Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: a retrospective cohort study

DOI record: { "DOI": "10.1002/jmv.26407", "ISSN": [ "0146-6615", "1096-9071" ], "URL": "http://dx.doi.org/10.1002/jmv.26407", "abstract": "<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>P</jats:italic> = .213). After adjusting for potentially 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.</jats:p>", "alternative-id": [ "10.1002/jmv.26407" ], "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2020-06-16" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 1, "value": "2020-08-03" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 2, "value": "2020-09-28" } ], "author": [ { "ORCID": "http://orcid.org/0000-0003-3685-4289", "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "authenticated-orcid": false, "family": "Giacomelli", "given": "Andrea", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-1668-7543", "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "authenticated-orcid": false, "family": "Pagani", "given": "Gabriele", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" } ], "family": "Ridolfo", "given": "Anna L.", "sequence": "additional" }, { "affiliation": [ { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Oreni", "given": "Letizia", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Conti", "given": "Federico", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Pezzati", "given": "Laura", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Bradanini", "given": "Lucia", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Casalini", "given": "Giacomo", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Bassoli", "given": "Cinzia", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Morena", "given": "Valentina", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" } ], "family": "Passerini", "given": "Simone", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "School of Clinical Medicine, Faculty of Health Science University of the Witwatersrand Johannesburg South Africa" } ], "family": "Rizzardini", "given": "Giuliano", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, ASST Fatebenefratelli‐Sacco Luigi Sacco Hospital Milan Italy" } ], "family": "Cogliati", "given": "Chiara", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Internal Medicine, ASST Fatebenefratelli‐Sacco Luigi Sacco Hospital Milan Italy" } ], "family": "Ceriani", "given": "Elisa", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Anesthesiology and Intensive Care, ASST Fatebenefratelli‐Sacco Luigi Sacco Hospital Milan Italy" } ], "family": "Colombo", "given": "Riccardo", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-0375-9990", "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "authenticated-orcid": false, "family": "Rusconi", "given": "Stefano", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" } ], "family": "Gervasoni", "given": "Cristina", "sequence": "additional" }, { "affiliation": [ { "name": "Unit of Clinical Pharmacology, ASST Fatebenefratelli‐Sacco Luigi Sacco University Hospital Milan Italy" } ], "family": "Cattaneo", "given": "Dario", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Antinori", "given": "Spinello", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Infectious Diseases ASST Fatebenefratelli‐Sacco, Luigi Sacco University Hospital Milan Italy" }, { "name": "Luigi Sacco Department of Biomedical and Clinical Sciences DIBIC University of Milan Milan Italy" } ], "family": "Galli", "given": "Massimo", "sequence": "additional" } ], "container-title": "Journal of Medical Virology", "container-title-short": "Journal of Medical Virology", "content-domain": { "crossmark-restriction": true, "domain": [ "onlinelibrary.wiley.com" ] }, "created": { "date-parts": [ [ 2020, 8, 10 ] ], "date-time": "2020-08-10T21:49:39Z", "timestamp": 1597096179000 }, "deposited": { "date-parts": [ [ 2023, 8, 28 ] ], "date-time": "2023-08-28T03:53:12Z", "timestamp": 1693194792000 }, "indexed": { "date-parts": [ [ 2024, 5, 1 ] ], "date-time": "2024-05-01T01:30:35Z", "timestamp": 1714527035115 }, "is-referenced-by-count": 18, "issue": "3", "issued": { "date-parts": [ [ 2020, 9, 28 ] ] }, "journal-issue": { "issue": "3", "published-print": { "date-parts": [ [ 2021, 3 ] ] } }, "language": "en", "license": [ { "URL": "http://onlinelibrary.wiley.com/termsAndConditions#vor", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 9, 28 ] ], "date-time": "2020-09-28T00:00:00Z", "timestamp": 1601251200000 } } ], "link": [ { "URL": "https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fjmv.26407", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.26407", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jmv.26407", "content-type": "application/xml", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.26407", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "311", "original-title": [], "page": "1421-1427", "prefix": "10.1002", "published": { "date-parts": [ [ 2020, 9, 28 ] ] }, "published-online": { "date-parts": [ [ 2020, 9, 28 ] ] }, "published-print": { "date-parts": [ [ 2021, 3 ] ] }, "publisher": "Wiley", "reference": [ { "key": "e_1_2_9_2_1", "unstructured": "World Health Organization. Coronavirus disease (COVID‐19) Situation Report– 111. Data as received by WHO from national authorities by 10:00 CEST 15 June2020.