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

Abstract

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 weight-adjusted mixed-effect Cox model including Italian regions and NHS centers as random effects and treatment as the only covariate demonstrated that nirmatrelvir plus ritonavir was associated to a significant reduction in the risk of death by day 28 compared to molnupiravir (HR 0.68 [95% CI 0.56–0.83]). Moreover, we performed separated analyses to assess treatment effect on specific sets of patients and found that a significant reduction in the risk of death associated with the use of nirmatrelvir plus ritonavir was identified in female patients (p<0.001), fully vaccinated patients (p<0.001), patients treated within day 2 since symptom onset (p=0.01) and patients without (haemato)-oncological diseases (p<0.001).

Interpretation: In this prospective, nationwide cohort, early initiation of nirmatrelvir plus ritonavir was associated with a reduced risk of all-cause mortality compared to molnupiravir. Reduced risk of mortality was consistently observed in all overall population and in most patient subgroups. Nirmatrelvir plus ritonavir can be considered the preferred option for early treatment of SARS-CoV-2 infected patients at risk of clinical progression notwithstanding receipt of a full vaccine course.

Funding: This study did not receive funding.

Declaration 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. 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.

Ethical Approval: According to decree 196/2003 (“Italian Privacy Code”) and decree 101/2018 (“Harmonization Decree” harmonizing the Italian data protection laws with the provision of the General Data Protection Regulation 679/2016—GDPR), the processing of anonymized data does not require authorization by patients if carried out in the performance of public interest or public powers based on a provision of law.

Keywords: COVID-19, SARS-CoV-2, nirmatrelvir/ritonavir, molnupiravir, real-world, effectiveness