CLINICAL TRIALS/CLINICAL STUDIES Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia Jovana Milic, 1,2 Alessio Novella, 3 Marianna Meschiari, 4 Marianna Menozzi, 4 Antonella Santoro, 4 Andrea Bedini, 4 Gianluca Cuomo, 4 Erica Franceschini, 4 Margherita Digaetano, 4 Federica Carli, 4 Giacomo Ciusa, 4 Sara Volpi, 4 Erica Bacca, 4 Giacomo Franceschi, 4 Dina Yaacoub, 4 Carlotta Rogati, 4 Marco Tutone, 4 Giulia Burastero, 4 Matteo Faltoni, 4 Vittorio Iadisernia, 4 Giovanni Dolci, 4 Andrea Cossarizza, 5 Cristina Mussini, 1,4 Luca Pasina, 3, * and Giovanni Guaraldi 1,4, * Abstract The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary ob- jective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug–drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan–Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (–13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch ( p > .05). The same was observed for duration of hospital stay [13.2 (–8.9) for DRV/c vs. 13.4 (–7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials. Keywords: COVID-19, SARS-CoV-2, darunavir/cobicistat, negative outcomes Background A few antiviral agents for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been studied, among others, remdesivir, lopinavir, and dar- unavir (DRV). 1,2 Clinical trials with Ebola and influenza promoted remdesivir as a promising and potent drug against SARS-CoV-2. 3 Results from randomized clinical trials (RCTs) are still inconclusive, while discouraging data were obtained in a Chinese RCT [hazard ratio (HR) = 1.23; (95% confidence interval, CI = 0.87–1.75)], 4 a phase 3 RCT showed that remdesivir was superior to placebo in shortening the time to recovery (11 vs. 15 days). 5 In consideration of these results, remdesivir is now approved for the treatment of coronavirus disease 2019 (COVID-19) in at least 50 countries. In consideration of the gained clinical experience with lopinavir/ritonavir as a treatment option for SARS and MERS outbreaks in 2012, this compound was also suggested for SARS-CoV-2 infection. 6 Lopinavir/ritonavir is a HIV pro- tease inhibitor and it has been widely used in HIV setting in the previous decade. 7 In an RCT conducted in China, there was no difference in mortality and time to clinical 1 Department of Surgical, Medical, Dental, and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy. 2 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy. 3 Pharmacotherapy and Appropriateness of Drug Prescription Unit, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. 4 Infectious Diseases Unit, Azienda Ospedaliero-Universitaria di Modena, Modena, Italy. 5 Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy. *These authors share senior authorship. AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 37, Number 4, 2021 ª Mary Ann Liebert, Inc. DOI: 10.1089/aid.2020.0305 283 Downloaded by 3.85.97.26 from www.liebertpub.com at 10/31/21. For personal use only.