Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

Bajema et al., medRxiv, doi:10.1101/2022.12.05.22283134, Dec 2022

https://c19early.org/bajemam.html

Retrospective 112,380 high-risk patients in the USA, showing significantly higher acute or long-term care admission at 180 days with molnupiravir treatment, and no significant difference for other outcomes. The title and headers of Table S14 are conflicting but the data appears to match be title.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-15. Multiple analyses have identified variants potentially created by molnupiravir16-20.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments21. Only expensive, high-profit treatments were approved for early treatment. Low-cost treatments were excluded, reducing the probability of early treatment due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

Important missing comments or errors? Let us know.

Study covers paxlovid and molnupiravir.

risk of death, 18.0% lower, HR 0.82, p = 0.40, treatment 24 of 897 (2.7%), control 29.0 of 897 (3.2%), NNT 179, cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of death, 49.3% lower, RR 0.51, p = 0.19, treatment 7 of 897 (0.8%), control 13.8 of 897 (1.5%), NNT 132, propensity score matching, day 30.

risk of mechanical ventilation, 16.7% lower, RR 0.83, p = 1.00, treatment 3 of 897 (0.3%), control 3.6 of 897 (0.4%), NNT 1495, propensity score matching, day 30.

risk of ICU admission, 1.0% lower, RR 0.99, p = 1.00, treatment 10 of 897 (1.1%), control 10.1 of 897 (1.1%), NNT 8970, propensity score matching, day 30.

risk of hospitalization, 30.0% higher, HR 1.30, p = 0.04, treatment 162 of 897 (18.1%), control 124.3 of 897 (13.9%), cumulative 0-180 days, propensity score matching, day 180, Table S14.

risk of hospitalization, 8.6% lower, RR 0.91, p = 0.73, treatment 37 of 897 (4.1%), control 40.5 of 897 (4.5%), NNT 256, propensity score matching, 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.

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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. Huntsman (B) et al., Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays, Toxicological Sciences, doi:10.1093/toxsci/kfaf093.oup.com, doi.org.

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.

21. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Bajema et al., 6 Dec 2022, retrospective, USA, preprint, median age 67.0, 18 authors, study period 1 January, 2022 - 28 February, 2022.

This Paper Molnupiravir All

Effectiveness of COVID-19 treatment with nirmatrelvir-ritonavir or molnupiravir among U.S. Veterans: target trial emulation studies with one-month and six-month outcomes

MD, MSc Kristina L Bajema, PhD Kristin Berry, PhD Elani Streja, PhD Nallakkandi Rajeevan, MS Yuli Li, PhD Lei Yan, PharmD Francesca Cunningham, MPH Denise M Hynes, MPH Mazhgan Rowneki, PhD, MHS Amy Bohnert, Edward J Boyko, MD, PhD Theodore J Iwashyna, PhD Matthew L Maciejewski, Thomas F Osborne, MD, MPH, MSc Elizabeth M Viglianti, PhD Mihaela Aslan, MPH, PhD Grant D Huang, BMBCh George N Ioannou

doi:10.1101/2022.12.05.22283134

Background: Information about the effectiveness of oral antivirals in preventing short-and longterm COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or longterm care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, ). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, . A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir-or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral. for use under a CC0 license.

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DOI record: { "DOI": "10.1101/2022.12.05.22283134", "URL": "http://dx.doi.org/10.1101/2022.12.05.22283134", "abstract": "Background: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI -16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. 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