Effectiveness of Molnupiravir Treatment in Patients with COVID-19 in Korea: A Propensity Score Matched Study

Park et al., Infection & Chemotherapy, doi:10.3947/ic.2023.0087

Nov 2023

PSM retrospective 190,692 COVID-19 patients treated with molnupiravir and 762,768 matched controls, showing lower mortality and combined severe/critical illness and mortality with treatment.

Confounding by treatment propensity. This study analyzes a population where only a fraction of eligible patients received the treatment. Patients receiving treatment may be more likely to follow other recommendations, more likely to receive additional care, and more likely to use additional treatments that are not tracked in the data (e.g., nasal/oral hygiene c19early.org, c19early.org (B), vitamin D c19early.org (C), etc.) — either because the physician recommending molnupiravir also recommended them, or because the patient seeking out molnupiravir is more likely to be familiar with the efficacy of additional treatments and more likely to take the time to use them. Therefore, these kind of studies may overestimate the efficacy of treatments.

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.

1. c19early.org, c19early.org/p.c19early.org/p.

2. c19early.org (B), c19early.org/ph.c19early.org/ph.

3. c19early.org (C), c19early.org/d.c19early.org/d.

4. 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.

5. 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.

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. 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.

8. 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.

9. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.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. 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. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

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

14. 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.

15. 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.

16. 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.

Important missing comments or errors? Let us know.

risk of death, 25.1% lower, OR 0.75, p < 0.001, RR approximated with OR.

risk of progression, 28.6% lower, OR 0.71, p < 0.001, RR approximated with OR.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Park et al., 22 Nov 2023, retrospective, South Korea, peer-reviewed, 6 authors, study period 1 August, 2022 - 31 March, 2023. Contact: erijykim@korea.kr.

This Paper Molnupiravir All

Effectiveness of Molnupiravir Treatment in Patients with COVID-19 in Korea: A Propensity Score Matched Study

Hye Rim Park, Min-Gyu Yoo, Jong Mu Kim, Soon Jong Bae, Hyungmin Lee, PhD Jungyeon Kim

Infection & Chemotherapy, doi:10.3947/ic.2023.0087

Background: The MOVe-OUT (efficacy and safety of molnupiravir in non-hospitalized adult participants with ) trial reported that the administration of molnupiravir in unvaccinated patients with coronavirus disease 2019 (COVID-19) before the Omicron epidemic showed a preventive effect of 31% against hospitalization and death. However, studies on the preventive effect of molnupiravir against progression to severe disease and death in patients with COVID-19 during the Omicron epidemic are limited. This study aimed to evaluate the preventive effect of molnupiravir against severe/critical illness or death and death in Korean patients with COVID-19 who were vaccinated mostly during the Omicron epidemic. Materials and Methods: This study used large-scale retrospective cohort data to select patients with COVID-19 who were either treated or not treated with molnupiravir, between August 2022 and March 2023, at a ratio of 1 : 4 using the propensity score matching method. In total, 762,768 patients comprised the non-administered group, and 190,692 patients comprised the molnupiravir-administered group. The preventive effect of molnupiravir against severe/ critical illness or death and death was analyzed using logistic regression analysis. Results: The preventive effect of molnupiravir against severe/critical illness or death and death, represented by the odds ratio (OR) and 95% confidence interval (CI), in the molnupiravir-administered and non-administered group was (OR: 0.714; CI: 0.667 -0.764) and (OR: 0.749; CI: 0.682 -0.823), respectively. As age increased, the preventive effect against severe/critical illness or death and death increased. The preventive effect against severe/critical illness or death at ≥60 years was (OR: 0.

Conflict of interest No conflict of interest. Author Contributions

References

Arbel, Sagy, Hoshen, Battat, Lavie et al., Nirmatrelvir use and severe Covid-19 outcomes during the omicron surge, N Engl J Med, doi:10.1056/NEJMoa2204919

Bajema, Berry, Streja, Rajeevan, Li et al., 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, Ann Intern Med, doi:10.7326/M22-3565

Bernal, Da Silva, Musungaie, Kovalchuk, Gonzalez et al., Williams-8/10 icjournal

Bestetti, Furlan-Daniel, Silva, Pharmacological Treatment of Patients with Mild to Moderate COVID-19: a comprehensive review, Int J Environ Res Public Health, doi:10.3390/ijerph18137212

Butler, Hobbs, Gbinigie, Rahman, Hayward et al., Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an openlabel, platform-adaptive randomised controlled trial, Lancet, doi:10.1016/S0140-6736(22)02597-1

Diaz, Brown, Du, Pedley, Assaid et al., Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients, N Engl J Med, doi:10.1056/NEJMoa2116044

Fiolet, Kherabi, Macdonald, Ghosn, Peiffer-Smadja, Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: a narrative review, Clin Microbiol Infect, doi:10.1016/j.cmi.2021.10.005

