Abstract: ORIGINAL RESEARCH published: 04 March 2022 doi: 10.3389/fmed.2022.826247 Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients: Observational Prospective Multicenter Investigation in Saudi Arabia Edited by: Murat Akova, Hacettepe University, Turkey Saleh Al-Muhsen 1*† , Nouf S. Al-Numair 2† , Narjes Saheb Sharif-Askari 3† , Roaa Basamh 4 , Banan Alyounes 4 , Amjad Jabaan 4 , Fatemeh Saheb Sharif-Askari 3 , Mohammed F. Alosaimi 1 , Fahad Alsohime 1 , Rabih Halwani 1,3,5* and Haya Al-Saud 4,6* 1 Reviewed by: Carmen Silvia Valente Barbas, University of São Paulo, Brazil Gökhan Metan, Hacettepe University, Turkey *Correspondence: Saleh Al-Muhsen almuhsen@ksu.edu.sa Rabih Halwani rhalwani@sharjah.ac.ae Haya Al-Saud hayakbaa@gmail.com † These authors have contributed equally to this work Specialty section: This article was submitted to Infectious Diseases – Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine Received: 30 November 2021 Accepted: 28 January 2022 Published: 04 March 2022 Citation: Al-Muhsen S, Al-Numair NS, Saheb Sharif-Askari N, Basamh R, Alyounes B, Jabaan A, Saheb Sharif-Askari F, Alosaimi MF, Alsohime F, Halwani R and Al-Saud H (2022) Favipiravir Effectiveness and Safety in Hospitalized Moderate-Severe COVID-19 Patients: Observational Prospective Multicenter Investigation in Saudi Arabia. Front. Med. 9:826247. doi: 10.3389/fmed.2022.826247 Frontiers in Medicine | www.frontiersin.org Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia, 2 The Saudi Ministry of Health and Center of Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, 3 Sharjah Institute of Medical Research, University of Sharjah, Sharjah, United Arab Emirates, 4 King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia, 5 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates, 6 Hevolution Foundation, Riyadh, Saudi Arabia Objectives: There are limited data on the efficacy and safety of favipiravir antiviral in coronavirus disease 2019 (COVID-19), particularly in the more progressed disease phase. This study aims to evaluate the favipiravir effect on reducing the length of hospital stay and in-hospital mortality among moderate and severe hospitalized COVID-19 patients. Methods: A prospective, multicenter observational study was conducted that included moderate and severe hospitalized adult COVID-19 patients in four major regions (Riyadh (Riyadh), Eastern (Dammam), Al-Qassem (Buraydah), and Macca (Jeddah) of Saudi Arabia. For the primary outcome of all-cause mortality, a Cox proportional hazard analysis was performed. While the association between favipiravir use and length of hospital stay was determined using adjusted generalized linear model. This study was approved by the Central Institutional Review Board in The Saudi Ministry of Health (MoH) with the approval number IRB # 20-85-M. Results: This study included 598 moderate and severe COVID-19 patients, of whom 156 (26%) received favipiravir. Favipiravir treatment was associated with more extended hospital stays (14 vs. 10 median days, P = 0.034) and higher mortality rate (aHR 3.63; 95% CI 1.06–12.45) compared to no favipiravir regimen. Despite lack of effectiveness, favipiravir use was only associated with higher diarrhea..