Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study
Augusto Di Castelnuovo, Simona Costanzo, Andrea Antinori, Nausicaa Berselli, Lorenzo Blandi, Marialaura Bonaccio, Raffaele Bruno, Roberto Cauda, Alessandro Gialluisi, Giovanni Guaraldi, Lorenzo Menicanti, Marco Mennuni, Ilaria My, Agostino Parruti, Giuseppe Patti, Stefano Perlini, Francesca Santilli, Carlo Signorelli, Giulio G Stefanini, Alessandra Vergori, Walter Ageno, Luca Aiello, Piergiuseppe Agostoni, Samir Al Moghazi, Rosa Arboretti, Filippo Aucella, Greta Barbieri, Martina Barchitta, Alessandro Bartoloni, Carolina Bologna, Paolo Bonfanti, Lucia Caiano, Laura Carrozzi, Antonio Cascio, Giacomo Castiglione, Mauro Chiarito, Arturo Ciccullo, Antonella Cingolani, Francesco Cipollone, Claudia Colomba, Crizia Colombo, Francesco Crosta, Giovanni Dalena, Chiara Dal Pra, Gian Battista Danzi, Damiano D'ardes, Katleen De Gaetano Donati, Francesco Di Gennaro, Giuseppe Di Tano, Gianpiero D'offizi, Tommaso Filippini, Francesco Maria Fusco, Carlo Gaudiosi, Ivan Gentile, Giancarlo Gini, Elvira Grandone, Gabriella Guarnieri, Gennaro L F Lamanna, Giovanni Larizza, Armando Leone, Veronica Lio, Angela Raffaella Losito, Gloria Maccagni, Stefano Maitan, Sandro Mancarella, Rosa Manuele, Massimo Mapelli, Riccardo Maragna, Lorenzo Marra, Giulio Maresca, Claudia Marotta, Franco Mastroianni, Maria Mazzitelli, Alessandro Mengozzi, Francesco Menichetti, Jovana Milic, Filippo Minutolo, Beatrice Molena, R Mussinelli, Cristina Mussini, Maria Musso, Anna Odone, Marco Olivieri, Emanuela Pasi, Annalisa Perroni, Francesco Petri, Biagio Pinchera, Carlo A Pivato, Venerino Poletti, Claudia Ravaglia, Marco Rossato, Marianna Rossi, Anna Sabena, Francesco Salinaro, Vincenzo Sangiovanni, Carlo Sanrocco, Laura Scorzolini, Raffaella Sgariglia, Paola Giustina Simeone, Michele Spinicci, Enrico Maria Trecarichi, Giovanni Veronesi, Roberto Vettor, Andrea Vianello, Marco Vinceti, Elena Visconti, Laura Vocciante, Raffaele De Caterina, Licia Iacoviello
Frontiers in Medicine, doi:10.3389/fmed.2021.639970
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.
ETHICS STATEMENT The study was approved by the institutional ethics board of all recruiting centers (N = 33). The ethics committee waived the requirement of written informed consent for participation.
AUTHOR CONTRIBUTIONS LI and AD: had full access to all data in the study, took responsibility for the integrity of the data and the accuracy of the data analysis, drafting of the manuscript, and supervision. AD, LI, and RD: concept and design. AD, SC, AG, RA, GV, and GS: statistical analysis. All authors: acquisition, analysis, interpretation of data, critical revision of the manuscript for important intellectual content, administrative, technical, or material support. Disclaimer: The Authors alone are responsible for the views expressed in this article. They do not necessarily represent the views, decisions, or policies of the Institutions with which they are affiliated.
Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2021 Di Castelnuovo, Costanzo, Antinori, Berselli, Blandi, Bonaccio, Bruno, Cauda, Gialluisi, Guaraldi, Menicanti, Mennuni, My, Parruti, Patti, Perlini, Santilli, Signorelli, Stefanini, Vergori, Ageno, Aiello, Agostoni, Al Moghazi, Arboretti, Aucella, Barbieri, Barchitta, Bartoloni, Bologna, Bonfanti, Caiano, Carrozzi, Cascio, Castiglione, Chiarito, Ciccullo, Cingolani, Cipollone, Colomba, Colombo,..
