Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 COVID-19 outpatients
Matthieu Million, Jean-Christophe Lagier, Hervé Tissot-Dupont, Isabelle Ravaux, Catherine Dhiver, Christelle Tomei, Nadim Cassir, Léa Delorme, Sébastien Cortaredona, Sophie Amrane, Camille Aubry, Karim Bendamardji, Cyril Berenger, Barbara Doudier, Sophie Edouard, Marie Hocquart, Morgane Mailhe, Coralie Porcheto, Piseth Seng, Catherine Triquet, Stéphanie Gentile, Elisabeth Jouve, Audrey Giraud-Gatineau, Herve Chaudet, Laurence Camoin-Jau, Philippe Colson, Philippe Gautret, Pierre-Edouard Fournier, Baptiste Maille, Jean-Claude Deharo, Paul Habert, Jean-Yves Gaubert, Alexis Jacquier, Stéphane Honore, Katell Guillon-Lorvellec, Yolande Obadia, Philippe Parola, Philippe Brouqui, Didier Raoult
Reviews in Cardiovascular Medicine, doi:10.31083/j.rcm2203116
We evaluated the age-specific mortality of unselected adult outpatients infected with SARS-CoV-2 treated early in a dedicated COVID-19 day hospital and we assessed whether the use of hydroxychloroquine (HCQ) + azithromycin (AZ) was associated with improved survival in this cohort. A retrospective monocentric cohort study was conducted in the day hospital of our center from March to December 2020 in adults with PCR-proven infection who were treated as outpatients with a standardized protocol. The primary endpoint was 6-week mortality, and secondary endpoints were transfer to the intensive care unit and hospitalization rate. Among 10,429 patients (median age, 45 [IQR 32-57] years; 5597 [53.7%] women), 16 died (0.15%). The infection fatality rate was 0.06% among the 8315 patients treated with HCQ+AZ. No deaths occurred among the 8414 patients younger than 60 years. Older age and male sex were associated with a higher risk of death, ICU transfer, and hospitalization. Treatment with HCQ+AZ (0.17 [0.06-0.48]) was associated with a lower risk of death, independently of age, sex and epidemic period. Metaanalysis evidenced consistency with 4 previous outpatient studies (32,124 patients-Odds ratio 0.31 [0.20-0.47], I 2 = 0%). Early ambulatory treatment of COVID-19 with HCQ+AZ as a standard of care is associated with very low mortality, and HCQ+AZ improve COVID-19 survival compared to other regimens.
Abbreviations HCQ, hydroxychloroquine; AZ, azithromycin; IFR, infection fatality rate.
Author contributions MMillion designed and supervised the study, conducted the investigation, formal analysis and wrote the first draft of the manuscript, JCL participated in the study design, investigation and critical review, all authors (HTD, IR, CD, CT, NC, SA, CA, KB, BD, SE, MH, MMailhe, CP, PS, CT, SG, EJ, AGG, HC, LCJ, PC, PG, PEF, BM, JCD, PH, JYG, AJ, SH, KGL, YO, PP, PB) participated in the investigation and provided constructive criticism and comments, LD, CB and SC conducted the formal analysis and meta-analysis, DR designed and supervised the study, and final proofreading with key finalization of the text.
Ethics approval and consent to participate Data presented herein were collected retrospectively from the routine care setting using the electronic health recording system of the hospital. The retrospective nature of the study was approved by our institutional review board committee (Méditerranée Infection N • : 2021-007). As previously reported [15] , for all patients, the prescription of HCQ+AZ was made during day hospital attendance by one of the physicians, after a collegial decision based on the most recent scientific data available and after assessment of the benefit/harm ratio of the treatment. According to European General Data Protection Regulation No 2016/679, patients were informed of the potential use of their medical data and that they could refuse the use..
