Efficacy of Molnupiravir in Reducing the Risk of Severe Outcomes in Patients with SARS-CoV-2 Infection: A Real-Life Full-Matched Case–Control Study (SAVALO Study)

Gentile et al., Microorganisms, doi:10.3390/microorganisms13030669 (date from preprint), 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.

Confounding by treatment propensity. This study analyzes a population where only a fraction of eligible patients received the treatment. Patients receiving treatment may be more likely to follow other recommendations, more likely to receive additional care, and more likely to use additional treatments that are not tracked in the data (e.g., nasal/oral hygiene1,2, vitamin D3, etc.) — either because the physician recommending molnupiravir also recommended them, or because the patient seeking out molnupiravir is more likely to be familiar with the efficacy of additional treatments and more likely to take the time to use them. Therefore, these kind of studies may overestimate the efficacy of treatments.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity4-17. Multiple analyses have identified variants potentially created by molnupiravir18-22.

Important missing comments or errors? Let us know.

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. c19early.org, c19early.org/p.c19early.org/p.

2. c19early.org (B), c19early.org/ph.c19early.org/ph.

3. c19early.org (C), c19early.org/d.c19early.org/d.

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10. 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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13. Rahman, M., Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs, tokyo-metro-u.repo.nii.ac.jp/records/2000972.ac.jp.

14. 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.

15. 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.

16. Standing et al., Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients, Nature Communications, doi:10.1038/s41467-024-45641-0.nature.com, doi.org.

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18. Focosi et al., The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country, Intervirology, doi:10.1159/000540282.karger.com, doi.org.

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

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

Gentile et al., 9 Sep 2024, retrospective, Italy, peer-reviewed, 19 authors, study period 1 January, 2022 - 31 December, 2022, SAVALO trial. Contact: riccardo.scotto@unina.it (corresponding author), ri.scotto@gmail.com, ivan.gentile@unina.it, mmichelascirocco@hotmail.com, francescodibrizzi@gmail.com, federicacuccurullo94@gmail.com, mariasilvitelli94@gmail.com, luigi.ametrano@outlook.com, francescoantimoalfe@gmail.com, pietroluongo.daria@gmail.com, irisirene@hotmail.it, chiariello.mr@outlook.it, noemidefelice@gmail.com, simoneseverino5f@gmail.com, giulio.viceconte@gmail.com, veghan@gmail.com, albertomaraolo@yahoo.com, antonioriccardobuonomo@gmail.com, agnesegiaccone94@gmail.com.

This Paper Molnupiravir All

Efficacy of Molnupiravir in Reducing the Risk of Severe Outcomes in Patients with SARS-CoV-2 Infection: A Real-Life Full-Matched Case–Control Study (SAVALO Study)

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

Microorganisms, doi:10.3390/microorganisms13030669

We conducted a real-life case-control study among outpatients with Omicron SARS-CoV-2 infection to assess the effectiveness of molnupiravir (MNP) in reducing hospital admission, admission to the intensive care unit, and death at day 28. Cases were SARS-CoV-2-positive patients seeking medical care within five days of symptom onset from 1 January to 31 December 2022, who received MNP. Controls were selected from a regional database among positive subjects who did not receive antiviral treatment for SARS-CoV-2. A total of 1382 patients were included (146 cases, 1236 controls). Vaccinated patients had a lower risk of mortality and of the composite outcome (hospital admission, ICU admission, or all-cause death) than unvaccinated ones (0.6% vs. 7.8%, p < 0.001 and 2% vs. 7.8%, p = 0.001, respectively). After full-matching propensity score analysis, MNPtreated subjects had a lower incidence of the composite outcome, although no effect was observed on individual outcomes. In subgroup analyses by vaccination status, MNP was effective in preventing all outcomes among unvaccinated patients and reduced the risk of ICU admission in both vaccinated and unvaccinated patients. Molnupiravir treatment effectively reduced the composite outcome risk in outpatients with SARS-CoV-2 infection, with a more pronounced benefit in unvaccinated patients. These findings highlight MNP's potential to help prevent disease progression in high-risk patients, thereby supporting its role as an outpatient therapeutic option for COVID-19.

Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/microorganisms13030669/s1 , Supplementary File S1: SAVALO Study telephone interview and case report form. Supplementary Table S1 : Number of patients stratified and outcome rates among included patients according to vaccination status. Supplementary Figure S1 Informed Consent Statement: Informed consent was obtained from all patients included in the study. For control patients, consent was obtained via telephone interview, a method that was rigorously reviewed and approved by the ethics committee to ensure it met all ethical standards. Informed consent from case patients was obtained in written form. Records of the telephone interviews with control participants, including their verbal consent, are securely stored by the study's data manager at the Department of Clinical Medicine and Surgery, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy. These records are available for review by any relevant authority upon reasonable request. Data Availability Statement: The datasets generated and/or analyzed during the current study, along with the study's Case Report Forms (CRFs), the written informed consent from case participants, and Conflicts of Interest: 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..

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