References
"san, Marco, AOU Policlinico-Vittorio Emanuele
Ameri, Inciardi, Pasquale, Agostoni, Bellasi et al., Pulmonary embolism in patients with COVID-19: characteristics and outcomes in the Cardio-COVID Italy multicenter study, Clin Res Cardiol,
doi:10.1007/s00392-020-01766-yAsst Milano, Bassini, None
Beck, Bonggun, Yoonjung, Sungsoop, Keunsoo, Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model, Comput Struct Biotechnol J,
doi:10.1016/j.csbj.2020.03.025Burger, Calmy, Marzolini, Cobicistat: a case of mislabelled drugdrug interaction risk?, Br J Clin Pharmacol,
doi:10.1111/bcp.14262Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavirritonavir in adults hospitalized with severe Covid-19, N Engl J Med,
doi:10.1056/NEJMc2008043Castelnuovo, Bonaccio, Costanzo, Gialluisi, Antinori et al., 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, Nutr Metab Cardiovasc Dis,
doi:10.1016/j.numecd.2020.07.031Castelnuovo, Caterina, De Gaetano, Iacoviello, Controversial relationship between renin-angiotensin system inhibitors and severity of COVID-19: announcing a large multicentre case-control study in Italy, Hypertension,
doi:10.1161/HYPERTENSIONAHA.120.15370Castelnuovo, Costanzo, Antinori, COvid-19 RISk and Treatments (CORIST) collaboration. 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, Vasc Pharmacol,
doi:10.1016/j.vph.2020.106805Chen, Xia, Liu, Xu, Ling et al., Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19, Open Forum Infect Dis,
doi:10.1093/ofid/ofaa241Chu, Cheng, Hung, Wong, Chan et al., Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings, Thorax,
doi:10.1136/thorax.2003.012658Clinicizzato, Annunziata, None
Del, None, ASL NA
Di Cremona, None
Di, AUSL della Romagna
Di, Ospedale di Circolo e Fondazione
Donato Milanese, IRCCS Policlinico San Donato
Ee Ospedale, Miulli, Acquaviva delle Fonti
Fondazione, Casa Sollievo della Sofferenza
Fondazione, Policlinico San, Matteo, None
Forlì, None
Garrido, Kelley, Paris, Roza, Meier et al., Methods for constructing and assessing propensity scores, Health Serv Res,
doi:10.1111/1475-6773.12182Giaccone, None
Glidden, Vittinghoff, Modelling clustered survival data from multicentre clinical trials, Stat Med,
doi:10.1002/sim.1599Hariyanto, Hardi, Kurniawan, Efficacy of lopinavir/ritonavir compared with standard care for treatment of coronavirus disease 2019 (COVID-19): a systematic review, Infect Disord Drug Targets,
doi:10.2174/1871526520666201029125725Hossain, Tran, Chen, Mikus, Greenblatt, Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat, J Pharm Pharmacol,
doi:10.1111/jphp.12820Hunt, Hughes, Hills-Nieminen, Protease inhibitorassociated QT interval prolongation, Ann Pharmacother,
doi:10.1345/aph.1Q422Joseph, Dibas, Evanson, Paranjape, Vegivinti et al., Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: a systematic review, Expert Rev Anti Infect Ther,
doi:10.1080/14787210.2021.1848545Khan, Zia, Ashraf, Uddin, Ul-Haq, Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach, J Biomol Struct Dyn,
doi:10.1080/07391102.2020.1751298Li, Xie, Lin, Cai, Wen et al., Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial, Med (N Y),
doi:10.1016/j.medj.2020.04.001Maggiore, Carità, None
Maria, Loreto Nuovo -ASL Napoli 1 Centro
Marzolini, Gibbons, Khoo, Back, Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with comedications, J Antimicrob Chemother,
doi:10.1093/jac/dkw032Meyer, Bojkova, Cinatl, Van Damme, Buyck et al., Lack of antiviral activity of darunavir against SARS-CoV-2, Int J Infect Dis,
doi:10.1016/j.ijid.2020.05.085Milic, Meschiari, Menozzi, Santoro, Bedini, Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia, AIDS Res Hum Retroviruses,
doi:10.1089/aid.2020.0305Navarro, Curran, Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS, HIV AIDS,
doi:10.2147/HIV.S56158Nicolini, Mikulska, Signori, Biagio, Portunato et al., Reply to: "antiviral activity and safety of darunavir/cobicistat for treatment of COVID-19, Open Forum Infect Dis,
doi:10.1093/ofid/ofaa321Nutho, Mahalapbutr, Hengphasatporn, Pattaranggoon, Simanon et al., Why are lopinavir and ritonavir effective against the newly emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms, Biochemistry,
doi:10.1021/acs.biochem.0c00160Orkin, Dejesus, Khanlou, Stoehr, Supparatpinyo et al., Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial, HIV Med,
