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.
Authors
- Gardin Samuele
- Vincenzo Scaglione (ORCID: https://orcid.org/0000-0002-2911-2255)
- Miriam Lichtner (ORCID: https://orcid.org/0000-0002-7730-3953)
- Antonio Riccardo Buonomo (ORCID: https://orcid.org/0000-0002-4378-8366)
- Maria Chiara Pellegrino
- Andrea Antinori (ORCID: https://orcid.org/0000-0003-2121-4684)
- Andrea Marino (ORCID: https://orcid.org/0000-0002-9854-7885)
- Maria MAZZITELLI
- Nicola Schiano Moriello (ORCID: https://orcid.org/0000-0001-8474-4776)
- Sebastiano Leone (ORCID: https://orcid.org/0000-0001-7852-4101)
- Emanuele Nicastri (ORCID: https://orcid.org/0000-0002-5606-8712)
- Maria Michela Scirocco
- Agnese Giaccone (ORCID: https://orcid.org/0000-0003-4002-0930)
- Antonio Cascio (ORCID: https://orcid.org/0000-0002-1992-1796)
- Giulia Zumbo
- Valentina Mazzotta (ORCID: https://orcid.org/0000-0002-0240-7504)
- Riccardo Scotto (ORCID: https://orcid.org/0000-0002-0178-2986)
- Nicola Coppola (ORCID: https://orcid.org/0009-0000-3202-5489)
- Alberto Enrico Maraolo (ORCID: https://orcid.org/0000-0002-7218-7762)
- Mario Tumbarello (ORCID: https://orcid.org/0000-0002-9519-8552)
- Emilia Trucillo
- Alfonso Masullo
- Tumbarello Mario
- Alessio Vinicio Codella (ORCID: https://orcid.org/0000-0003-1657-6613)
- Maraolo Alberto Enrico
- Ivan Gentile (ORCID: https://orcid.org/0000-0002-5199-8451)
- Caterina Campoli (ORCID: https://orcid.org/0000-0002-5951-639X)
- Buonomo Antonio Riccardo
- Cattelan Annamaria
- Matteo Montironi
- Marino Andrea
- Cosmo Del Borgo (ORCID: https://orcid.org/0000-0002-7715-1232)
- Raffaella Marocco
- Claudio Mastroianni (ORCID: https://orcid.org/0000-0002-1286-467X)
- Antinori Andrea
- Mazzitelli Maria
- Codella Alessio Vinicio
- Mazzotta Valentina
- Zumbo Giulia
- Cascio Antonio
- Grimaldi Alessandra
- Zordan Marta
- Di Trento Daniela
- Masullo Alfonso
- Ajassa Camilla
- Leone Sebastiano
- Scotto Riccardo
- Gullì Sara
- Luigi Coppola
- Coppola Luigi
- Pellegrino Maria Chiara
- Montironi Matteo
- Sambo Margherita
- Coppola Nicola
- Rotundo Salvatore
- Annamaria Cattelan
- Pisaturo Mariantonietta
- Carlo Torti
- Lichtner Miriam
- Scirocco Maria Michela
- Pensalfine Giulia
- Todisco Vera
- Campoli Caterina
- Torti Carlo
- Gentile Ivan
- Di Chiara Michela
- Marocco Raffaella
- Trucillo Emilia
- Di Lorenzo Andrea
- Giaccone Agnese
- Ferrari Anna
- Ciccone Federica
- Schiano Moriello Nicola
- Nicastri Emanuele
- Rancan Ilaria
- the PRIMA Study Group
- Del Borgo Cosmo
- Scaglione Vincenzo
- Russo Antonio
- Mastroianni Claudio
Institutions
- University of Siena (IT)
- Università Cattolica del Sacro Cuore (IT)
- University of Padua (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- Agostino Gemelli University Polyclinic (IT)
- Magna Graecia University (IT)
- University of Catania (IT)
- Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Azienda Ospedaliera G.Rummo (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- Azienda Ospedaliera S.Giuseppe Moscati (IT)
- Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT)
- Policlinico Tor Vergata (IT)
- Ospedale Santa Maria Goretti (IT)
- Azienda Ospedale - Università Padova (IT)
- Azienda Ospedaliera Universitaria Policlinico "Paolo Giaccone" di Palermo (IT)
- University of the Sacred Heart (JP)
- University of Naples Federico II (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- BMC Infectious Diseases
- Published
- 2026-09-21
- DOI
- https://doi.org/10.1186/s12879-026-14363-7
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00