{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T02:26:39Z","timestamp":1773973599046,"version":"3.50.1"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T00:00:00Z","timestamp":1623196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.<\/jats:p><jats:p><jats:bold>Objectives:<\/jats:bold> To describe the association between lopinavir\/ritonavir (LPV\/r) or darunavir\/cobicistat (DRV\/c) use and in-hospital mortality in COVID-19 patients.<\/jats:p><jats:p><jats:bold>Study Design:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> 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.<\/jats:p>","DOI":"10.3389\/fmed.2021.639970","type":"journal-article","created":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T15:44:10Z","timestamp":1623253450000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Lopinavir\/Ritonavir and Darunavir\/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study"],"prefix":"10.3389","volume":"8","author":[{"given":"Augusto","family":"Di Castelnuovo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Costanzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Antinori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nausicaa","family":"Berselli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Blandi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marialaura","family":"Bonaccio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Cauda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Gialluisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Guaraldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Menicanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Mennuni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilaria","family":"My","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agostino","family":"Parruti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Patti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Perlini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Santilli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Signorelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulio G.","family":"Stefanini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Vergori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter","family":"Ageno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Aiello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piergiuseppe","family":"Agostoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samir","family":"Al Moghazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Arboretti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Aucella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greta","family":"Barbieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Barchitta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Bartoloni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Bologna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Bonfanti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Caiano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Carrozzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Cascio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Castiglione","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Chiarito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arturo","family":"Ciccullo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Cingolani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Cipollone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Colomba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crizia","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Crosta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Dalena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Dal Pra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gian Battista","family":"Danzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damiano","family":"D'Ardes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katleen","family":"de Gaetano Donati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Di Gennaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Di Tano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianpiero","family":"D'Offizi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommaso","family":"Filippini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Maria Fusco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Gaudiosi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Gentile","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Gini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvira","family":"Grandone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Guarnieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gennaro L. F.","family":"Lamanna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Larizza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Armando","family":"Leone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Lio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela Raffaella","family":"Losito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gloria","family":"Maccagni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Maitan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandro","family":"Mancarella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Manuele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Mapelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Maragna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Marra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulio","family":"Maresca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Marotta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franco","family":"Mastroianni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Mazzitelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Mengozzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Menichetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jovana","family":"Milic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Minutolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatrice","family":"Molena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Mussinelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Mussini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Musso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Odone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Olivieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuela","family":"Pasi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Perroni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Petri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biagio","family":"Pinchera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo A.","family":"Pivato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Venerino","family":"Poletti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Ravaglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Rossato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sabena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Salinaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Sangiovanni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Sanrocco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Scorzolini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaella","family":"Sgariglia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola Giustina","family":"Simeone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Spinicci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico Maria","family":"Trecarichi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Veronesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Vettor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Vianello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Vinceti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Visconti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Vocciante","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raffaele","family":"De Caterina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Licia","family":"Iacoviello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"The COVID-19 RISK and Treatments (CORIST) Collaboration","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.antiviral.2015.01.011","article-title":"Protease inhibitors targeting coronavirus and filovirus entry","volume":"116","author":"Zhou","year":"2015","journal-title":"Antiviral Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1136\/thorax.2003.012658","article-title":"Role of lopinavir\/ritonavir in the treatment of SARS: initial virological and clinical findings","volume":"59","author":"Chu","year":"2004","journal-title":"Thorax."},{"key":"B3","doi-asserted-by":"publisher","first-page":"10012","DOI":"10.1073\/pnas.0403596101","article-title":"Small molecules targeting severe acute respiratory syndrome human coronavirus","volume":"101","author":"Wu","year":"2004","journal-title":"Proc Natl Acad Sci USA."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1021\/acs.biochem.0c00160","article-title":"Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms","volume":"59","author":"Nutho","year":"2020","journal-title":"Biochemistry."},{"key":"B5","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/nrd.2015.37","article-title":"Coronaviruses-drug discovery and therapeutic options","volume":"15","author":"Zumla","year":"2016","journal-title":"Nat Rev Drug Discov."},{"key":"B6","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1002\/jmv.25729","article-title":"A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-a possible reference for coronavirus disease-19 treatment option","volume":"92","author":"Yao","year":"2020","journal-title":"J Med Virol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0140-6736(20)32013-4","article-title":"Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial","volume":"396","year":"2020","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1056\/NEJMoa2023184","article-title":"Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results","volume":"384","author":"Pan","year":"2021","journal-title":"N Engl J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1056\/NEJMc2008043","article-title":"A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19","volume":"382","author":"Cao","year":"2020","journal-title":"N Engl J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/14787210.2021.1848545","article-title":"Efficacy and safety of lopinavir\/ritonavir in the treatment of COVID-19: a systematic review","volume":"1","author":"Joseph","year":"2020","journal-title":"Expert Rev Anti Infect Ther."},{"key":"B11","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/j.1468-1293.2012.01060.x","article-title":"Final 192-week efficacy and safety of once-daily darunavir\/ritonavir compared with lopinavir\/ritonavir in HIV-1-infected treatment-na\u00efve patients in the ARTEMIS trial","volume":"14","author":"Orkin","year":"2013","journal-title":"HIV Med."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2174\/1871526520666201029125725.","article-title":"Efficacy of lopinavir\/ritonavir compared with standard care for treatment of coronavirus disease 2019 (COVID-19): a systematic review","author":"Hariyanto","year":"2020","journal-title":"Infect Disord Drug Targets"},{"key":"B13","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic options for the 2019 novel coronavirus (2019-nCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat Rev Drug Discov."},{"key":"B14","unstructured":"Lopinavir\/Ritonavir Nella Terapia dei Pazienti Adulti con COVID"},{"key":"B15","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1161\/HYPERTENSIONAHA.120.15370","article-title":"Controversial relationship between renin-angiotensin system inhibitors and severity of COVID-19: announcing a large multicentre case-control study in Italy","volume":"76","author":"Di Castelnuovo","year":"2020","journal-title":"Hypertension."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1016\/j.numecd.2020.07.031","article-title":"Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study","volume":"30","author":"Di Castelnuovo","year":"2020","journal-title":"Nutr Metab Cardiovasc Dis."