doi:10.1111/j.1468-1293.2012.01060.xOspedale San, Monza, None
Pan, Peto, Henao-Restrepo, Preziosi, Sathiyamoorthy, Repurposed antiviral drugs for Covid-19 -interim WHO solidarity trial results, N Engl J Med,
doi:10.1056/NEJMoa2023184Policlinico, Gemelli, None
Rubin, Multiple Imputation for Nonresponse in Surveys
San, Moscati, Taranto, Azienda Ospedaliero Universitaria Mater Domini
Shen, Runnan, Jingdong, Xinhao, Xushun, Molecular modeling evaluation of the binding effect of ritonavir, lopinavir and darunavir to severe acute respiratory syndrome coronavirus 2 proteases, bioRxviv,
doi:10.1101/2020.01.31.929695Vanderweele, Ding, Sensitivity analysis in observational research: introducing the e-value, Ann Intern Med,
doi:10.7326/M16-2607Wu, Jan, Ma, Kuo, Juan et al., Small molecules targeting severe acute respiratory syndrome human coronavirus, Proc Natl Acad Sci,
doi:10.1073/pnas.0403596101Yao, Qian, Zhu, Wang, Wang, A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-a possible reference for coronavirus disease-19 treatment option, J Med Virol,
doi:10.1002/jmv.25729Zumla, Chan, Azhar, Hui, Yuen, Coronaviruses-drug discovery and therapeutic options, Nat Rev Drug Discov,
doi:10.1038/nrd.2015.37DOI record:
{
"DOI": "10.3389/fmed.2021.639970",
"ISSN": [
"2296-858X"
],
"URL": "http://dx.doi.org/10.3389/fmed.2021.639970",
"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>",
"alternative-id": [
"10.3389/fmed.2021.639970"
],
"author": [
{
"affiliation": [],
"family": "Di Castelnuovo",
"given": "Augusto",
"sequence": "first"
},
{
"affiliation": [],
"family": "Costanzo",
"given": "Simona",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Antinori",
"given": "Andrea",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Berselli",
"given": "Nausicaa",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Blandi",
"given": "Lorenzo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bonaccio",
"given": "Marialaura",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bruno",
"given": "Raffaele",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Cauda",
"given": "Roberto",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Gialluisi",
"given": "Alessandro",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Guaraldi",
"given": "Giovanni",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Menicanti",
"given": "Lorenzo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mennuni",
"given": "Marco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "My",
"given": "Ilaria",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Parruti",
"given": "Agostino",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Patti",
"given": "Giuseppe",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Perlini",
"given": "Stefano",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Santilli",
"given": "Francesca",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Signorelli",
"given": "Carlo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Stefanini",
"given": "Giulio G.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Vergori",
"given": "Alessandra",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Ageno",
"given": "Walter",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Aiello",
"given": "Luca",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Agostoni",
"given": "Piergiuseppe",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Al Moghazi",
"given": "Samir",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Arboretti",
"given": "Rosa",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Aucella",
"given": "Filippo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Barbieri",
"given": "Greta",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Barchitta",
"given": "Martina",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bartoloni",
"given": "Alessandro",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bologna",
"given": "Carolina",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Bonfanti",
"given": "Paolo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Caiano",
"given": "Lucia",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Carrozzi",
"given": "Laura",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Cascio",
"given": "Antonio",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Castiglione",