Gandhi, Lynch, Rio, Mild or moderate Covid-19, N Engl J Med, doi:10.1056/NEJMcp2009249

Guan, Liang, Zhao, Liang, Chen et al., China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis, Eur Respir J, doi:10.1183/13993003.00547-2020

Hammond, Leister-Tebbe, Gardner, Abreu, Wisemandle et al., Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2118542

Hoertel, Boulware, Sánchez-Rico, Burgun, Limosin, Prevalence of contraindications to nirmatrelvir-ritonavir among hospitalized patients with COVID-19 at risk for progression to severe disease, JAMA Netw Open, doi:10.1001/jamanetworkopen.2022.42140

Ito, Piantham, Nishiura, Relative instantaneous reproduction number of Omicron SARS-CoV-2 variant with respect to the Delta variant in Denmark, J Med Virol, doi:10.1002/jmv.27560

Kim, Yoo, Bae, Kim, Lee, Effectiveness of paxlovid, an oral antiviral drug, against the Omicron BA.5 variant in Korea: severe progression and death between July and November 2022, J Korean Med Sci, doi:10.3346/jkms.2023.38.e211

Lee, Hsieh, Ko, Molnupiravir-A novel oral anti-SARS-CoV-2 agent, Antibiotics, doi:10.3390/antibiotics10111294

Lv, Lv, Clinical characteristics and analysis of risk factors for disease progression of COVID-19: a retrospective Cohort Study, Int J Biol Sci, doi:10.7150/ijbs.50654

Najjar-Debbiny, Gronich, Weber, Khoury, Amar et al., Effectiveness of molnupiravir in highrisk patients: a propensity score matched analysis, Clin Infect Dis, doi:10.1093/cid/ciac781

Painter, Holman, Bush, Almazedi, Malik et al., Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2, Antimicrob Agents Chemother, doi:10.1128/AAC.02428-20

Paraskevis, Gkova, Mellou, Gerolymatos, Psalida et al., Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir as treatments for COVID-19 in high-risk patients, J Infect Dis

Park, Park, Lee, Yu, Song et al., The effectiveness of Paxlovid treatment in long-term care facilities in South Korea during the outbreak of the Omicron variant of SARS-CoV-2, Osong Public Health Res Perspect, doi:10.24171/j.phrp.2022.0262

Rosenbaum, Db, The central role of the propensity score in observational studies for causal effects, Biometrika

Ross, Bortolussi-Courval, Hanula, Lee, Wilson et al., Drug interactions with nirmatrelvirritonavir in older adults using multiple medications, JAMA Netw Open, doi:10.1001/jamanetworkopen.2022.20184

Siddiqi, Mehra, COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal, J Heart Lung Transplant, doi:10.1016/j.healun.2020.03.012

Soy, Keser, Atagündüz, Pathogenesis and treatment of cytokine storm in COVID-19, Turk J Biol, doi:10.3906/biy-2105-37

Suzuki, Shibata, Minemura, Nikaido, Tanino et al., Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic, Clin Exp Med, doi:10.1007/s10238-022-00949-3

Takashita, Kinoshita, Yamayoshi, Sakai-Tagawa, Fujisaki et al., Efficacy of antibodies and antiviral drugs against Covid-19 omicron variant, N Engl J Med, doi:10.1056/NEJMc2119407

Takashita, Yamayoshi, Simon, Van Bakel, Sordillo et al., Efficacy of antibodies and antiviral drugs against omicron BA.2.12.1, BA.4, and BA.5 subvariants, N Engl J Med, doi:10.1056/NEJMc2207519

Watson, Barnsley, Toor, Hogan, Winskill et al., Global impact of the first year of COVID-19 vaccination: a mathematical modelling study, Lancet Infect Dis, doi:10.1016/S1473-3099(22)00320-6

Wen, Chen, Tang, Wang, Zhou et al., Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19:a meta-analysis, Ann Med, doi:10.1080/07853890.2022.2034936

Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of early molnupiravir or nirmatrelvirritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study, Lancet Infect Dis, doi:10.1016/S1473-3099(22)00507-2

Wong, Au, Lau, Lau, Cowling et al., Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study, Lancet, doi:10.1016/S0140-6736(22)01586-0

Wu, Chen, Cai, Xia, Zhou et al., Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China, JAMA Intern Med, doi:10.1001/jamainternmed.2020.0994

Xie, Bowe, Al-Aly, Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records, BMJ, doi:10.1136/bmj-2022-072705

Yang, Zheng, Gou, Pu, Chen et al., Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis, Int J Infect Dis, doi:10.1016/j.ijid.2020.03.017

Ying-Hao, Yuan-Yuan, Dong, Qiu-Hua, Xue-Ran et al., Clinical characteristics and analysis of risk factors for disease progression of patients with SARS-CoV-2 omicron variant infection: a retrospective study of 25207 cases in a Fangcang hospital, Front Cell Infect Microbiol, doi:10.3389/fcimb.2022.1009894

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