Real-World Effectiveness of Hydroxychloroquine, Azithromycin, and Ivermectin Among Hospitalized COVID-19 Patients: Results of a Target Trial Emulation Using Observational Data from a Nationwide Healthcare System in Peru

Abstract

Background: Peru is one of the most impacted countries due to COVID-19. Given the authorized use of hydroxychloroquine (HCQ), azithromycin (AZIT), and ivermectin (IVM), we aimed to evaluate their effectiveness alone or combined to reduce mortality among COVID-19 hospitalized patients without life-threatening illness.Methods: Retrospective cohort emulating a target trial, using nationwide data of mid- and high-level hospitals from the Peruvian Social Health Insurance 01/April/2020–19/July/2020. Patients 18 yo and above with PCR-confirmed SARS-CoV-2, and no life-threatening illness at admission were included. Five treatment groups (HCQ alone, IVM alone, AZIT alone, HCQ+AZIT, and IVM+AZIT within 48 hours of admission) were compared with standard of care alone. Primary outcome was all-cause mortality rate; secondary outcomes were all-cause death and/or ICU transfer, and all-cause death and/or oxygen prescription. Analyses were adjusted using inverse probability of treatment weighting. Propensity scores were estimated using machine learning boosting models. Weighted hazard ratios (wHR) were calculated using Cox regression.Findings: Among 5683 patients, 200 received HCT, 203 IVM, 1600 AZIT, 692 HCQ+AZIT, 358 IVM+AZIT, and 2630 standard of care. HCQ+AZIT was associated with 84% higher all-cause mortality rate compared to standard care (wHR=1·84, 95%CI 1·12-3·02). Consistently, HCQ+AZIT was also associated with higher death and/or ICU transfer (wHR=1·49, 95%CI 1·01-2·19), and death and/or oxygen prescription (wHR=1·70, 95%CI 1·07-2·69). HCQ was only associated with death and/or oxygen prescription. No effect was found for AZIT or IVM+AZIT. Interpretation: Our study reported no beneficial effects of hydroxychloroquine, ivermectin, azithromycin. The HCQ+AZIT treatment seems to increase risk of all-cause mortality.Trial Registration: Peruvian Health Research Projects repository (PRISA, by its acronym in Spanish) ID EI-1243 (31).Funding: Instituto de Evaluación de Tecnologías en Salud e Investigación – IETSI, EsSaludDeclaration of Interests: All the authors declare that there is no conflict of interest regarding the content of this study.Ethics Approval Statement: This study has followed all the recommendations of the Declaration of Helsinki regarding research involving human subjects. The protocol was approved by EsSalud’s Institutional Review Board for COVID studies with letter 91-SGRyGIS-DIS-IETSIESSALUD- 2020.