Effectiveness of Molnupiravir in High Risk Patients: a Propensity Score Matched Analysis

Najjar-Debbiny et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac781, Sep 2022

PSM retrospective 2,661 molnupiravir patients in Israel, showing lower mortality and severe COVID-19, without statistical significance. Significant benefit was seen in some subgroups, and significant harm was seen in the <75 subgroup.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-14. Multiple analyses have identified variants potentially created by molnupiravir15-19.

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risk of death, 19.0% lower, HR 0.81, p = 0.48, treatment 22 of 2,661 (0.8%), control 27 of 2,661 (1.0%), NNT 532, propensity score matching.

risk of progression, 17.0% lower, HR 0.83, p = 0.34, treatment 50 of 2,661 (1.9%), control 60 of 2,661 (2.3%), NNT 266, severe COVID-19 or COVID-19 mortality, propensity score matching.

risk of severe case, 25.0% lower, HR 0.75, p = 0.15, treatment 43 of 2,661 (1.6%), control 57 of 2,661 (2.1%), NNT 190, propensity score matching.

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

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6. 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.

7. 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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12. 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.

13. 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.

14. Mori et al., Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir, Free Radical Research, doi:10.1080/10715762.2025.2469738.tandfonline.com, doi.org.

15. 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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19. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Najjar-Debbiny et al., 20 Sep 2022, retrospective, Israel, peer-reviewed, 8 authors, study period January 2022 - February 2022. Contact: ronzana@clalit.org.il, ronza.najjar@gmail.com, saliba_wa@clalit.org.il, salibuss@technion.ac.il.

This Paper Molnupiravir All

Effectiveness of Molnupiravir in High Risk Patients: a Propensity Score Matched Analysis

MD Ronza Najjar-Debbiny, MD Naomi Gronich, MD Gabriel Weber, MD Johad Khoury, MD Maisam Amar, MPH Nili Stein, Hilary Lee, MD Goldstein, MD, MPH Walid Saliba

Background: Molnupiravir was granted emergency use authorization for the treatment of mild to moderate . In this study we used population-based real-world data to evaluate the effectiveness of Molnupiravir. Methods: The database of the largest healthcare provider in Israel was used to identify all adults with first ever positive test for SARS-CoV-2 performed in the community during January-February 2022, who were at high risk for severe COVID-19 and had no contraindications for Molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status. A total of 2661 patients who received Molnupiravir were propensity score-matched with 2661 patients who have not received Molnupiravir (control group). Patients were followed through 10 March 2022 for up to 28 days for the first occurrence of the composite severe COVID-19 or COVID-19 specific mortality. Results: The composite outcome occurred in 50 patients in the Molnupiravir group and 60 patients in the control group. Molnupiravir was associated with a nonsignificant reduced risk of the composite outcome HR, 0.83 (95% CI, 0.57-1.21). However, subgroup analyses showed that Molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients 0.54 (0.34-0.86), in females 0.41 (0.22-0.77), and in patients with inadequate COVID-19 vaccination 0.45 (0.25-0.82). The results were similar when each component of the composite outcome were examined separately. Conclusions: This study suggests that in the era of omicron and in real life setting Molnupiravir might be effective in reducing the risk of severe COVID-19 and COVID-19 related mortality, particularly in specific subgroups.

Conflict of interest The authors report no potential conflicts of interest. A C C E P T E D

References

Austin, An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies, Multivariate Behav Res, doi:10.1080/00273171.2011.568786

Barda, Dagan, Ben-Shlomo, Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting, N Engl J Med, doi:10.1056/NEJMoa2110475

Bernal, Da Silva, Musungaie, Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients, N Engl J Med, doi:10.1056/NEJMoa2116044

Doweck, Yanir, Najjar-Debbiny, Shibli, Saliba, Sudden Sensorineural Hearing Loss During the COVID-19 Pandemic, JAMA Otolaryngol Head Neck Surg, doi:10.1001/jamaoto.2021.4105

