Real-Life Comparison of Mortality in Non-Hospitalised Patients with SARS-CoV-2 Infection at Risk for Clinical Progression Treated with Molnupiravir or Nirmatrevir Plus Ritonavir During the Omicron Era in Italy: A Nationwide, Observational Study

Torti et al., Elsevier BV, doi:10.2139/ssrn.4444431

May 2023

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Prospective study of 17,977 outpatients treated with molnupiravir and 11,576 treated with paxlovid, showing significant mortality with both treatments, and lower mortality with paxlovid.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity1-10. Multiple analyses have identified variants potentially created by molnupiravir11-15.

Important missing comments or errors? Let us know.

Study covers molnupiravir and paxlovid.

risk of death, 47.1% higher, HR 1.47, p < 0.001, treatment 17,977, control 11,576, adjusted per study, inverted to make HR<1 favor treatment, Cox proportional hazards.

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

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10. 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.

11. 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.

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Torti et al., 10 May 2023, prospective, Italy, preprint, 24 authors, study period 8 February, 2022 - 30 April, 2022, this trial compares with another treatment - results may be better when compared to placebo.

This Paper Molnupiravir All

Real-life comparison of mortality in non-hospitalised patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrevir plus ritonavir during the Omicron era in Italy: a nationwide, observational study

Carlo Torti, Pier Paolo Olimpieri, Paolo Bonfanti, Carlo Tascini, Simone Celant, Danilo Tacconi, Emanuele Nicastri, Evelina Tacconelli, Bruno Cacopardo, Alessandro Perrella, Giovanni Battista Buccoliero, Giustino Parruti, Matteo Bassetti, Carlo Biagetti, Andrea Giacometti, Elke Maria Erne, Maria Frontuto, Massimiliano Lanzafame, Summa Valentina, Alessandra Spagnoli, Annarita Vestri, Giovanni Di Perri, Pierluigi Russo, Giorgio Palù

Background Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are scarce and inconclusive. In particular, no adequately powered studies have demonstrated statistically significant differences in mortality between the two oral antivirals. We therefore aimed to provide a comparison of all-cause mortality in community-dwelling COVID-19 patients treated during the Omicron era. Methods In this observational study we used data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA). Patient inclusion in the AIFA registry was mandatory for clinicians to prescribe molnupiravir or nirmatrelvir plus ritonavir. We included in this study patients infected by SARS-CoV-2 treated within 5 days after the test-positive date and symptom onset between February 8 and April 30, 2022. Molnupiravir and nirmatrelvir plus ritonavir all-cause mortality by day 28 was compared after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. Given the nationwide nature of the study, mixed effect Cox regression was performed to account for the underlying variation among Italian regions and National Health System (NHS) centers. Importantly, to increase completeness of the recorded deaths and date correctness, a cross-check with the National Death Registry provided by the Ministry of the Interior was performed. Findings In the considered timeframe, 31619 patients were registered in the AIFA registry. After exclusion of patients who did not meet the inclusion or the quality control criteria, 17977 patients treated with molnupiravir and 11576 patients with nirmatrelvir plus ritonavir were included in the analysis. Molnupiravir-treated patients were older (median age: 74 years; 47.1% >75 years old) than those treated with nirmatrelvir plus ritonavir (median age: 66.3 years; 29.1% >75 years old). Median time from symptom onset was 3 days in both groups. Mild impairment of renal function, chronic kidney disease, uncontrolled diabetes, cardio-cerebrovascular diseases and asthma requiring daily medications were more frequent in patients who received molnupiravir, while primary or secondary immunodeficiencies and (haemato)-oncological diseases were more frequent in those who received nirmatrelvir plus ritonavir. Most patients received SARS-CoV-2 vaccination (91.8%) with a full vaccine course (86.7%). A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrervir/ritonavir users (22.29 per 100,000 person-days). Comparing the weight-adjusted cumulative incidences using the Aalen estimator, by day 28 the adjusted cumulative incidence rates were 1.23% (95% CI 1.07%-1.38%) for molnupiravir-treated and 0.78% (95% CI 0.58%-0.98%) for nirmatrelvir plus ritonavir-treated patients (adjusted log rank p=0.0002). The..

Conflicts of interest PPO, SC, VS, PR, Giorgio Palù, CT, AS, AV, DT, ET, AP, CB, AG, EME, MF,GBB and ML report no competing interests regarding this article. PB reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Viiv, Gilead, Jannsen, Merck and Pfizer. CT reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Gilead, Merck, Pfizer, Menarini, GSK, Sanofi, Angelini, thermofischer, Biotest and Diasorin. EN reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Gilead, Eli Lilly, Roche, SOBI. BC reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Angelini, Menarini. This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4444431 P r e p r i n t n o t p e e r r e v i e w e d Giustino Parruti reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Gilead, Merck, AlphaSigma, Angelini, Pfizer, Lusofarmaco, GSK, Janssen. MB reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Angelini, BioMérieux, Cidara, Menarini, MSD, Pfizer and Shionogi. GDP reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from GS, MSD, ViiV, Abbvie, Janssen, GSK, AZ, Pfizer, Roche. The views expressed in this work are personal and may not be understood or..

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