"given": "Giacomo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Chiarito",
"given": "Mauro",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Ciccullo",
"given": "Arturo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Cingolani",
"given": "Antonella",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Cipollone",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Colomba",
"given": "Claudia",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Colombo",
"given": "Crizia",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Crosta",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Dalena",
"given": "Giovanni",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Dal Pra",
"given": "Chiara",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Danzi",
"given": "Gian Battista",
"sequence": "additional"
},
{
"affiliation": [],
"family": "D'Ardes",
"given": "Damiano",
"sequence": "additional"
},
{
"affiliation": [],
"family": "de Gaetano Donati",
"given": "Katleen",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Di Gennaro",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Di Tano",
"given": "Giuseppe",
"sequence": "additional"
},
{
"affiliation": [],
"family": "D'Offizi",
"given": "Gianpiero",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Filippini",
"given": "Tommaso",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maria Fusco",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Gaudiosi",
"given": "Carlo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Gentile",
"given": "Ivan",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Gini",
"given": "Giancarlo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Grandone",
"given": "Elvira",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Guarnieri",
"given": "Gabriella",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Lamanna",
"given": "Gennaro L. F.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Larizza",
"given": "Giovanni",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Leone",
"given": "Armando",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Lio",
"given": "Veronica",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Losito",
"given": "Angela Raffaella",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maccagni",
"given": "Gloria",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maitan",
"given": "Stefano",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mancarella",
"given": "Sandro",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Manuele",
"given": "Rosa",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mapelli",
"given": "Massimo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maragna",
"given": "Riccardo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Marra",
"given": "Lorenzo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Maresca",
"given": "Giulio",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Marotta",
"given": "Claudia",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mastroianni",
"given": "Franco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mazzitelli",
"given": "Maria",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mengozzi",
"given": "Alessandro",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Menichetti",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Milic",
"given": "Jovana",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Minutolo",
"given": "Filippo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Molena",
"given": "Beatrice",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mussinelli",
"given": "R.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Mussini",
"given": "Cristina",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Musso",
"given": "Maria",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Odone",
"given": "Anna",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Olivieri",
"given": "Marco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Pasi",
"given": "Emanuela",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Perroni",
"given": "Annalisa",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Petri",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Pinchera",
"given": "Biagio",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Pivato",
"given": "Carlo A.",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Poletti",
