Abstract: Received: 16 June 2020 | Accepted: 3 August 2020 DOI: 10.1002/jmv.26407 RESEARCH ARTICLE Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS‐CoV‐2 infection: A retrospective cohort study Andrea Giacomelli MD1,2 | Gabriele Pagani MD1,2 | Anna L. Ridolfo MD1 | Letizia Oreni BIT2 | Federico Conti MD1,2 | Laura Pezzati MD1,2 | Lucia Bradanini MD1,2 | Giacomo Casalini MD1,2 | Cinzia Bassoli MD1,2 | Valentina Morena MD1,2 | Simone Passerini MD1 | Giuliano Rizzardini MD1,3 | Chiara Cogliati MD4 | Elisa Ceriani MD4 | Riccardo Colombo MD5 | Stefano Rusconi MD1,2 | Cristina Gervasoni MD1 | Dario Cattaneo PharmD, PhD6 | Spinello Antinori MD1,2 | Massimo Galli MD1,2 1 Department of Infectious Diseases, ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital, Milan, Italy 2 Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC, University of Milan, Milan, Italy 3 School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg, South Africa 4 Department of Internal Medicine, ASST Fatebenefratelli‐Sacco, Luigi Sacco Hospital, Milan, Italy 5 Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli‐Sacco, Luigi Sacco Hospital, Milan, Italy 6 Unit of Clinical Pharmacology, ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital, Milan, Italy Abstract As it has been shown that lopinavir (LPV) and hydroxychloroquine (HCQ) have in vitro activity against coronaviruses, they were used to treat COVID‐19 during the first wave of the epidemic in Lombardy, Italy. To compare the rate of clinical improvement between those who started LPV/ritonavir (LPV/r)+HCQ within 5 days of symptom onset (early treatment, ET) and those who started later (delayed treatment, DT). This was a retrospective intent‐to‐treat analysis of the hospitalized patients who started LPV/r + HCQ between 21 February and 20 March 2020. The association between the timing of treatment and the probability of 30‐day mortality was assessed using univariable and multivariable logistic models. The study involved 172 patients: 43 (25%) in the ET and 129 (75%) in the DT group. The rate of clinical improvement increased over time to 73.3% on day 30, without any significant difference between the two groups (Gray's test P = .213). After adjusting for potentially Correspondence Andrea Giacomelli, MD, Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC, University of Milan, III Infectious Diseases Unit, L. Sacco Hospital, Via G.B. Grassi 74, 20157 Milano, Italy. Email: andrea.giacomelli@unimi.it relevant clinical variables, there was no significant association between the timing of the start of treatment and the probability of 30‐day mortality (adjusted odds ratio [aOR] ET vs DT = 1.45, 95% confidence interval 0.50‐4.19). Eight percent of the patients discontinued the treatment becausebecause of severe gastrointestinal disorders attributable to LPV/r. The timing of the start of LPV/r + HCQ treatment does not seem to affect the clinical course of hospitalized patients with COVID‐19. Together with the severe adverse events attributable to LPV/r, this raises concerns about the benefit of using this combination to treat COVID‐19. KEYWORDS antiviral treatment, COVID‐19, early, hydroxychloroquine, lopinavir, mortality Andrea Giacomelli, Gabriele Pagani, and Anna L. Ridolfo contributed equally to the study. J Med Virol...