Clinical outcomes, safety and predictors of disease progression in high-risk COVID-19 outpatients treated with nirmatrelvir/ritonavir: an Italian multicenter retrospective cohort study (PRIMA study)

Widespread vaccination, hybrid immunity following natural infection, and the Omicron variant altered COVID-19 severity, challenging oral antiviral benefits in immunocompetent populations. We characterized real-world clinical outcomes, tolerability, and predictors of disease progression among high-risk, non-hospitalized Italian adults treated with nirmatrelvir/ritonavir (N/r). This multicenter retrospective cohort study included symptomatic outpatients from 15 centers meeting high-risk criteria, who initiated N/r within five days of symptom onset. The primary outcome was 30-day all-cause hospitalization or death. Among 3,916 patients (median age 66; median three vaccine doses), the 30-day composite outcome (defined as hospital admission or all-cause death) occurred in 0.9% (0.7% hospitalization, 0.4% mortality). In adjusted multivariable analyses (backward selection model), solid neoplasms (OR 6.32, 95% CI 1.91–20.87), lymphoma (OR 14.33, 95% CI 5.15–39.88) and leukemia (OR 5.81, 95% CI 1.24–27.37) emerged as the strongest independent predictors of the composite outcome. Adverse events occurred in 10.7% (mainly dysgeusia and gastrointestinal symptoms), with a 0.7% toxicity-related discontinuation rate. In a largely triple-vaccinated, frail outpatient cohort, early N/r was associated with few adverse events and very low rates of severe outcomes. However, patients with active solid or hematologic malignancies remain at higher risk, requiring intensified preventive and therapeutic strategies.