Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK

Goodwin et al., PLOS ONE, doi:10.1371/journal.pone.0281915, Mar 2023

https://c19early.org/goodwinm.html

Retrospective 604 outpatients in the UK, showing lower risk of hospitalization with molnupiravir treatment, without statistical significance due to the small number of hospitalizations.

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, the United Kingdom, is very poor with very low average efficacy for approved treatments20. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of treatment—especially early—due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.

Important missing comments or errors? Let us know.

Study covers molnupiravir and sotrovimab.

risk of death, 110.0% higher, RR 2.10, p = 0.47, treatment 1 of 80 (1.2%), control 2 of 336 (0.6%).

risk of hospitalization, 58.0% lower, RR 0.42, p = 0.70, treatment 1 of 80 (1.2%), control 10 of 336 (3.0%), NNT 58, COVID-19 related.

risk of hospitalization, 53.3% lower, RR 0.47, p = 0.39, treatment 2 of 80 (2.5%), control 18 of 336 (5.4%), NNT 35, all cause.

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/united-kingdom.html.c19early.org/soc/united-kingdom.html.

Goodwin et al., 15 Mar 2023, retrospective, United Kingdom, peer-reviewed, 3 authors, study period 22 December, 2021 - 20 February, 2022. Contact: amanda.goodwin@nottingham.ac.uk.

This Paper Molnupiravir All

Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK

Amanda T Goodwin, Jonathan S Thompson, Ian P Hall

PLOS ONE, doi:10.1371/journal.pone.0281915

Introduction Antivirals, such as molnupiravir, and SARS-CoV-2 neutralising monoclonal antibodies (nMAbs), such as sotrovimab, reduced the risk of hospitalisation and death in clinical trials of high-risk non-hospitalised patients with Covid-19. However, the real-world benefits of these drugs are unclear. Aims To evaluate the characteristics and outcomes of high-risk patients referred for outpatient antiviral or nMAb treatment for symptomatic Covid-19. Methods The records of patients referred to a large UK Covid Medicines Delivery Unit (CMDU) over nine weeks (December 2021-February 2022) were reviewed. Data were collected on demographics, referral indications, vaccination, deprivation, treatment, complications, hospital admission, and mortality. Results 1820 patients were referred to the CMDU, with 604 (33.2%) suitable for further assessment. 169 patients received sotrovimab, 80 patients received molnupiravir, 70 patients declined treatment, and 266 were ineligible for treatment because of resolving symptoms. There were trends towards higher proportions of female and white patients, lower deprivation scores, and malignancy-or transplant-related indications in the groups receiving treatment compared with untreated patients. Covid-19-related hospitalisations occurred in 1.2% of the treated group and 3.0% of the untreated group indicating a potential treatment effect, however Covid-related hospitalisations were lower than reported in the original clinical trials (2.2% compared with 7-10%). Conclusion The referral pathways for outpatient treatment of Covid-19 are inefficient, and the UK system may not be serving all groups equitably. Hospitalisation with Covid-19 was rare

References

Bernal, Da Silva, Musungaie, Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Eng J Med, doi:10.1056/NEJMoa2116044

Bruel, Hadjadj, Maes, Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies, Nat Med, doi:10.1038/s41591-022-01792-5

Chavarot, Melenotte, Amrouche, Early treatment with sotrovimab monoclonal antibody in kidney transplant recipients with Omicron infection, Kidney Int, doi:10.1016/j.kint.2022.04.003

Deng, Heybati, Ba, Differential efficacy and safety of anti-SARS-CoV-2 antibody therapies for the management of COVID-19: a systematic review and network meta-analysis, Infection, doi:10.1007/s15010-022-01825-8

Dhand, Okumura, Wolfe, Sotrovimab for treatment of COVID-19 in solid organ transplant recipients, Transplantation, doi:10.1097/TP.0000000000004136

Gupta, Gonzales-Rojas, Juarez, Early treatment for Covid-19 with SARS-CoV-2 Neutralizing antibody sotrovimab, N Engl J Med, doi:10.1056/NEJMoa2107934

Gupta, Gonzales-Rojas, Juarez, Effect of sotrovimab on hospitalisation or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial, JAMA, doi:10.1001/jama.2022.2832

Nhs England, Statistical work areas: COVID-19 therapeutics (antivirals, neutralising monoclonal antibodies, and interleukin 6 inhibitors

