Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients

Yip et al., Clinical Infectious Diseases, doi:10.1093/cid/ciac687, May 2022 (preprint)

https://c19early.org/yip.html

Propensity score weighted retrospective of 93,883 outpatients in Hong Kong, 5,808 treated with molnupiravir and 4,921 treated with paxlovid, showing higher hospitalization and higher combined mortality/mechanical ventilation/ICU admission with molnupiravir, without statistical significance; and lower hospitalization and combined mortality/mechanical ventilation/ICU admission with paxlovid, statistically significant only for hospitalization.

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.

Standard of Care (SOC) for COVID-19 in the study country, China, is poor with low average efficacy for approved treatments20.

Important missing comments or errors? Let us know.

Study covers paxlovid and molnupiravir.

combined death/ventilation/ICU, 12.0% higher, HR 1.12, p = 0.66, treatment 53 of 5,808 (0.9%), control 151 of 83,154 (0.2%), propensity score weighting, Cox proportional hazards, day 30.

risk of hospitalization, 17.0% higher, HR 1.17, p = 0.06, treatment 437 of 5,808 (7.5%), control 1,322 of 83,154 (1.6%), propensity score weighting, Cox proportional hazards, day 30.

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. 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.

4. 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.

5. 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.

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.

8. 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.

9. 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.

10. 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.

11. 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.

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.

16. 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.

17. 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.

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

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

20. c19early.org, c19early.org/soc/china.html.c19early.org/soc/china.html.

Yip et al., 24 May 2022, retrospective, placebo-controlled, China, peer-reviewed, 11 authors, study period 16 February, 2022 - 31 March, 2022. Contact: wonglaihung@cuhk.edu.hk.

This Paper Molnupiravir All

PhD Terry Cheuk-Fung Yip, MD Chung-Yan Lui, BSc Mandy Sze-Man Lai, MD Wai-Sun Wong, MPhil Yee-Kit Tse, Hon-Ming Bosco, MD Ma, MD Elsie Hui, MFM Maria Kw Leung, Henry Lik-Yuen, MD Chan, MD Shu-Cheong Hui, Lai-Hung Grace, MBChB Wong

Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients

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DOI record: { "DOI": "10.1093/cid/ciac687", "ISSN": [ "1058-4838", "1537-6591" ], "URL": "http://dx.doi.org/10.1093/cid/ciac687", "abstract": "ABSTRACT\n \n Background\n We examined the effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and deaths in a real-world cohort of non-hospitalized COVID-19 patients.\n \n \n Methods\n This was a territory-wide retrospective cohort study in Hong Kong. Non-hospitalized COVID-19 patients who attended designated outpatient clinics between 16 February and 31 March 2022 were identified. Patients hospitalized on the day of the first clinic appointment or used both oral antivirals were excluded. The primary endpoint was hospitalization. The secondary endpoint was a composite of intensive care unit admission, invasive mechanical ventilation use, and/or death.\n \n \n Results\n Of 93,883 patients, 83,154 (88.6%), 5,808 (6.2%), and 4,921 (5.2%) were oral antiviral non-users, molnupiravir users, and nirmatrelvir/ritonavir users respectively. Compared to non-users, oral antiviral users were older and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year. Molnupiravir users were older, and had more comorbidities, lower complete vaccination rate, and more hospitalizations in the previous year than nirmatrelvir/ritonavir users. At a median follow-up of 30 days, 1,931 (2.1%) patients were hospitalized and 225 (0.2%) patients developed the secondary endpoint. After propensity score weighting, nirmatrelvir/ritonavir use (weighted hazard ratio 0.79, 95%CI 0.65-0.95, P = 0.011) but not molnupiravir use (weighted hazard ratio 1.17, 95%CI 0.99-1.39, P = 0.062) was associated with a reduced risk of hospitalization than non-users. The use of molnupiravir or nirmatrelvir/ritonavir was not associated with a lower risk of the secondary endpoint as compared to non-users.\n \n \n Conclusion\n Use of nirmatrelvir/ritonavir but not molnupiravir was associated with a reduced risk of hospitalization in real-world non-hospitalized COVID-19 patients.\n ", "author": [ { "ORCID": "http://orcid.org/0000-0002-1819-2464", "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Institute of Digestive Disease" } ], "authenticated-orcid": false, "family": "Yip", "given": "Terry Cheuk Fung", "sequence": "first" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Stanley Ho Centre for Emerging Infectious Diseases, Jockey Club School of Public Health & Primary Care" } ], "family": "Lui", "given": "Grace Chung Yan", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" } ], "family": "Lai", "given": "Mandy Sze Man", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Stanley Ho Centre for Emerging Infectious Diseases, Jockey Club School of Public Health & Primary Care" } ], "family": "Wong", "given": "Vincent Wai Sun", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Institute of Digestive Disease" } ], "family": "Tse", "given": "Yee Kit", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" } ], "family": "Ma", "given": "Bosco Hon Ming", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" } ], "family": "Hui", "given": "Elsie", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Family Medicine, Prince of Wales Hospital, Hospital Authority , Hong Kong" } ], "family": "Leung", "given": "Maria KW", "sequence": "additional" }, { "affiliation": [ { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Faculty of Medicine, The Chinese University of Hong Kong ; Hong Kong" }, { "name": "Department of Internal Medicine, Union Hospital , Hong Kong" } ], "family": "Chan", "given": "Henry Lik Yuen", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Stanley Ho Centre for Emerging Infectious Diseases, Jockey Club School of Public Health & Primary Care" } ], "family": "Hui", "given": "David Shu Cheong", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-2863-9389", "affiliation": [ { "name": "Department of Medicine and Therapeutics" }, { "name": "Medical Data Analytics Centre (MDAC)" }, { "name": "Institute of Digestive Disease" } ], "authenticated-orcid": false, "family": "Wong", "given": "Grace Lai Hung", "sequence": "additional" } ], "container-title": "Clinical Infectious Diseases", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 8, 29 ] ], "date-time": "2022-08-29T01:48:15Z", "timestamp": 1661737695000 }, "deposited": { "date-parts": [ [ 2022, 8, 29 ] ], "date-time": "2022-08-29T01:48:16Z", "timestamp": 1661737696000 }, "indexed": { "date-parts": [ [ 2022, 8, 29 ] ], "date-time": "2022-08-29T02:11:14Z", "timestamp": 1661739074182 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2022, 8, 29 ] ] }, "language": "en", "license": [ { "URL": "https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model", "content-version": "am", "delay-in-days": 0, "start": { "date-parts": [ [ 2022, 8, 29 ] ], "date-time": "2022-08-29T00:00:00Z", "timestamp": 1661731200000 } } ], "link": [ { "URL": "https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciac687/45601511/ciac687.pdf", "content-type": "application/pdf", "content-version": "am", "intended-application": "syndication" }, { "URL": "https://academic.oup.com/cid/advance-article-pdf/doi/10.1093/cid/ciac687/45601511/ciac687.pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "286", "original-title": [], "prefix": "10.1093", "published": { "date-parts": [ [ 2022, 8, 29 ] ] }, "published-online": { "date-parts": [ [ 2022, 8, 29 ] ] }, "publisher": "Oxford University Press (OUP)", "reference-count": 0, "references-count": 0, "relation": {}, "resource": { "primary": { "URL": "https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac687/6678124" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Infectious Diseases", "Microbiology (medical)" ], "subtitle": [], "title": "Impact of the use of oral antiviral agents on the risk of hospitalization in community COVID-19 patients", "type": "journal-article" }

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