References
Altman, Bland, How to obtain the P value from a confidence interval, British Medical Journal
Amrane, Tissot-Dupont, Doudier, Eldin, Hocquart et al., Rapid viral diagnosis and ambulatory management of suspected COVID-19 cases presenting at the infectious diseases referral hospital in Marseille, France, -January 31st to March 1st, 2020: a respiratory virus snapshot, Travel Medicine and Infectious Disease
Andreani, Bideau, Duflot, Jardot, Rolland et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis
Anglemyer, Horvath, Bero, Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. The Cochrane Database of Systematic Reviews
Ayerbe, Risco, Ayis, The association between treatment with heparin and survival in patients with Covid-19. Journal of Thrombosis, and Thrombolysis
Cangiano, Fatti, Danesi, Gazzano, Croci et al., Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests, Aging
Carlucci, Ahuja, Petrilli, Rajagopalan, Jones et al., Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients, Journal of Medical Microbiology
Colson, Levasseur, Gautret, Fenollar, Hoang et al., Introduction into the Marseille geographical area of a mild SARS-CoV-2 variant originating from sub-Saharan Africa: an investigational study, Travel Medicine and Infectious Disease
Concato, Shah, Horwitz, Randomized, Controlled Trials, Observational Studies, and the Hierarchy of Research Designs, New England Journal of Medicine
Erikstrup, Hother, Pedersen, Mølbak, Skov et al., Estimation of SARS-CoV-2 Infection Fatality Rate by Real-time Antibody Screening of Blood Donors, Clinical Infectious Diseases
Fonseca, De, Sousa, Wolkoff, Moreira et al., Risk of hospitalization for Covid-19 outpatients treated with various drug regimens in Brazil: Comparative analysis, Travel Medicine and Infectious Disease
Fournier, Colson, Levasseur, Devaux, Gautret et al., Emergence and outcomes of the SARS-CoV-2 'Marseille-4' variant, International Journal of Infectious Diseases
Fournier, Zandotti, Ninove, Prudent, Colson et al., Contribution of VitaPCR SARS-CoV-2 to the emergency diagnosis of COVID-19, Journal of Clinical Virology
Gangopadhyay, Sinha, Ghosal, Compliance of the Indian National Task Force guidelines for COVID-19 recommendation by Indian doctors -a survey, Diabetes & Metabolic Syndrome
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, International Journal of Antimicrobial Agents
Gautret, Million, Jarrot, Camoin-Jau, Colson et al., Natural history of COVID-19 and therapeutic options, Expert Review of Clinical Immunology
Godlee, Covid-19: The lost lessons of Tamiflu, British Medical Journal
Gordon, Hiatt, Bouhaddou, Rezelj, Ulferts et al., Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms, Science
Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature
Gudbjartsson, Norddahl, Melsted, Gunnarsdottir, Holm et al., Humoral Immune Response to SARS-CoV-2 in Iceland, New England Journal of Medicine
Heras, Garibaldi, Boix, Valero, Castillo et al., COVID-19 mortality risk factors in older people in a long-term care center, European Geriatric Medicine
Ip, Ahn, Zhou, Goy, Hansen et al., Hydroxychloroquine in the treatment of outpatients with mildly symptomatic COVID-19: a multi-center observational study, BMC Infectious Diseases
Izoulet, National consumption of antimalarial drugs and COVID-19 deaths dynamics: An econometric study, Journal of Clinical Toxicology
Jaafar, Aherfi, Wurtz, Grimaldier, Hoang et al., Correlation between 3790 Quantitative Polymerase Chain Reaction-Positives Samples and Positive Cell Cultures, Including 1941 Severe Acute Respiratory Syndrome Coronavirus 2 Isolates, Clinical Infectious Diseases
Jiménez-Jáimez, Macías-Ruiz, Bermúdez-Jiménez, Rubini-Costa, Ramírez-Taboada et al., Absence of relevant QT interval prolongation in not critically ill COVID-19 patients, Scientific Reports
Ladapo, Mckinnon, Mccullogh, Risch, Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine
