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

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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.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.

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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

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.

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4. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

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. Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.wiley.com, doi.org.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

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

13. 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

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