Dóra Paróczai M.D. ^1,2 András Bikov ^3,4 Andrea Blidaru ⁵ Emanuel Bobu ⁶ Ana Lascu ^7,8* Cristian Ion Mot ^10,9 STEFAN MIHAICUTA ^11,5 Stefan Frent ^11,12

• ¹ Department of Medical Microbiology, University of Szeged, Szeged, Hungary
• ² Albert Szent-Györgyi Health Center, Pulmonology Clinic, University of Szeged,, Deszk, Hungary
• ³ North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust,, Manchester, United Kingdom
• ⁴ Division of Immunology, Immunity to Infection and Respiratory Medicine, University of Manchester,, Manchester,, United Kingdom
• ⁵ Infectious Diseases and Pulmonology Clinical Hospital, Timisoara, Romania
• ⁶ University of Medicine and Pharmacy, Timisoara, Romania
• ⁷ Department of Functional Sciences, Discipline of Pathophysiology, Centre for Translational Research and Systems Medicine, University of Medicine and Pharmacy "Victor Babes" Timisoara,, Timisoara, Romania
• ⁸ Institute for Cardiovascular Diseases of Timisoara, Clinic for Cardiovascular Surgery,, Timisoara, Romania
• ⁹ ENT Department, Municipal Emergency Hospital Timisoara,, Timisoara, Romania
• ¹⁰ Department of Surgery, University of Medicine and Pharmacy Timisoara,, Timisoara, Romania
• ¹¹ Centre for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara,, Timisoara, Romania
• ¹² Infectious Diseases and Pulmonology Clinical Hospital, Timisoara,, Timisoara, Romania

Drug repurposing has become a widely adopted strategy to minimise research time, costs, and associated risks. Combinations of protease inhibitors such as lopinavir and darunavir with ritonavir have been repurposed as treatments for COVID-19. Although lopinavir-ritonavir (LPV/r) and darunavir-ritonavir (DRV/r) have shown in vitro efficacy against COVID-19, the results in human studies have been inconsistent. Therefore, our objective was to compare the efficacy of LPV/r and DRV/r in COVID-19 patients admitted to a tertiary centre in Romania.A clinical dataset from 417 hospitalised patients was analysed. Patients were assigned to the LPV/r, DRV/r, or control (standard-of-care) group based on clinical decisions made by the attending infectious disease specialists, aligned with national treatment protocols. Kaplan-Meier and Cox proportional hazards regression analyses were conducted to compare in-hospital mortality and to identify factors associated with clinical improvement or fatal outcomes.By day 10, more patients showed improvement with LPV/r and DRV/r (p=0.03 and 0.01, respectively), but only LPV/r was associated with improved survival compared to the control group (p=0.05).Factors associated with mortality included male gender (HR: 3.63, p=0.02), diabetes (HR: 2.49, p=0.03), oxygen saturation below 90% at admission (HR: 5.23, p<0.01), high blood glucose levels (HR: 3.68, p=0.01), age (HR: 1.04, p=0.02), and more than 25% lesion extension on chest CT scan (HR: 2.28, p=0.03).LPV/r, but not DRV/r, showed a survival benefit in patients hospitalised with COVID-19, but these findings deserve further investigation in a randomized clinical trial.