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200615-covid-19-sitrep-147.pdf?sfvrsn=2497a605_4" }, { "DOI": "10.1016/S0140-6736(20)30183-5", "doi-asserted-by": "publisher", "key": "e_1_2_9_3_1" }, { "DOI": "10.1016/j.phrs.2020.104931", "doi-asserted-by": "publisher", "key": "e_1_2_9_4_1" }, { "DOI": "10.1038/s41577-020-0311-8", "doi-asserted-by": "publisher", "key": "e_1_2_9_5_1" }, { "key": "e_1_2_9_6_1", "unstructured": "Covid‐19Regione Lombardia 16 June2020.https://experience.arcgis.com/experience/0a5dfcc103d0468bbb6b14e713ec1e30/" }, { "key": "e_1_2_9_7_1", "unstructured": "Società Italiana di Malattie Infettive e Tropicali. Sezione regione Lombardia. Linee guida sulla gestione terapeutica e di supporto per pazienti con infezione da coronavirus COVID‐19.Edizione marzo2020.http://www.simit.org/medias/1555-covid19-linee-guida-trattamento-01mar.pdf" }, { "key": "e_1_2_9_8_1", "unstructured": "Lombardy Section Italian Society Infectious And Tropical Diseases. Vademecum for the treatment of people with COVID‐19Infez Med.2020;28:143–152." }, { "DOI": "10.1016/j.bbrc.2004.08.085", "doi-asserted-by": "publisher", "key": "e_1_2_9_9_1" }, { "DOI": "10.1007/978-1-4615-1325-4_31", "doi-asserted-by": "publisher", "key": "e_1_2_9_10_1" }, { "DOI": "10.1038/s41422-020-0282-0", "doi-asserted-by": "publisher", "key": "e_1_2_9_11_1" }, { "article-title": "Induction of pro‐inflammatory cytokines (IL‐1 and IL‐6) and lung inflammation by Coronavirus‐19 (COVI‐19 or SARS‐CoV‐2): anti‐inflammatory strategies", "author": "Conti P", "first-page": "327", "issue": "2", "journal-title": "J Biol Regul Homeost Agents", "key": "e_1_2_9_12_1", "volume": "34", "year": "2020" }, { "DOI": "10.1016/j.jcv.2004.03.003", "doi-asserted-by": "publisher", "key": "e_1_2_9_13_1" }, { "DOI": "10.1016/j.jinf.2013.09.029", "doi-asserted-by": "publisher", "key": "e_1_2_9_14_1" }, { "article-title": "Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study", "author": "Chan KS", "first-page": "399", "journal-title": "Hong Kong Med J", "key": "e_1_2_9_15_1", "volume": "9", "year": "2003" }, { "DOI": "10.1056/NEJMoa2001282", "doi-asserted-by": "publisher", "key": "e_1_2_9_16_1" }, { "DOI": "10.1056/NEJMoa2012410", "doi-asserted-by": "publisher", "key": "e_1_2_9_17_1" }, { "DOI": "10.1016/S0140-6736(14)62449-1", "doi-asserted-by": "publisher", "key": "e_1_2_9_18_1" }, { "DOI": "10.1371/journal.pone.0122642", "article-title": "Outcomes of early administration of cidofovir in non‐immunocompromised patients with severe adenovirus pneumonia", "author": "Kim SJ", "doi-asserted-by": "crossref", "first-page": "e0122642", "journal-title": "PLOS One", "key": "e_1_2_9_19_1", "volume": "10", "year": "2015" }, { "DOI": "10.1093/infdis/jiw033", "doi-asserted-by": "publisher", "key": "e_1_2_9_20_1" }, { "article-title": "Early cidofovir administration might be associated with a lower probability of respiratory failure in treating human adenovirus pneumonia: a retrospective cohort study", "author": "Ko J‐H", "journal-title": "Clin Microbiol Infect", "key": "e_1_2_9_21_1", "year": "2019" }, { "key": "e_1_2_9_22_1", "unstructured": "WHO.Clinical management of severe acute respiratory infection when COVID‐19 is suspected.https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected" }, { "DOI": "10.1093/cid/ciaa199", "doi-asserted-by": "publisher", "key": "e_1_2_9_23_1" }, { "key": "e_1_2_9_24_1", "unstructured": "WHO R&D Blueprint and COVID‐19" }, { "DOI": "10.1016/j.phrs.2020.104898", "doi-asserted-by": "publisher", "key": "e_1_2_9_25_1" }, { "DOI": "10.1002/cpt.1856", "doi-asserted-by": "publisher", "key": "e_1_2_9_26_1" }, { "DOI": "10.1093/jac/dkaa190", "doi-asserted-by": "publisher", "key": "e_1_2_9_27_1" } ], "reference-count": 26, "references-count": 26, "relation": { "has-preprint": [ { "asserted-by": "object", "id": "10.1101/2020.06.05.20123299", "id-type": "doi" } ] }, "resource": { "primary": { "URL": "https://onlinelibrary.wiley.com/doi/10.1002/jmv.26407" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS‐CoV‐2 infection: A retrospective cohort study", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1002/crossmark_policy", "volume": "93" }