Lagier, Million, Gautret, Colson, Cortaredona et al., Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis, Travel Medicine and Infectious Disease
Lenze, Mattar, Zorumski, Stevens, Schweiger et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial, Journal of the American Medical Association
Lima-Morales, Méndez-Hernández, Flores, Osorno-Romero, Hernández et al., Effectiveness of a multidrug therapy consisting of Ivermectin, Azithromycin, Montelukast, and Acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico, International Journal of Infectious Diseases
Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery
Long, Wu, Chen, Zhou, Wu et al., Effect of early oxygen therapy and antiviral treatment on disease progression in patients with COVID-19: A retrospective study of medical charts in China, PLoS Neglected Tropical Diseases
Ly, Zanini, Laforge, Arlotto, Gentile et al., Pattern of SARS-CoV-2 infection among dependant elderly residents living in long-term care facilities in Marseille, France, March, International Journal of Antimicrobial Agents
Maille, Wilkin, Million, Rességuier, Franceschi et al., Smartwatch Electrocardiogram and Artificial Intelligence for Assessing Cardiac-Rhythm Safety of Drug Therapy in the COVID-19 Pandemic. The QT-logs study, International Journal of Cardiology
Mccullough, Alexander, Armstrong, Arvinte, Bain et al., Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19), Reviews in Cardiovascular Medicine
Mccullough, Kelly, Ruocco, Lerma, Tumlin et al., Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection, The American Journal of Medicine
Mehra, Desai, Ruschitzka, Patel, RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis, The Lancet
Mokhtari, Mohraz, Gouya, Tabar, Tabrizi et al., Clinical outcomes of patients with mild COVID-19 following treatment with hydroxychloroquine in an outpatient setting, International Immunopharmacology
Procter, Ross, Pickard, Smith, Hanson et al., Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection, Reviews in Cardiovascular Medicine
Rajter, Sherman, Fatteh, Vogel, Sacks et al., Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with Coronavirus Disease, Chest
Reis, Silva, Silva, Thabane, Singh et al., Effect of Early Treatment with Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization among Patients with COVID-19, JAMA Network Open
Seftel, Boulware, Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19, Open Forum Infectious Diseases
Su, Ling, Ma, Tao, Miao et al., Efficacy of early hydroxychloroquine treatment in preventing COVID-19 pneumonia aggravation, the experience from Shanghai, China, Bioscience Trends
Sulaiman, Mohana, Alawdah, Mahmoud, Hassanein et al., The Effect of Early Hydroxychloroquine-based Therapy
Tang, Bai, Chen, Gong, Li et al., Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy, Journal of Thrombosis and Haemostasis
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Research
White, Cardiotoxicity of antimalarial drugs, The Lancet Infectious Diseases
Worldometer, COVID-19 Coronavirus pandemic
{ 'indexed': {'date-parts': [[2024, 4, 1]], 'date-time': '2024-04-01T08:21:11Z', 'timestamp': 1711959671257},
'reference-count': 0,
'publisher': 'IMR Press',
'issue': '3',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2021]]},
'DOI': '10.31083/j.rcm2203116',
'type': 'journal-article',
'created': {'date-parts': [[2021, 9, 26]], 'date-time': '2021-09-26T02:35:45Z', 'timestamp': 1632623745000},
'page': '1063',
'source': 'Crossref',
'is-referenced-by-count': 22,
'title': 'Early combination therapy with hydroxychloroquine and azithromycin reduces mortality in 10,429 '
'COVID-19 outpatients',
'prefix': '10.31083',
'volume': '22',
'author': [ {'given': 'Matthieu', 'family': 'MILLION', 'sequence': 'first', 'affiliation': []},
{'given': 'Jean-Christophe', 'family': 'LAGIER', 'sequence': 'first', 'affiliation': []},
