ABSTRACT
Introduction In Latin America, Peru is the most impacted country due to COVID-19 pandemic. Given the authorized nationwide use of hydroxychloroquine, azithromycin, and ivermectin in COVID-19 patients, we aimed to evaluate their effectiveness alone or combined to reduce 30-day mortality among COVID-19 hospitalized patients without life-threatening illness.
Methods Design. Retrospective cohort study using electronic health records to emulate a target trial. Settings. Nationwide data of mid- and high-level complexity hospitals from the Peruvian Social Health Insurance (EsSalud) between April 1 and July 19, 2020. Participants. Patients 18 years old and above with confirmed SARS-CoV-2 by PCR, and no diagnosis of severe disease at admission. Interventions. Five treatment groups, hydroxychloroquine/chloroquine alone (HCQ), ivermectin alone (IVM), azithromycin alone (AZIT), HCQ + AZIT group, and IVM + AZIT within 48 hours of admission at doses recommended by the Peruvian Ministry of Health. Comparison. Standard of care treatment without receiving any of the mentioned drugs within 48 of admission. Outcomes: Primary outcome was all-cause mortality rate, and secondary outcomes were survival without death or ICU transfer, and survival without death or oxygen prescription. Analysis. Analysis were adjusted for confounding factors using inverse probability of treatment weighting. Propensity scores were estimated using machine learning boosting models. Weighted hazard ratios (wHR) were calculated using Cox regression
Results Among 5683 patients, 200 received HCT, 203 IVM, 1600 AZIT, 692 HCQ + AZIT, 358 IVM + AZIT, and 2630 received standard of care. The AZIT + HCQ group was associated with 84% higher all-cause mortality hazard rate compared to standard care (wHR=1.84, 95%CI 1.12-3.02). Consistently, AZIT + HCQ treatment was associated with deaths or ICU transfer ICU (wHR=1.49, 95%CI 1.01-2.19), and deaths or oxygen prescription (wHR=1.70, 95%CI 1.07-2.69). HCQ treatment was only associated with death or oxygen prescription (wHR=1.77, 95% CI 1.01-3.11), and IVM was only associated with death or ICU transfer (wHR=1.58, 95%CI 1.11-2.25). No effect was found for AZIT or AZIT + IVM.
Conclusion Our study reported no beneficial effects of hydroxychloroquine, ivermectin, azithromycin, or their combinations. The AZIT+HCQ treatment reported increased risk of all-cause mortality.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study was funded by the Instituto de Evaluacion de Tecnologias en Salud e Investigacion (IETSI), EsSalud, Peru.
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:
This study was classified with minimal risk of vulnerability for participants. In order to maintain the privacy of the patients, the data extraction was anonymized by the EsSalud informatics office before data manipulation or analysis. This target trial protocol was approved by EsSalud Institutional Review Board of COVID studies (91-SGRyGIS-DIS-IETSI-ESSALUD-2020).
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
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).
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Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv
The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, University of Washington, and Vrije Universiteit Amsterdam.