Oral antivirals for COVID-19 among patients with cancer

Guermazi et al., Research Square, doi:10.21203/rs.3.rs-3876022/v1

Jan 2024

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Retrospective 67 cancer outpatients treated with nirmatrelvir/ritonavir or molnupiravir, compared to 56 untreated concurrent controls, reporting lower mortality with treatment. However, Figure 3 shows the opposite results for invasive mechanical ventilation, ~2 times higher for the treatment groups versus the control group. The discrepancy suggests that the groups are not comparable in some key aspect such as treatment availability or decisions, baseline conditions, and/or prevalence of non-COVID-19 related death. ECOG ≥2 was much more common for controls vs. treated patients. One possibility is that controls had more advanced existing disease and were more likely to choose not to receive life-sustaining treatments. The higher use of remdesivir for controls may also indicate greater severity and/or more delayed treatment based on prescribing guidelines, and may also contribute to increased mortality due to side effects within a more vulnerable population. Remdesivir shows increased mortality with longer followup c19early.org.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Chamod, Gruber, Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zhou, Zibat. Multiple analyses have identified variants potentially created by molnupiravir Fountain-Jones, Kosakovsky Pond, Sanderson, twitter.com.

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5. 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.

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

8. 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.

9. 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.

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

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

12. 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.

13. 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.

14. 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.

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Study covers molnupiravir and paxlovid.

Guermazi et al., 24 Jan 2024, retrospective, preprint, 5 authors, study period 1 April, 2020 - 1 August, 2023. Contact: dorra_guermazi@brown.edu.

This Paper Molnupiravir All

Oral antivirals for COVID-19 among patients with cancer

Dorra Guermazi, Panos Arvanitis, Kendra Vieira, Jeremy L Warner, Dimitrios Farmakiotis

doi:10.21203/rs.3.rs-3876022/v1

Purpose: Immunocompromised individuals, such as those diagnosed with cancer, are at a signi cantly higher risk for severe illness and mortality when infected with SARS-CoV-2 (COVID-19) than the general population. Two oral antiviral treatments are approved for COVID-19: Paxlovid® (nirmatrelvir/ritonavir) and Lagevrio® (molnupiravir). There is a paucity of data regarding the bene t from these antivirals among immunocompromised patients with cancer, and recent studies have questioned their e cacy among vaccinated patients, even those with risk factors for severe COVID-19. Methods: We evaluated the e cacy and safety of nirmatrelvir/ritonavir and molnupiravir in preventing severe illness and death using our database of 457 patients with cancer and COVID-19 from Brown University-a liated hospitals. 67 patients received nirmatrelvir/ritonavir or molnupiravir and were compared to 56 concurrent controls who received no antiviral treatment despite being eligible to receive it. Results: Administration of nirmatrelvir/ritonavir or molnupiravir was associated with improved survival and lower 90-day all-cause and COVID-19-attributed mortality (p<0.05) and with lower peak O2 requirements (ordinal odds ratio [OR] 1.52, 95% con dence interval [CI] 0.92-2.56). Conclusion: Acknowledging the small size of our sample as a limitation, we concluded that early antiviral treatment might be bene cial to immunocompromised individuals, particularly those with cancer, when infected with SARS-CoV-2. Larger-scale, well-strati ed studies are needed in this patient population.

Declarations Competing Interests DF has received research support from Viracor, Astellas and Merck, and consultant fee from Viracor. All other authors have nothing to disclose. Ethics approval: The study was approved by the Lifespan Institutional Review Board (IRB). The study was conducted in accordance with the declaration of Helsinki. Consent to publish: All authors agreed to the publication of the manuscript. Consent to participate: The study was approved by the Lifespan Institutional Review Board (IRB) with a waiver of informed consent given its retrospective design and de-identi ed data. Supplementary Files This is a list of supplementary les associated with this preprint. Click to download. SupplementaryMaterial.pdf

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