},{"key":"B17","doi-asserted-by":"publisher","first-page":"106805","DOI":"10.1016\/j.vph.2020.106805","article-title":"RAAS inhibitors are not associated with mortality in COVID-19 patients: findings from an observational multicenter study in Italy and a meta-analysis of 19 studies","volume":"135","author":"Di Castelnuovo","year":"2020","journal-title":"Vasc Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.ejim.2020.08.019","article-title":"Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: findings from the observational multicentre Italian CORIST study","volume":"82","year":"2020","journal-title":"Eur J Intern Med"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.1002\/9780470316696","volume-title":"Multiple Imputation for Nonresponse in Surveys","author":"Rubin","year":"1987"},{"key":"B20","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1097\/00001648-200009000-00011","article-title":"Marginal structural models and causal inference in epidemiology","volume":"11","author":"Robins","year":"2000","journal-title":"Epidemiology."},{"key":"B21","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1002\/sim.1599","article-title":"Modelling clustered survival data from multicentre clinical trials","volume":"23","author":"Glidden","year":"2004","journal-title":"Stat Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1111\/1475-6773.12182","article-title":"Methods for constructing and assessing propensity scores","volume":"49","author":"Garrido","year":"2014","journal-title":"Health Serv Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"268","DOI":"10.7326\/M16-2607","article-title":"Sensitivity analysis in observational research: introducing the e-value","volume":"167","author":"VanderWeele","year":"2017","journal-title":"Ann Intern Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.medj.2020.04.001","article-title":"Efficacy and safety of lopinavir\/ritonavir or arbidol in adult patients with mild\/moderate COVID-19: an exploratory randomized controlled trial","volume":"1","author":"Li","year":"2020","journal-title":"Med (N Y)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1345\/aph.1Q422","article-title":"Protease inhibitor-associated QT interval prolongation","volume":"45","author":"Hunt","year":"2011","journal-title":"Ann Pharmacother."},{"key":"B26","unstructured":"European Agencies Medicine Report2020"},{"key":"B27","doi-asserted-by":"publisher","first-page":"175","DOI":"10.2147\/HIV.S56158","article-title":"Profile of once-daily darunavir\/cobicistat fixed-dose combination for the treatment of HIV\/AIDS","volume":"8","author":"Navarro","year":"2016","journal-title":"HIV AIDS."},{"key":"B28","doi-asserted-by":"publisher","first-page":"ofaa241","DOI":"10.1093\/ofid\/ofaa241","article-title":"Antiviral activity and safety of darunavir\/cobicistat for the treatment of COVID-19","volume":"7","author":"Chen","year":"2020","journal-title":"Open Forum Infect Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ijid.2020.05.085","article-title":"Lack of antiviral activity of darunavir against SARS-CoV-2","volume":"97","author":"De Meyer","year":"2020","journal-title":"Int J Infect Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1016\/j.csbj.2020.03.025","article-title":"Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model","volume":"18","author":"Beck","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1101\/2020.01.31.929695","article-title":"Molecular modeling evaluation of the binding effect of ritonavir, lopinavir and darunavir to severe acute respiratory syndrome coronavirus 2 proteases","author":"Shen","year":"2020","journal-title":"bioRxviv [Preprint]"},{"key":"B32","doi-asserted-by":"publisher","first-page":"5771","DOI":"10.26434\/chemrxiv.12111297.v1","article-title":"Computational determination of potential inhibitors of SARS-CoV-2 main protease","volume":"60","author":"Ngo","year":"2020","journal-title":"J Chem Inf Model."},{"key":"B33","doi-asserted-by":"publisher","first-page":"15775","DOI":"10.1039\/D0RA01899F","article-title":"Anti-HIV drug repurposing against SARS-CoV-2\u2020","volume":"10","author":"Sang","year":"2020","journal-title":"RSC Adv"},{"key":"B34","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.1080\/07391102.2020.1751298","article-title":"Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach","volume":"39","author":"Khan","year":"2020","journal-title":"J Biomol Struct Dyn."},{"key":"B35","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1089\/aid.2020.0305","article-title":"Darunavir\/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia","volume":"37","author":"Milic","year":"2021","journal-title":"AIDS Res Hum Retroviruses."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1786","DOI":"10.1111\/jphp.12820","article-title":"Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat","volume":"69","author":"Hossain","year":"2017","journal-title":"J Pharm Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1093\/jac\/dkw032","article-title":"Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications","volume":"71","author":"Marzolini","year":"2016","journal-title":"J Antimicrob Chemother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1111\/bcp.14262","article-title":"Cobicistat: a case of mislabelled drug-drug interaction risk?","volume":"86","author":"Burger","year":"2020","journal-title":"Br J Clin Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00392-020-01766-y","article-title":"Pulmonary embolism in patients with COVID-19: characteristics and outcomes in the Cardio-COVID Italy multicenter study","volume":"1","author":"Ameri","year":"2020","journal-title":"Clin Res Cardiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"ofaa321","DOI":"10.1093\/ofid\/ofaa321","article-title":"Reply to: \u201cantiviral activity and safety of darunavir\/cobicistat for treatment of COVID-19","volume":"7","author":"Nicolini","year":"2020","journal-title":"Open Forum Infect Dis."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.639970\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,9]],"date-time":"2021-06-09T15:44:16Z","timestamp":1623253456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.639970\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,9]]},"references-count":40,"alternative-id":["10.3389\/fmed.2021.639970"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.639970","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,9]]},"article-number":"639970"}}