Early Treatment with Hydroxychloroquine and Azithromycin: A ‘Real-Life’ Monocentric Retrospective Cohort Study of 30,423 COVID-19 Patients

Objective To estimate the comparative effectiveness of combination therapy with hydroxychloroquine (HCQ) and azithromycin for coronavirus disease 2019 (COVID-19)- related death based on a large monocentric cohort independent of investigators’ putative biases in a real-world setting. Design Retrospective monocentric cohort study, with comprehensive data collection authenticated by an external bailiff and death reports from a national database (French National Death Registry). Setting Institut Hospitalo-Universitaire Méditerranée Infection Center in Marseille, France. Participants All adults older than 18 years with PCR-proven COVID-19 who were treated directly in our centre between 2 March 2020 and 31 December 2021 and did not refuse the use of their data. Interventions HCQ and azithromycin (HCQ-AZ) as a reference treatment were compared to other regimens containing HCQ, ivermectin and azithromycin alone, combined, or none of these three drugs. The effect of vaccination was also evaluated. Main outcome measures 6-week all-cause mortality. Multivariable logistic regression estimated treatment effectiveness with adjustments for age, sex, comorbidities, vaccination, period of infection or virus variant, and outpatient or inpatient care. Results Total 30,423 COVID-19 patients were analysed (86 refused the analysis of their data) including 30,202 with available treatment data, and 535 died (1.77%). All-cause mortality was very low among patients < 50 years (8/15,925 (0.05%)) and among outpatients treated with HCQ-AZ (21 deaths out of 21,135 (0.1%), never exceeding 0.2% regardless of epidemic period). HCQ-AZ treatment was associated with a significantly lower mortality rate than no HCQ-AZ after adjustment for sex, age, period and patient care setting (adjusted OR (aOR) 95% confidence interval (CI) 0.55, 0.45-0.68). The effect was greater among outpatients (71% death protection rate) than among inpatients (45%). In a subset of 16,063 patients with available comorbidities and vaccinations status, obesity (2.01, 1.23-3.29), chronic respiratory disease (2.93, 1.29-6.64), and immunodeficiency (4.01, 1.69-9.50), on the one hand, and vaccination (0.29, 0.12-0.67) and HCQ-AZ treatment (0.47, 0.29-0.76), on the other hand, were independent factors associated with mortality. HCQ, alone or in any association, was associated with significant protection from death among outpatients (0.41, 0.21-0.79) and inpatients (0.59, 0.47-0.73). Conclusions HCQ prescribed early or late protects in part from COVID-19-related death. During pandemic health crises, financial stakes are enormous. Authentication of the data by an independent external judicial officer should be required. Public sharing of anonymized databases, ensuring their verifiability, should be mandatory in this context to avoid fake publications. ### Competing Interest Statement All authors have completed the Unified Competing Interest form (available on request from the corresponding author). DR declare grants or contracts and royalties or licenses from Hitachi High-Technologies Corporation, Tokyo, Japan. DR is scientific board member of Eurofins company. DR is founder and shareholder of a microbial culture company (Culture Top), two biotechnology companies (Techno-jouvence, and Gene and Green TK), and a rapid diagnosis of infectious diseases company (Pocrame). All authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work. Our group used widely available generic drugs distributed by many pharmaceutical companies. ### Funding Statement This work was performed by academic doctors working in the IHU Mediterranee Infection. IHU Mediterranee Infection was funded by the French government and benefited from a grant from Agence Nationale de la Recherche: ANR-15-CE36-0004-01 and by ANR Investissements d avenir, Mediterranee infection 10-IAHU-03, and was also supported by Region Provence-Alpes-Cote d Azur. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical committee of the Institut Hospitalo-Universitaire Mediterranee Infection gave ethical approval for this work (N: 2021-007 for outpatients and 2021-015 for inpatients). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data and Script Availability Statement Raw data are publicly available online in two public open access repositories (Science Data Bank, https://doi.org/10.57760/sciencedb.07803 and DRYAD, https://doi.org/10.5061/dryad.ksn02v78v). Conditions of reuse are license Creative Commons Zero (CC0) for both deposits. The SAS code is available upon request from the authors.