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POST-EXPOSURE LOPINAVIR-RITONAVIR PROPHYLAXIS VERSUS SURVEILLANCE FOR INDIVIDUALS EXPOSED TO SARS-COV-2: THE COPEP PRAGMATIC OPEN-LABEL, CLUSTER RANDOMIZED TRIAL
Author
Labhardt, Niklaus D.
Smit, Mikaela
Petignat, Ianis
Perneger, Thomas
Marinosci, Annalisa
Ustero, Pilar
Ribeiro, Maria Pia Diniz
Ragozzino, Silvio
Nicoletti, Giovanni Jacopo
Faré, Pietro Benedetto
Andrey, Diego O.
Jacquerioz, Frederique
Lebowitz, Dan
Agoritsas, Thomas
Meyer, Benjamin
Spechbach, Hervé
Salamun, Julien
Guessous, Idris
Chappuis, François
Kaiser, Laurent
Decosterd, Laurent Arthur
Grinsztejn, Beatriz
Bernasconi, Enos
Cardoso, Sandra Wagner
Calmy, Alexandra
Smit, Mikaela
Petignat, Ianis
Perneger, Thomas
Marinosci, Annalisa
Ustero, Pilar
Ribeiro, Maria Pia Diniz
Ragozzino, Silvio
Nicoletti, Giovanni Jacopo
Faré, Pietro Benedetto
Andrey, Diego O.
Jacquerioz, Frederique
Lebowitz, Dan
Agoritsas, Thomas
Meyer, Benjamin
Spechbach, Hervé
Salamun, Julien
Guessous, Idris
Chappuis, François
Kaiser, Laurent
Decosterd, Laurent Arthur
Grinsztejn, Beatriz
Bernasconi, Enos
Cardoso, Sandra Wagner
Calmy, Alexandra
Affilliation
University of Basel. Department of Infectious Diseases and Hospital Epidemiology. Basel, Switzerland / Swiss Tropical and Public Health Institute. Department of Medicine. Basel, Switzerland / University of Basel. Basel, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / University of Geneva. Faculty of Medicine. Department of Medicine. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Geneva University Hospitals. Division of Clinical Epidemiology. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of Basel. Department of Infectious Diseases and Hospital Epidemiology. Basel, Switzerland.
University of Basel. Department of Infectious Diseases and Hospital Epidemiology. Basel, Switzerland / Swiss Tropical and Public Health Institute. Department of Medicine. Basel, Switzerland.
University of Southern Switzerland. Ospedale Regionale di Lugano and Faculty of Medicine. Division of Infectious Diseases. Lugano, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / Geneva University Hospitals. Diagnostic Department. Division of Laboratory Medicine. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Infection Control Program. Geneva, Switzerland.
Geneva University Hospital. Division of General Internal Medicine. Geneva, Switzerland / McMaster University. Department of Health Research Methods, Evidence, and Impact. Hamilton, Ontario, Canada.
University of Geneva. Department of Pathology and Immunology. Centre for Vaccinology. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / Geneva University Hospitals. Geneva Centre for Emerging Viral Diseases. Geneva, Switzerland.
University of Lausanne. Laboratory of Clinical Pharmacology. Lausanne, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of Southern Switzerland. Ospedale Regionale di Lugano and Faculty of Medicine. Division of Infectious Diseases. Lugano, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / University of Geneva. Faculty of Medicine. Department of Medicine. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / University of Geneva. Faculty of Medicine. Department of Medicine. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Geneva University Hospitals. Division of Clinical Epidemiology. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of Basel. Department of Infectious Diseases and Hospital Epidemiology. Basel, Switzerland.
University of Basel. Department of Infectious Diseases and Hospital Epidemiology. Basel, Switzerland / Swiss Tropical and Public Health Institute. Department of Medicine. Basel, Switzerland.
University of Southern Switzerland. Ospedale Regionale di Lugano and Faculty of Medicine. Division of Infectious Diseases. Lugano, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / Geneva University Hospitals. Diagnostic Department. Division of Laboratory Medicine. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Infection Control Program. Geneva, Switzerland.
Geneva University Hospital. Division of General Internal Medicine. Geneva, Switzerland / McMaster University. Department of Health Research Methods, Evidence, and Impact. Hamilton, Ontario, Canada.
University of Geneva. Department of Pathology and Immunology. Centre for Vaccinology. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Geneva University Hospitals. Division and Department of Primary Care. Geneva, Switzerland.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / Geneva University Hospitals. Geneva Centre for Emerging Viral Diseases. Geneva, Switzerland.
University of Lausanne. Laboratory of Clinical Pharmacology. Lausanne, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of Southern Switzerland. Ospedale Regionale di Lugano and Faculty of Medicine. Division of Infectious Diseases. Lugano, Switzerland.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
Faculty of Medicine. Geneva University Hospitals. Division of Infectious Diseases. Geneva, Switzerland / University of Geneva. Faculty of Medicine. Department of Medicine. Geneva, Switzerland.
Abstract
Background: Since the beginning of the COVID-19 pandemic, no direct antiviral treatment is effective as post-exposure prophylaxis (PEP). Lopinavir/ritonavir (LPV/r) was repurposed as a potential PEP agent against COVID-19. Methods: We conducted a pragmatic open-label, parallel, cluster-randomised superiority trial in four sites in Switzerland and Brazil between March 2020 to March 2021. Clusters were randomised to receive LPV/r PEP (400/100 mg) twice daily for 5 days or no PEP (surveillance). Exposure to SARS-CoV-2 was defined as a close contact of >15 minutes in <2 metres distance or having shared a closed space for ≥2 hours with a person with confirmed SARS-CoV-2 infection. The primary outcome is the occurrence of COVID-19 defined by a SARS-CoV-2 infection (positive oropharyngeal SARS-CoV-2 PCR and/or a seroconversion) and ≥1 compatible symptom within 21 days post-enrolment. ClinicalTrials.gov (Identifier: NCT04364022); Swiss National Clinical Trial Portal: SNCTP 000003732. Findings: Of 318 participants, 157 (49.4%) were women; median age was 39 (interquartile range, 28-50) years. A total of 209 (179 clusters) participants were randomised to LPV/r PEP and 109 (95 clusters) to surveillance. Baseline characteristics were similar, with the exception of baseline SARS-CoV-2 PCR positivity, which was 3-fold more frequent in the LPV/r arm (34/209 [16.3%] vs 6/109 [5.5%], respectively). During 21-day follow-up, 48/318 (15.1%) participants developed COVID-19: 35/209 (16.7%) in the LPV/r group and 13/109 (11.9%) in the surveillance group (unadjusted hazard ratio 1.44; 95% CI, 0.76-2.73). In the primary endpoint analysis, which was adjuted for baseline imbalance, the hazard ratio for developing COVID-19 in the LPV/r group vs surveillance was 0.60 (95% CI, 0.29-1.26; p =0.18). Interpretation: The role of LPV/r as PEP for COVID-19 remains unanswered. Although LPV/r over 5 days did not significantly reduce the incidence of COVID-19 in exposed individuals, we observed a change in the directionality of the effect in favour of LPV/r after adjusting for baseline imbalance. LPV/r for this indication merits further testing against SARS-CoV-2 in clinical trials. Funding: Swiss National Science Foundation (project no.: 33IC30_166819) and the Private Foundation of Geneva University Hospitals (Edmond Rothschild (Suisse) SA, Union Bancaire Privée and the Fondation pour la recherche et le traitement médical).
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