Nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of Covid-19: a population-based cohort study

Jorda et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofae631.2173

Jan 2025

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Retrospective 113,399 outpatients in Austria showing lower hospitalization and mortality with paxlovid treatment in patients over 60, but no significant differences with molnupiravir. Viral rebound was observed after treatment with both antivirals. For paxlovid, authors do not show the results for all patients, selectively showing only results for the subgroup ≥60, and authors do not appear to have excluded patients with contraindications to paxlovid. The paper references supplementary tables but no supplementary appendix is currently available.

Confounding by contraindication. Hoertel et al. find that over 50% of patients that died had a contraindication for the use of paxlovid1. Retrospective studies that do not exclude contraindicated patients may significantly overestimate the efficacy of paxlovid.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity2-15. Multiple analyses have identified variants potentially created by molnupiravir16-20.

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risk of death, 27.0% higher, HR 1.27, p = 0.50, treatment 14 of 10,752 (0.1%), control 21 of 21,504 (0.1%), propensity score matching.

risk of hospitalization, 1.0% higher, HR 1.01, p = 0.93, treatment 150 of 10,752 (1.4%), control 297 of 21,504 (1.4%), propensity score matching.

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

1. Hoertel et al., Prevalence of Contraindications to Nirmatrelvir-Ritonavir Among Hospitalized Patients With COVID-19 at Risk for Progression to Severe Disease, JAMA Network Open, doi:10.1001/jamanetworkopen.2022.42140.jamanetwork.com, doi.org.

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

3. 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.

4. 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.hku.hk.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

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

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

Jorda et al., 29 Jan 2025, retrospective, Austria, peer-reviewed, 7 authors, study period January 2022 - May 2023.

This Paper Molnupiravir All

P-2016. Nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of Covid-19: a population-based cohort study

MD Anselm Jorda, ; Dominik Ensle, Hubert Eser, Florentin Glötzl, Benjamin Riedl, Ursula Karnthaler, MD Markus Zeitlinger

Background. The real-world effectiveness of the oral antivirals nirmatrelvirritonavir and molnupiravir against the SARS-CoV-2 Omicron variant remains uncertain. Our aim was to evaluate their effectiveness in non-hospitalized adults with Covid-19 in Vienna, Austria.