Hammond, Leister-Tebbe, Gardner, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2118542

Imran, Arora, Asdaq, Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19, Molecules, doi:10.3390/molecules26195795

Menéndez-Arias, Decoding molnupiravir-induced mutagenesis in SARS-CoV-2, J Biol Chem, doi:10.1016/j.jbc.2021.100867

Najjar-Debbiny, Gronich, Weber, Effectiveness of Paxlovid in Reducing Severe COVID-19 and Mortality in High Risk Patients

Rosenberg, Holtgrave, Dorabawila, New COVID-19 Cases and Hospitalizations Among Adults, by Vaccination Status -New York, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7034e1

Tenforde, Self, Naioti, Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults -United States, March, MMWR Morb Mortal Wkly Rep, doi:10.15585/mmwr.mm7034e2

DOI record: { "DOI": "10.1093/cid/ciac781", "ISSN": [ "1058-4838", "1537-6591" ], "URL": "http://dx.doi.org/10.1093/cid/ciac781", "abstract": "Abstract\n \n Background\n Molnupiravir was granted emergency use authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19). In this study, we used population-based real-world data to evaluate the effectiveness of molnupiravir.\n \n \n Methods\n The database of the largest healthcare provider in Israel was used to identify all adults with first-ever positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) performed in the community during January–February 2022, who were at high risk for severe COVID-19, and had no contraindications for molnupiravir use. Patients were included regardless of SARS-CoV-2 vaccination status. A total of 2661 patients who received molnupiravir were propensity score matched with 2661 patients who have not received molnupiravir (control group). Patients were followed through 10 March 2022 for up to 28 days for the first occurrence of the composite severe COVID-19 or COVID-19-specific mortality.\n \n \n Results\n The composite outcome occurred in 50 patients in the molnupiravir group and 60 patients in the control group. Molnupiravir was associated with a nonsignificant reduced risk of the composite outcome: hazard ratio, 0.83 (95% confidence interval, .57–1.21). However, subgroup analyses showed that molnupiravir was associated with a significant decrease in the risk of the composite outcome in older patients 0.54 (0.34–0.86), in females 0.41 (0.22–0.77), and in patients with inadequate COVID-19 vaccination 0.45 (0.25–0.82). The results were similar when each component of the composite outcome was examined separately.\n \n \n Conclusions\n This study suggests that in the era of Omicron and in real-life setting, molnupiravir might be effective in reducing the risk of severe COVID-19 and COVID-19-related mortality, particularly in specific subgroups.\n ", "author": [ { "ORCID": "http://orcid.org/0000-0001-7586-3714", "affiliation": [ { "name": "Infection Control and Prevention Unit, Lady Davis Carmel Medical Center , Haifa , Israel" }, { "name": "Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa , Israel" } ], "authenticated-orcid": false, "family": "Najjar-Debbiny", "given": "Ronza", "sequence": "first" }, { "affiliation": [ { "name": "Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa , Israel" }, { "name": "Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center , Haifa , Israel" } ], 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Lady Davis Carmel Medical Center , Haifa , Israel" }, { "name": "Statistical Unit, Lady Davis Carmel Medical Center , Haifa , Israel" } ], "family": "Stein", "given": "Nili", "sequence": "additional" }, { "affiliation": [ { "name": "Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa , Israel" }, { "name": "Internal Medicine C, Emek Medical Center , Afula , Israel" }, { "name": "Pharmacology Unit, Emek Medical Center , Afula , Israel" } ], "family": "Goldstein", "given": "Lee Hilary", "sequence": "additional" }, { "affiliation": [ { "name": "Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa , Israel" }, { "name": "Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center , Haifa , Israel" }, { "name": "Translational Epidemiology Unit and Research Authority, Lady Davis Carmel Medical Center , Haifa , Israel" } ], "family": "Saliba", "given": "Walid", "sequence": "additional" } 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