"given": "Venerino",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Ravaglia",
"given": "Claudia",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Rossato",
"given": "Marco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Rossi",
"given": "Marianna",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Sabena",
"given": "Anna",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Salinaro",
"given": "Francesco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Sangiovanni",
"given": "Vincenzo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Sanrocco",
"given": "Carlo",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Scorzolini",
"given": "Laura",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Sgariglia",
"given": "Raffaella",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Simeone",
"given": "Paola Giustina",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Spinicci",
"given": "Michele",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Trecarichi",
"given": "Enrico Maria",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Veronesi",
"given": "Giovanni",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Vettor",
"given": "Roberto",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Vianello",
"given": "Andrea",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Vinceti",
"given": "Marco",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Visconti",
"given": "Elena",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Vocciante",
"given": "Laura",
"sequence": "additional"
},
{
"affiliation": [],
"family": "De Caterina",
"given": "Raffaele",
"sequence": "additional"
},
{
"affiliation": [],
"family": "Iacoviello",
"given": "Licia",
"sequence": "additional"
},
{
"affiliation": [],
"name": "The COVID-19 RISK and Treatments (CORIST) Collaboration",
"sequence": "additional"
}
],
"container-title": "Frontiers in Medicine",
"container-title-short": "Front. Med.",
"content-domain": {
"crossmark-restriction": true,
"domain": [
"frontiersin.org"
]
},
"created": {
"date-parts": [
[
2021,
6,
9
]
],
"date-time": "2021-06-09T11:44:10Z",
"timestamp": 1623239050000
},
"deposited": {
"date-parts": [
[
2021,
6,
9
]
],
"date-time": "2021-06-09T11:44:16Z",
"timestamp": 1623239056000
},
"indexed": {
"date-parts": [
[
2024,
8,
7
]
],
"date-time": "2024-08-07T16:23:43Z",
"timestamp": 1723047823480
},
"is-referenced-by-count": 16,
"issued": {
"date-parts": [
[
2021,
6,
9
]
]
},
"license": [
{
"URL": "https://creativecommons.org/licenses/by/4.0/",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2021,
6,
9
]
],
"date-time": "2021-06-09T00:00:00Z",
"timestamp": 1623196800000
}
}
],
"link": [
{
"URL": "https://www.frontiersin.org/articles/10.3389/fmed.2021.639970/full",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "1965",
"original-title": [],
"prefix": "10.3389",
"published": {
"date-parts": [
[
2021,
6,
9
]
]
},
"published-online": {
"date-parts": [
[
2021,
6,
9
]
]
},
"publisher": "Frontiers Media SA",
"reference": [
{
"DOI": "10.1016/j.antiviral.2015.01.011",
"article-title": "Protease inhibitors targeting coronavirus and filovirus entry",
"author": "Zhou",
"doi-asserted-by": "publisher",
"first-page": "76",
"journal-title": "Antiviral Res.",
"key": "B1",
"volume": "116",
"year": "2015"
},
{
"DOI": "10.1136/thorax.2003.012658",
"article-title": "Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings",
"author": "Chu",
"doi-asserted-by": "publisher",
"first-page": "252",
"journal-title": "Thorax.",
"key": "B2",
"volume": "59",
"year": "2004"
},
{
"DOI": "10.1073/pnas.0403596101",
"article-title": "Small molecules targeting severe acute respiratory syndrome human coronavirus",
"author": "Wu",
"doi-asserted-by": "publisher",
"first-page": "10012",
"journal-title": "Proc Natl Acad Sci USA.",
"key": "B3",
"volume": "101",
"year": "2004"
},
{
"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",
"author": "Nutho",
"doi-asserted-by": "publisher",
"first-page": "1769",
"journal-title": "Biochemistry.",
"key": "B4",
"volume": "59",
"year": "2020"
},
{
"DOI": "10.1038/nrd.2015.37",
"article-title": "Coronaviruses-drug discovery and therapeutic options",
"author": "Zumla",
"doi-asserted-by": "publisher",
"first-page": "327",
"journal-title": "Nat Rev Drug Discov.",
"key": "B5",
"volume": "15",
"year": "2016"
},
{
