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Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

  • Di Castelnuovo, Augusto1
  • Costanzo, Simona2
  • Antinori, Andrea3
  • Berselli, Nausicaa4
  • Blandi, Lorenzo5
  • Bonaccio, Marialaura2
  • Bruno, Raffaele6, 7
  • Cauda, Roberto8, 9
  • Gialluisi, Alessandro2
  • Guaraldi, Giovanni10
  • Menicanti, Lorenzo5
  • Mennuni, Marco11
  • My, Ilaria12
  • Parruti, Agostino13
  • Patti, Giuseppe11
  • Perlini, Stefano14, 15
  • Santilli, Francesca16
  • Signorelli, Carlo17
  • Stefanini, Giulio G.12
  • Vergori, Alessandra18
  • And 89 more
  • 1 Mediterranea Cardiocentro, Napoli , (Italy)
  • 2 Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli , (Italy)
  • 3 UOC Immunodeficienze Virali, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Roma , (Italy)
  • 4 Section of Public Health, Department of Biomedical, Metabolic and Neural Sciences, University of Modena, Modena , (Italy)
  • 5 IRCCS Policlinico San Donato, San Donato Milanese , (Italy)
  • 6 Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Pavia , (Italy)
  • 7 Department of Clinical, Surgical, Diagnostic, and Paediatric Sciences, University of Pavia, Pavia , (Italy)
  • 8 Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma , (Italy)
  • 9 Università Cattolica del Sacro Cuore- Dipartimento di Sicurezza e Bioetica Sede di Roma, Roma , (Italy)
  • 10 Infectious Disease Unit, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena , (Italy)
  • 11 University of Eastern Piedmont, Maggiore della Carità Hospital, Novara , (Italy)
  • 12 Humanitas Clinical and Research Hospital IRCCS, Rozzano , (Italy)
  • 13 Department of Infectious Disease, Azienda Sanitaria Locale (AUSL) di Pescara, Pescara , (Italy)
  • 14 Emergency Department, IRCCS Policlinico San Matteo Foundation, Pavia , (Italy)
  • 15 Department of Internal Medicine, University of Pavia, Pavia , (Italy)
  • 16 Department of Medicine and Aging, Clinica Medica, SS. Annunziata Hospital and University of Chieti, Chieti , (Italy)
  • 17 School of Medicine, Vita-Salute San Raffaele University, Milano , (Italy)
  • 18 HIV/AIDS Department, National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS, Roma , (Italy)
  • 19 Department of Medicine and Surgery, University of Insubria, Varese , (Italy)
  • 20 UOC, Anestesia e Rianimazione, Dipartimento di Chirurgia Generale Ospedale Morgagni-Pierantoni, Forlì , (Italy)
  • 21 Centro Cardiologico Monzino IRCCS, Milano , (Italy)
  • 22 Cardiovascular Section, Department of Clinical Sciences and Community Health, University of Milano, Milano , (Italy)
  • 23 UOC Infezioni Sistemiche dell'Immunodepresso, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome , (Italy)
  • 24 Department of Civil Environmental and Architectural Engineering, University of Padova, Padova , (Italy)
  • 25 Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia , (Italy)
  • 26 Department of Clinical and Experimental Medicine, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa , (Italy)
  • 27 Department of Medical and Surgical Sciences and Advanced Technologies G.F. Ingrassia, University of Catania, Catania , (Italy)
  • 28 Department of Experimental and Clinical Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Firenze , (Italy)
  • 29 Ospedale del Mare, ASL Napoli 1, Napoli , (Italy)
  • 30 UOC Malattie Infettive, Ospedale San Gerardo, ASST Monza, Monza , (Italy)
  • 31 School of Medicine and Surgery, University of Milano-Bicocca, Milano , (Italy)
  • 32 Cardiovascular and Thoracic Department, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa , (Italy)
  • 33 Infectious and Tropical Diseases Unit- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE) - University of Palermo, Palermo , (Italy)
  • 34 Servizio di Anestesia e Rianimazione II UO Rianimazione Ospedale San Marco, AOU Policlinico-Vittorio Emanuele, Catania , (Italy)
  • 35 COVID-19 Unit, EE Ospedale Regionale F. Miulli, Acquaviva delle Fonti , (Italy)
  • 36 Clinica Medica 3, Department of Medicine - DIMED, University Hospital of Padova, Padova , (Italy)
  • 37 Department of Cardiology, Ospedale di Cremona, Cremona , (Italy)
  • 38 Medical Direction, IRCCS Neuromed, Pozzilli , (Italy)
  • 39 UOC Malattie Infettive-Epatologia, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Roma , (Italy)
  • 40 UOC Infezioni Sistemiche e dell'Immunodepresso, Azienda Ospedaliera dei Colli, Ospedale Cotugno, Napoli , (Italy)
  • 41 Ospedale di Boscotrecase - ASL Napoli 3, Napoli , (Italy)
  • 42 Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli , (Italy)
  • 43 Respiratory Pathophysiology Division, Department of Cardiologic, Thoracic and Vascular Sciences, University of Padova, Padova , (Italy)
  • 44 UOC di Pneumologia, P.O. San Giuseppe Moscati, Taranto , (Italy)
  • 45 ASST Milano Nord - Ospedale Edoardo Bassini Cinisello Balsamo, Milan , (Italy)
  • 46 UOC Malattie Infettive e Tropicali, P.O. San Marco, AOU Policlinico-Vittorio Emanuele, Catania , (Italy)
  • 47 UOC di Medicina - Presidio Ospedaliero S.Maria di Loreto Nuovo, Napoli , (Italy)
  • 48 Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro , (Italy)
  • 49 Dipartimento di Farmacia, Università di Pisa, Pisa , (Italy)
  • 50 UOC Malattie Infettive-Apparato Respiratorio, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Roma , (Italy)
  • 51 Computer Service, University of Molise, Campobasso , (Italy)
  • 52 Medicina Interna. Ospedale di Ravenna, AUSL della Romagna, Ravenna , (Italy)
  • 53 UOC Pneumologia, Dipartimento di Malattie Apparato Respiratorio e Torace, Ospedale Morgagni-Pierantoni, Forlì , (Italy)
  • 54 UOC Malattie Infettive ad Alta Intensità di Cura, National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome , (Italy)
  • 55 Department of Epidemiology, Boston University School of Public Health, Boston, MA , (United States)
Published Article
Frontiers in Medicine
Frontiers Media SA
Publication Date
Jun 09, 2021
DOI: 10.3389/fmed.2021.639970
  • Medicine
  • Original Research


Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

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