardo Buonomo, Agnese Giaccone

doi:10.1101/2024.09.09.24313305

Introduction Molnupiravir (MNP) is an orally administered prodrug which prevents disease progression in patients at high risk for severe COVID-19. We conducted a real-life case-control study on a cohort of outpatients, with Omicron SARS-CoV-2 infection to assess the e^ectiveness of MNP in reducing the occurrence of hospital admission, admission in intensive care unit (ICU) and death at day 28. Materials and methods Cases were enrolled among SARS-CoV-2 positive subjects that sought medical care during the first five days of symptoms from January 1st, 2022, to December 31st, 2022, and received MNP. Control participants were selected from a regional database among those who tested positive during the study period and did not receive antiviral treatment for SARS-CoV-2. Results 1382 patients were included (cases: 146, controls: 1236). Vaccinated patients showed lower risk of mortality and composite outcome (at least one among hospital admission, admission in ICU and allcause death) compared to unvaccinated ones (0.6% vs 7.8%, p<0.001 and 2% vs 7.8%, p=0.001 respectively). After full-matching propensity score, MNP-treated subjects showed a lower incidence of composite outcome, while no e^ect was observed on the single outcomes. In the subgroup analysis according to the vaccination status, MNP proved e^ective in preventing all the outcomes among unvaccinated patients, while showed to reduce the risk of ICU admission both in vaccinated and unvaccinated patients. Conclusions Treatment with MNP proved e^ective in reducing the risk of composite outcome among outpatients with SARS-CoV-2 infection. The beneficial e^ect of MNP treatment in reducing progression is more pronounced in unvaccinated patients.

Competing interests Prof. IVAN GENTILE reports personal fees from MSD, AbbVie, Gilead, Pfizer, GSK, SOBI, Nordic/Infecto Pharm, Angelini and Abbott, as well as departmental grants from Gilead and support for attending a meeting from Janssen, outside the submitted work. All other authors have no competing interests to declare Declaration of generative AI and AI-assisted technologies in the writing process During the preparation of this work the authors used Microsoft© Copilot, powered by Chat-GPT IV, after the completion of the first draft, in order to improve readability and the English grammar of the paper. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article

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