"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",
"author": "Yao",
"doi-asserted-by": "publisher",
"first-page": "556",
"journal-title": "J Med Virol.",
"key": "B6",
"volume": "92",
"year": "2020"
},
{
"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",
"doi-asserted-by": "publisher",
"first-page": "1345",
"journal-title": "Lancet",
"key": "B7",
"volume": "396",
"year": "2020"
},
{
"DOI": "10.1056/NEJMoa2023184",
"article-title": "Repurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results",
"author": "Pan",
"doi-asserted-by": "publisher",
"first-page": "497",
"journal-title": "N Engl J Med.",
"key": "B8",
"volume": "384",
"year": "2021"
},
{
"DOI": "10.1056/NEJMc2008043",
"article-title": "A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19",
"author": "Cao",
"doi-asserted-by": "publisher",
"first-page": "1787",
"journal-title": "N Engl J Med.",
"key": "B9",
"volume": "382",
"year": "2020"
},
{
"DOI": "10.1080/14787210.2021.1848545",
"article-title": "Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: a systematic review",
"author": "Joseph",
"doi-asserted-by": "publisher",
"first-page": "1",
"journal-title": "Expert Rev Anti Infect Ther.",
"key": "B10",
"volume": "1",
"year": "2020"
},
{
"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-naïve patients in the ARTEMIS trial",
"author": "Orkin",
"doi-asserted-by": "publisher",
"first-page": "49",
"journal-title": "HIV Med.",
"key": "B11",
"volume": "14",
"year": "2013"
},
{
"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",
"doi-asserted-by": "publisher",
"journal-title": "Infect Disord Drug Targets",
"key": "B12",
"year": "2020"
},
{
"DOI": "10.1038/d41573-020-00016-0",
"article-title": "Therapeutic options for the 2019 novel coronavirus (2019-nCoV)",
"author": "Li",
"doi-asserted-by": "publisher",
"first-page": "149",
"journal-title": "Nat Rev Drug Discov.",
"key": "B13",
"volume": "19",
"year": "2020"
},
{
"key": "B14",
"unstructured": "Lopinavir/Ritonavir Nella Terapia dei Pazienti Adulti con COVID"
},
{
"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",
"author": "Di Castelnuovo",
"doi-asserted-by": "publisher",
"first-page": "312",
"journal-title": "Hypertension.",
"key": "B15",
"volume": "76",
"year": "2020"
},
{
"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",
"author": "Di Castelnuovo",
"doi-asserted-by": "publisher",
"first-page": "1899",
"journal-title": "Nutr Metab Cardiovasc Dis.",
"key": "B16",
"volume": "30",
"year": "2020"
},
{
"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",
"author": "Di Castelnuovo",
"doi-asserted-by": "publisher",
"first-page": "106805",
"journal-title": "Vasc Pharmacol",
"key": "B17",
"volume": "135",
"year": "2020"
},
{
"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",
"doi-asserted-by": "publisher",
"first-page": "38",
"journal-title": "Eur J Intern Med",
"key": "B18",
"volume": "82",
"year": "2020"
},
{
"DOI": "10.1002/9780470316696",
"author": "Rubin",
"doi-asserted-by": "crossref",
"key": "B19",
"volume-title": "Multiple Imputation for Nonresponse in Surveys",
"year": "1987"
},
{
"DOI": "10.1097/00001648-200009000-00011",
"article-title": "Marginal structural models and causal inference in epidemiology",
"author": "Robins",
"doi-asserted-by": "publisher",
"first-page": "550",
"journal-title": "Epidemiology.",
"key": "B20",
"volume": "11",
"year": "2000"
},
{
"DOI": "10.1002/sim.1599",
"article-title": "Modelling clustered survival data from multicentre clinical trials",
"author": "Glidden",
"doi-asserted-by": "publisher",
"first-page": "369",
"journal-title": "Stat Med.",
"key": "B21",
"volume": "23",
"year": "2004"
},
{
"DOI": "10.1111/1475-6773.12182",
"article-title": "Methods for constructing and assessing propensity scores",
"author": "Garrido",
"doi-asserted-by": "publisher",
"first-page": "1701",
"journal-title": "Health Serv Res.",
"key": "B22",
"volume": "49",
"year": "2014"
},
{
"DOI": "10.7326/M16-2607",
"article-title": "Sensitivity analysis in observational research: introducing the e-value",
"author": "VanderWeele",
"doi-asserted-by": "publisher",
"first-page": "268",
"journal-title": "Ann Intern Med.",
"key": "B23",
"volume": "167",
"year": "2017"
},
{
"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",
"author": "Li",
"doi-asserted-by": "publisher",
"first-page": "105",
