TITLE: 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 Short Title: Target trial emulation of hydroxychloroquine, azithromycin, 

Introduction: In Latin America, Peru is the most impacted country due to COVID-19 pandemic. Given the authorized nationwide use of hydroxychloroquine, azithromycin, ivermectin and dexamethasone in COVID-19 patients, we aimed to evaluate their effectiveness alone or combined to prevent 30-day mortality among COVID-19 hospitalized patients without life-threatening illness. Methods: Design. Retrospective cohort study using digital clinical records to emulate a target trial. Setting. Nationwide data of midand high-level complexity hospitals from the Peruvian Social Health Insurance (EsSalud) between April 1 and July 19, 2020. Participants. Patients aged 18 years with confirmed SARS-CoV-2 infection by PCR, and non-severe pneumonia at admission. Interventions. We compared five treatment groups to the standard of care treatment regimen (control group) within 48 hours of admission to hospital: hydroxychloroquine/chloroquine alone (HCQ), ivermectin alone (IVM), azithromycin alone (AZIT), HCQ + AZIT group, and IVM + AZIT group with doses recommended by the Peruvian Ministry of Health. Main outcomes measures. The primary outcome was all-cause mortality rate, the secondary outcomes were survival without ICU rate, and survival without oxygen prescription rate. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. A doubly-adjustment method was done for sensitivity analysis. Results: Among 5683 patients eligible for analysis, 200 received hydroxychloroquine or chloroquine within 48 hours of hospital admission, 203 received ivermectin, 1600 received azithromycin, 692 received hydroxychloroquine or chloroquine plus azithromycin, 358 received ivermectin plus azithromycin and 2630 received standard of care. 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 survival without transfer to ICU (wHR = 1.49, 95% CI: 1.01-2.19) and survival without oxygen prescription (wHR = 1.70, 95% CI: 1.07-2.69). HCQ treatment was associated with 77% higher all-cause mortality or oxygen prescription hazard rate compared to standard treatment (wHR = 1.77, 95% CI: 1.01-3.11). Surprisingly, we observed that IVM treatment was associated with less survival rate without transfer to ICU in the weighted analysis (wHR = 1.58, 95% CI:1.11-2.25) By last, we did not find evidence of effect on reduce allcause mortality or increase survival rate without transfer to ICU or survival rate without oxygen prescription for AZIT group neither AZIT + IVM group in all analyses. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted October 8, 2020. ; https://doi.org/10.1101/2020.10. 06.20208066 doi: medRxiv preprint