Scobie, Morris, Quality and inequality: digging deeper

DOI record: { "DOI": "10.1371/journal.pone.0281915", "ISSN": [ "1932-6203" ], "URL": "http://dx.doi.org/10.1371/journal.pone.0281915", "abstract": "\nIntroduction\nAntivirals, such as molnupiravir, and SARS-CoV-2 neutralising monoclonal antibodies (nMAbs), such as sotrovimab, reduced the risk of hospitalisation and death in clinical trials of high-risk non-hospitalised patients with Covid-19. However, the real-world benefits of these drugs are unclear.\n\n\nAims\nTo evaluate the characteristics and outcomes of high-risk patients referred for outpatient antiviral or nMAb treatment for symptomatic Covid-19.\n\n\nMethods\nThe records of patients referred to a large UK Covid Medicines Delivery Unit (CMDU) over nine weeks (December 2021-February 2022) were reviewed. Data were collected on demographics, referral indications, vaccination, deprivation, treatment, complications, hospital admission, and mortality.\n\n\nResults\n1820 patients were referred to the CMDU, with 604 (33.2%) suitable for further assessment. 169 patients received sotrovimab, 80 patients received molnupiravir, 70 patients declined treatment, and 266 were ineligible for treatment because of resolving symptoms. There were trends towards higher proportions of female and white patients, lower deprivation scores, and malignancy- or transplant-related indications in the groups receiving treatment compared with untreated patients. Covid-19-related hospitalisations occurred in 1.2% of the treated group and 3.0% of the untreated group indicating a potential treatment effect, however Covid-related hospitalisations were lower than reported in the original clinical trials (2.2% compared with 7–10%).\n\n\nConclusion\nThe referral pathways for outpatient treatment of Covid-19 are inefficient, and the UK system may not be serving all groups equitably. Hospitalisation with Covid-19 was rare regardless of treatment. Ongoing service evaluation is required to ensure efficient use of resources for the outpatient management of Covid-19.\n", "author": [ { "ORCID": "http://orcid.org/0000-0002-1488-6549", "affiliation": [], "authenticated-orcid": true, "family": "Goodwin", "given": "Amanda T.", "sequence": "first" }, { "affiliation": [], "family": "Thompson", "given": "Jonathan S.", "sequence": "additional" }, { "affiliation": [], "family": "Hall", "given": "Ian P.", "sequence": "additional" } ], "container-title": "PLOS ONE", "container-title-short": "PLoS ONE", "content-domain": { "crossmark-restriction": false, "domain": [ "www.plosone.org" ] }, "created": { "date-parts": [ [ 2023, 3, 15 ] ], "date-time": "2023-03-15T17:25:42Z", "timestamp": 1678901142000 }, "deposited": { "date-parts": [ [ 2023, 3, 15 ] ], "date-time": "2023-03-15T17:25:57Z", "timestamp": 1678901157000 }, "editor": [ { "affiliation": [], "family": "Lee", "given": "Seung-Hwa", "sequence": "first" } ], "funder": [ { "DOI": "10.13039/501100000272", "award": [ "I.P. Hall holds a NIHR Senior Investigator award (NF-SI-0617-10096)" ], "doi-asserted-by": "publisher", "name": "National Institute for Health Research" }, { "DOI": "10.13039/501100000272", "award": [ "ATG holds an NIHR-funded Academic Clinical Lecturer post (CL-2020-12-003)" ], "doi-asserted-by": "publisher", "name": "National Institute for Health Research" } ], "indexed": { "date-parts": [ [ 2023, 3, 16 ] ], "date-time": "2023-03-16T04:42:29Z", "timestamp": 1678941749610 }, "is-referenced-by-count": 0, "issue": "3", "issued": { "date-parts": [ [ 2023, 3, 15 ] ] }, "journal-issue": { "issue": "3", "published-online": { "date-parts": [ [ 2023, 3, 15 ] ] } }, "language": "en", "license": [ { "URL": "http://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 3, 15 ] ], "date-time": "2023-03-15T00:00:00Z", "timestamp": 1678838400000 } } ], "link": [ { "URL": "https://dx.plos.org/10.1371/journal.pone.0281915", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "340", "original-title": [], "page": "e0281915", "prefix": "10.1371", "published": { "date-parts": [ [ 2023, 3, 15 ] ] }, "published-online": { "date-parts": [ [ 2023, 3, 15 ] ] }, "publisher": "Public Library of Science (PLoS)", "reference": [ { "key": "pone.0281915.ref001", "unstructured": "World Health Organisation (WHO) Coronavirus (COVID-19) dashboard. https://covid19.who.int Accessed 1/12/22." }, { "article-title": "Differential efficacy and safety of anti-SARS-CoV-2 antibody therapies for the management of COVID-19: a systematic review and network meta-analysis", "author": "J Deng", "journal-title": "Infection", "key": "pone.0281915.ref002", "year": "2022" }, { "key": "pone.0281915.ref003", "unstructured": "NHS