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

Background Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are inconclusive. We therefore compared all-cause mortality in community-dwelling COVID-19 patients treated with these drugs during the Omicron era.Methods Data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA) were used. To increase completeness of the recorded deaths and date correctness, a crosscheck with the National Death Registry provided by the Ministry of the Interior was performed. We included in this study all patients infected by SARS-CoV-2 treated within 5 days after the test date and symptom onset between February 8 and April 30, 2022. All-cause mortalities by day 28 were compared between the two treatment groups after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. Findings In the considered timeframe, 17,977 patients treated with molnupiravir and 11,576 patients with nirmatrelvir plus ritonavir were included in the analysis. Most patients (25,617/29,553 = 86.7%) received a full vaccine course including the booster dose. A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrelvir plus ritonavir users (22.29 per 100,000 person-days). However, molnupiravir-treated patients were older than those treated with nirmatrelvir plus ritonavir and differences between the two populations were found as far as types of co-morbidities wereconcerned. For this reason, we compared the weight-adjusted cumulative incidences using the Aalen estimator and found that 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). Moreover, the weight-adjusted mixed-effect Cox model includi