{'given': 'Hervé', 'family': 'TISSOT-DUPONT', 'sequence': 'first', 'affiliation': []},
{'given': 'Isabelle', 'family': 'RAVAUX', 'sequence': 'first', 'affiliation': []},
{'given': 'Catherine', 'family': 'DHIVER', 'sequence': 'first', 'affiliation': []},
{'given': 'Christelle', 'family': 'TOMEI', 'sequence': 'first', 'affiliation': []},
{'given': 'Nadim', 'family': 'CASSIR', 'sequence': 'first', 'affiliation': []},
{'given': 'Léa', 'family': 'DELORME', 'sequence': 'first', 'affiliation': []},
{'given': 'Sébastien', 'family': 'CORTAREDONA', 'sequence': 'first', 'affiliation': []},
{'given': 'Sophie', 'family': 'AMRANE', 'sequence': 'first', 'affiliation': []},
{'given': 'Camille', 'family': 'AUBRY', 'sequence': 'first', 'affiliation': []},
{'given': 'Karim', 'family': 'BENDAMARDJI', 'sequence': 'first', 'affiliation': []},
{'given': 'Cyril', 'family': 'BERENGER', 'sequence': 'first', 'affiliation': []},
{'given': 'Barbara', 'family': 'DOUDIER', 'sequence': 'first', 'affiliation': []},
{'given': 'Sophie', 'family': 'EDOUARD', 'sequence': 'first', 'affiliation': []},
{'given': 'Marie', 'family': 'HOCQUART', 'sequence': 'first', 'affiliation': []},
{'given': 'Morgane', 'family': 'MAILHE', 'sequence': 'first', 'affiliation': []},
{'given': 'Coralie', 'family': 'PORCHETO', 'sequence': 'first', 'affiliation': []},
{'given': 'Piseth', 'family': 'SENG', 'sequence': 'first', 'affiliation': []},
{'given': 'Catherine', 'family': 'TRIQUET', 'sequence': 'first', 'affiliation': []},
{'given': 'Stéphanie', 'family': 'GENTILE', 'sequence': 'first', 'affiliation': []},
{'given': 'Elisabeth', 'family': 'JOUVE', 'sequence': 'first', 'affiliation': []},
{'given': 'Audrey', 'family': 'GIRAUD-GATINEAU', 'sequence': 'first', 'affiliation': []},
{'given': 'Herve', 'family': 'CHAUDET', 'sequence': 'first', 'affiliation': []},
{'given': 'Laurence', 'family': 'CAMOIN-JAU', 'sequence': 'first', 'affiliation': []},
{'given': 'Philippe', 'family': 'COLSON', 'sequence': 'first', 'affiliation': []},
{'given': 'Philippe', 'family': 'GAUTRET', 'sequence': 'first', 'affiliation': []},
{'given': 'Pierre-Edouard', 'family': 'FOURNIER', 'sequence': 'first', 'affiliation': []},
{'given': 'Baptiste', 'family': 'MAILLE', 'sequence': 'first', 'affiliation': []},
{'given': 'Jean-Claude', 'family': 'DEHARO', 'sequence': 'first', 'affiliation': []},
{'given': 'Paul', 'family': 'HABERT', 'sequence': 'first', 'affiliation': []},
{'given': 'Jean-Yves', 'family': 'GAUBERT', 'sequence': 'first', 'affiliation': []},
{'given': 'Alexis', 'family': 'JACQUIER', 'sequence': 'first', 'affiliation': []},
{'given': 'Stéphane', 'family': 'HONORE', 'sequence': 'first', 'affiliation': []},
{'given': 'Katell', 'family': 'GUILLON-LORVELLEC', 'sequence': 'first', 'affiliation': []},
{'given': 'Yolande', 'family': 'OBADIA', 'sequence': 'first', 'affiliation': []},
{'given': 'Philippe', 'family': 'PAROLA', 'sequence': 'first', 'affiliation': []},
{'given': 'Philippe', 'family': 'BROUQUI', 'sequence': 'first', 'affiliation': []},
{'given': 'Didier', 'family': 'RAOULT', 'sequence': 'first', 'affiliation': []}],
'member': '16242',
'container-title': 'Reviews in Cardiovascular Medicine',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://rcm.imrpress.com/fileup/2153-8174/PDF/1632453113256-204528530.pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 1, 31]],
'date-time': '2022-01-31T19:48:18Z',
'timestamp': 1643658498000},
'score': 1,
'resource': {'primary': {'URL': 'https://imrpress.com/journal/RCM/22/3/10.31083/j.rcm2203116'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021]]},
'references-count': 0,
'journal-issue': {'issue': '3', 'published-print': {'date-parts': [[2021]]}},
'URL': 'http://dx.doi.org/10.31083/j.rcm2203116',
'relation': {},
'ISSN': ['2153-8174'],
'subject': ['Cardiology and Cardiovascular Medicine', 'General Medicine'],
'container-title-short': 'Reviews in Cardiovascular Medicine',
'published': {'date-parts': [[2021]]}}