interim clinical commissioning policy: neutralising monoclonal antibodies or antivirals for non-hospitalised patients with COVID-19. C1603. Published 24th February 2022. https://www.england.nhs.uk/coronavirus/documents/c1603-interim-clinical-commissioning-policy-antivirals-or-neutralising-monoclonal-antibodies-for-non-hospitalised-patients-with-covid-19-version-5. Accessed 21st April 2022" }, { "DOI": "10.1056/NEJMoa2107934", "article-title": "Early treatment for Covid-19 with SARS-CoV-2 Neutralizing antibody sotrovimab", "author": "A Gupta", "doi-asserted-by": "crossref", "first-page": "1941", "issue": "21", "journal-title": "N Engl J Med", "key": "pone.0281915.ref004", "volume": "385", "year": "2021" }, { "DOI": "10.1001/jama.2022.2832", "article-title": "Effect of sotrovimab on hospitalisation or death among high-risk patients with mild to moderate COVID-19: a randomized clinical trial", "author": "A Gupta", "doi-asserted-by": "crossref", "first-page": "1236", "issue": "13", "journal-title": "JAMA", "key": "pone.0281915.ref005", "volume": "327", "year": "2022" }, { "DOI": "10.1056/NEJMoa2116044", "article-title": "Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients", "author": "A Jayk Bernal", "doi-asserted-by": "crossref", "first-page": "509", "issue": "6", "journal-title": "N Eng J Med", "key": "pone.0281915.ref006", "volume": "386", "year": "2022" }, { "key": "pone.0281915.ref007", "unstructured": "NHS England. Statistical work areas: COVID-19 therapeutics (antivirals, neutralising monoclonal antibodies, and interleukin 6 inhibitors). https://www.england.nhs.uk/statistics/statistical-work-areas/covid-therapeutics-antivirals-and-neutralising-monoclonal-antibodies/. Accessed 14th May 2022." }, { "key": "pone.0281915.ref008", "unstructured": "UK Government. Indices of multiple deprivation maps 2015 and 2019. http://dclgapps.communities.gov.uk/imd/iod_index.html" }, { "key": "pone.0281915.ref009", "unstructured": "Ministry of Housing, Communities and Local Government. English indices of deprivation 2019 –LOSA level. https://opendatacommunities.org/resource?uri=http%3A%2F%2Fopendatacommunities.org%2Fdata%2Fsocietal-wellbeing%2Fimd2019%2Findices. Accessed April 2022" }, { "key": "pone.0281915.ref010", "unstructured": "UK Health Security Agency. SARS-CoV-2 variants of concern and variants under investigation in England: Technical briefing 37. Published 25th February 2022. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1057359/Technical-Briefing-37-25February2022.pdf" }, { "DOI": "10.1016/j.kint.2022.04.003", "article-title": "Early treatment with sotrovimab monoclonal antibody in kidney transplant recipients with Omicron infection", "author": "N Chavarot", "doi-asserted-by": "crossref", "first-page": "1290", "issue": "6", "journal-title": "Kidney Int", "key": "pone.0281915.ref011", "volume": "101", "year": "2022" }, { "DOI": "10.1097/TP.0000000000004136", "article-title": "Sotrovimab for treatment of COVID-19 in solid organ transplant recipients", "author": "A Dhand", "doi-asserted-by": "crossref", "first-page": "e336", "issue": "7", "journal-title": "Transplantation", "key": "pone.0281915.ref012", "volume": "106", "year": "2022" }, { "author": "S Scobie", "key": "pone.0281915.ref013", "volume-title": "Quality and inequality: digging deeper", "year": "2020" }, { "DOI": "10.1038/s41591-022-01792-5", "article-title": "Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies", "author": "T Bruel", "doi-asserted-by": "crossref", "first-page": "1297", "issue": "6", "journal-title": "Nat Med", "key": "pone.0281915.ref014", "volume": "28", "year": "2022" }, { "key": "pone.0281915.ref015", "unstructured": "UK Health Security Agency. SARS-CoV-2 therapeutics technical briefing 3: Genomic surveillance. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1074186/therapeutics-programme-technical-briefing-3.pdf. Accessed 13th July 2022." }, { "key": "pone.0281915.ref016", "unstructured": "US Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization. Accessed 22nd April 2022" } ], "reference-count": 16, "references-count": 16, "relation": {}, "resource": { "primary": { "URL": "https://dx.plos.org/10.1371/journal.pone.0281915" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Multidisciplinary" ], "subtitle": [], "title": "Evaluation of outpatient treatment for non-hospitalised patients with COVID-19: The experience of a regional centre in the UK", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1371/journal.pone.corrections_policy", "volume": "18" }

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0