"journal-title": "Med (N Y)",
"key": "B24",
"volume": "1",
"year": "2020"
},
{
"DOI": "10.1345/aph.1Q422",
"article-title": "Protease inhibitor-associated QT interval prolongation",
"author": "Hunt",
"doi-asserted-by": "publisher",
"first-page": "1544",
"journal-title": "Ann Pharmacother.",
"key": "B25",
"volume": "45",
"year": "2011"
},
{
"key": "B26",
"unstructured": "European Agencies Medicine Report2020"
},
{
"DOI": "10.2147/HIV.S56158",
"article-title": "Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS",
"author": "Navarro",
"doi-asserted-by": "publisher",
"first-page": "175",
"journal-title": "HIV AIDS.",
"key": "B27",
"volume": "8",
"year": "2016"
},
{
"DOI": "10.1093/ofid/ofaa241",
"article-title": "Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19",
"author": "Chen",
"doi-asserted-by": "publisher",
"first-page": "ofaa241",
"journal-title": "Open Forum Infect Dis.",
"key": "B28",
"volume": "7",
"year": "2020"
},
{
"DOI": "10.1016/j.ijid.2020.05.085",
"article-title": "Lack of antiviral activity of darunavir against SARS-CoV-2",
"author": "De Meyer",
"doi-asserted-by": "publisher",
"first-page": "7",
"journal-title": "Int J Infect Dis.",
"key": "B29",
"volume": "97",
"year": "2020"
},
{
"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",
"author": "Beck",
"doi-asserted-by": "publisher",
"first-page": "784",
"journal-title": "Comput Struct Biotechnol J",
"key": "B30",
"volume": "18",
"year": "2020"
},
{
"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",
"doi-asserted-by": "publisher",
"journal-title": "bioRxviv [Preprint]",
"key": "B31",
"year": "2020"
},
{
"DOI": "10.26434/chemrxiv.12111297.v1",
"article-title": "Computational determination of potential inhibitors of SARS-CoV-2 main protease",
"author": "Ngo",
"doi-asserted-by": "publisher",
"first-page": "5771",
"journal-title": "J Chem Inf Model.",
"key": "B32",
"volume": "60",
"year": "2020"
},
{
"DOI": "10.1039/D0RA01899F",
"article-title": "Anti-HIV drug repurposing against SARS-CoV-2†",
"author": "Sang",
"doi-asserted-by": "publisher",
"first-page": "15775",
"journal-title": "RSC Adv",
"key": "B33",
"volume": "10",
"year": "2020"
},
{
"DOI": "10.1080/07391102.2020.1751298",
"article-title": "Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach",
"author": "Khan",
"doi-asserted-by": "publisher",
"first-page": "2607",
"journal-title": "J Biomol Struct Dyn.",
"key": "B34",
"volume": "39",
"year": "2020"
},
{
"DOI": "10.1089/aid.2020.0305",
"article-title": "Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia",
"author": "Milic",
"doi-asserted-by": "publisher",
"first-page": "283",
"journal-title": "AIDS Res Hum Retroviruses.",
"key": "B35",
"volume": "37",
"year": "2021"
},
{
"DOI": "10.1111/jphp.12820",
"article-title": "Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat",
"author": "Hossain",
"doi-asserted-by": "publisher",
"first-page": "1786",
"journal-title": "J Pharm Pharmacol.",
"key": "B36",
"volume": "69",
"year": "2017"
},
{
"DOI": "10.1093/jac/dkw032",
"article-title": "Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications",
"author": "Marzolini",
"doi-asserted-by": "publisher",
"first-page": "1755",
"journal-title": "J Antimicrob Chemother.",
"key": "B37",
"volume": "71",
"year": "2016"
},
{
"DOI": "10.1111/bcp.14262",
"article-title": "Cobicistat: a case of mislabelled drug-drug interaction risk?",
"author": "Burger",
"doi-asserted-by": "publisher",
"first-page": "834",
"journal-title": "Br J Clin Pharmacol.",
"key": "B38",
"volume": "86",
"year": "2020"
},
{
"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",
"author": "Ameri",
"doi-asserted-by": "publisher",
"first-page": "1",
"journal-title": "Clin Res Cardiol.",
"key": "B39",
"volume": "1",
"year": "2020"
},
{
"DOI": "10.1093/ofid/ofaa321",
"article-title": "Reply to: “antiviral activity and safety of darunavir/cobicistat for treatment of COVID-19",
"author": "Nicolini",
"doi-asserted-by": "publisher",
"first-page": "ofaa321",
"journal-title": "Open Forum Infect Dis.",
"key": "B40",
"volume": "7",
"year": "2020"
}
],
"reference-count": 40,
"references-count": 40,
"relation": {},
"resource": {
"primary": {
"URL": "https://www.frontiersin.org/articles/10.3389/fmed.2021.639970/full"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.3389/crossmark-policy",
"volume": "8"
}
