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

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

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.

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. 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.

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.

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

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