DOI record: { "DOI": "10.1093/ofid/ofae631.2173", "ISSN": [ "2328-8957" ], "URL": "http://dx.doi.org/10.1093/ofid/ofae631.2173", "abstract": "Abstract\n \n Background\n The real-world effectiveness of the oral antivirals nirmatrelvir-ritonavir and molnupiravir against the SARS-CoV-2 Omicron variant remains uncertain. Our aim was to evaluate their effectiveness in non-hospitalized adults with Covid-19 in Vienna, Austria.Figure 1:Kaplan-Meier curves of (A) the hospitalization within 28 days between nirmatrelvir-ritonavir vs matched untreated controls, (B) hospitalization within 28 days between molnupiravir vs matched untreated controls, (C) all-cause death within 28 days between nirmatrelvir-ritonavir vs matched untreated controls, and (D) all-cause death within 28 days between molnupiravir vs matched untreated controls. All curves were based on propensity score-matched analysis. The shaded areas indicate 95% confidence intervals. The Y-axis does not range from 0 to 100% because of the low incidence.\n \n \n Methods\n This observational study used data from the Municipal Department for Public Health Services of Vienna to identify non-hospitalized adults with confirmed SARS-CoV-2 infection between Jan-2022 and May-2023. Untreated controls were matched to nirmatrelvir-ritonavir users and molnupiravir users in a 2:1 ratio using propensity scores. Outcomes were hospitalization and all-cause death within 28 days.Figure 2:CT values over time between (A) nirmatrelvir-ritonavir vs untreated controls and (B) molnupiravir vs untreated controls.\n Shaded areas represent the 95% CI of the mean CT value. Dots indicate the time points of group comparisons using an independent t-test. The numbers indicate the number of subjects per group on days 0, 4, 7, 10, and 14. The results of the mean differences with 95% confidence intervals are provided in Supplementary Tables 4 and 5 (wherever the 95% confidence intervals did not cross, a statistically significant difference was found). The horizontal dotted line indicates a CT value of 30, which is usually defined as the threshold for the end of the infection and contagiousness. Vertical dotted lines indicate the presumed start and end of the 5-day treatment course with (A) nirmatrelvir-ritonavir or (B) molnupiravir.\n \n \n Results\n We identified 113,399 eligible cases with SARS-CoV-2 infection. Of 90,481 untreated controls, 24,332 were matched to 12,166 nirmatrelvir-ritonavir users and 21,504 were matched to 10,752 molnupiravir users. In the nirmatrelvir-ritonavir matched analysis set, 52 (0.43%) of 12166 nirmatrelvir-ritonavir users and 194 (0.8%) of 24332 matched controls were hospitalized (HR 0.53, 95%CI 0.39-0.73). No (0%) nirmatrelvir-ritonavir users and 20 (0.08%) matched controls died (p&lt; 0.0001) (Figure 1). This finding for nirmatrelvir-ritonavir was independent of vaccination status but was restricted to people aged ≥60 years. In the molnupiravir-matched analysis set, 150 (1.4%) of 10752 molnupiravir users and 297 (1.38%) of 21504 matched controls were hospitalized (HR 1.01, 95%CI 0.83-1.23), with 14 (0.13%) and 21 (0.1%) deaths, respectively (HR 1.27, 95%CI 0.65-2.49) (Figure 1). Over 96% of the patients included were vaccinated. For both antiviral agents a rebound in viral load was observed after an initially accelerated viral clearance (Figure 2).\n \n \n Conclusion\n Among outpatients aged ≥60 years with Covid-19 caused by the Omicron variant, treatment with nirmatrelvir-ritonavir was associated with a significantly lower risk of hospitalization and all-cause mortality within 28 days. This finding was not observed in molnupiravir users and younger nirmatrelvir-ritonavir users.\n \n \n Disclosures\n All Authors: No reported disclosures\n ", "author": [ { "affiliation": [ { "name": "Medical University of Vienna , Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Jorda", "given": "Anselm", "sequence": "first" }, { "affiliation": [ { "name": "Municipal Department for Public Health Services of the City of Vienna , Vienna, Austria, Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Ensle", "given": "Dominik", "sequence": "additional" }, { "affiliation": [ { "name": "Municipal Department for Information Technology of the City of Vienna , Vienna, Austria, Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Eser", "given": "Hubert", "sequence": "additional" }, { "affiliation": [ { "name": "Institute for Ecological Economics, Department for Socioeconomics, Vienna University of Economics and Business , Austria, Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Glötzl", "given": "Florentin", "sequence": "additional" }, { "affiliation": [ { "name": "Institute for Ecological Economics, Department for Socioeconomics, Vienna University of Economics and Business , Austria, Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Riedl", "given": "Benjamin", "sequence": "additional" }, { "affiliation": [ { "name": "Municipal Department for Public Health Services of the City of Vienna , Vienna, Austria, Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Karnthaler", "given": "Ursula", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Clinical Pharmacology , Vienna, Wien ,", "place": [ "Austria" ] } ], "family": "Zeitlinger", "given": "Markus", "sequence": "additional" } ], "container-title": "Open Forum Infectious Diseases", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2025, 1, 29 ] ], "date-time": "2025-01-29T19:35:17Z", "timestamp": 1738179317000 }, "deposited": { "date-parts": [ [ 2025, 1, 29 ] ], "date-time": "2025-01-29T22:17:53Z", "timestamp": 1738189073000 }, "indexed": { "date-parts": [ [ 2025, 1, 30 ] ], "date-time": "2025-01-30T06:17:26Z", "timestamp": 1738217846994, "version": "3.34.0" }, "is-referenced-by-count": 0, "issue": "Supplement_1", "issued": { "date-parts": [ [ 2025, 1, 29 ] ] }, "journal-issue": { "issue": "Supplement_1", "published-print": { "date-parts": [ [ 2025, 1, 29 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2025, 1, 29 ] ], "date-time": "2025-01-29T00:00:00Z", "timestamp": 1738108800000 } } ], "link": [ { "URL": "https://academic.oup.com/ofid/article-pdf/12/Supplement_1/ofae631.2173/61679837/ofae631.2173.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/ofid/article-pdf/12/Supplement_1/ofae631.2173/61679837/ofae631.2173.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2025, 1, 29 ] ] }, "published-online": { "date-parts": [ [ 2025, 1, 29 ] ] }, "published-other": { "date-parts": [ [ 2025, 2 ] ] }, "published-print": { "date-parts": [ [ 2025, 1, 29 ] ] }, "publisher": "Oxford University Press (OUP)", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/ofid/article/doi/10.1093/ofid/ofae631.2173/7988734" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "P-2016. Nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of Covid-19: a population-based cohort study", "type": "journal-article", "volume": "12" }

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