Abstract: American Journal of Epidemiology Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US. Vol. 190, No. 11 https://doi.org/10.1093/aje/kwab183 Advance Access publication: June 24, 2021 Original Contribution Pharmacoepidemiology, Machine Learning, and COVID-19: An Intent-to-Treat Analysis of Hydroxychloroquine, With or Without Azithromycin, and COVID-19 Outcomes Among Hospitalized US Veterans ∗ Correspondence to Dr. Hanna Gerlovin, VA Boston Healthcare System, 150 South Huntington Avenue (151-MAV), Boston, MA 02130 (e-mail: Hanna.Gerlovin@va.gov). Initially submitted December 15, 2020; accepted for publication June 17, 2021. Hydroxychloroquine (HCQ) was proposed as an early therapy for coronavirus disease 2019 (COVID-19) after in vitro studies indicated possible benefit. Previous in vivo observational studies have presented conf licting results, though recent randomized clinical trials have reported no benefit from HCQ among patients hospitalized with COVID-19. We examined the effects of HCQ alone and in combination with azithromycin in a hospitalized population of US veterans with COVID-19, using a propensity score–adjusted survival analysis with imputation of missing data. According to electronic health record data from the US Department of Veterans Affairs health care system, 64,055 US Veterans were tested for the virus that causes COVID-19 between March 1, 2020 and April 30, 2020. Of the 7,193 veterans who tested positive, 2,809 were hospitalized, and 657 individuals were prescribed HCQ within the first 48-hours of hospitalization for the treatment of COVID-19. There was no apparent benefit associated with HCQ receipt, alone or in combination with azithromycin, and there was an increased risk of intubation when HCQ was used in combination with azithromycin (hazard ratio = 1.55; 95% confidence interval: 1.07, 2.24). In conclusion, we assessed the effectiveness of HCQ with or without azithromycin in treatment of patients hospitalized with COVID-19, using a national sample of the US veteran population. Using rigorous study design and analytic methods to reduce confounding and bias, we found no evidence of a survival benefit from the administration of HCQ. COVID-19; gradient boosting; hydroxychloroquine; pharmacoepidemiology; propensity score; survival analysis; treatment outcome Abbreviations: CI, confidence interval; GBM, gradient boosting machine; HCQ, hydroxychloroquine; HR, hazard ratio; SARSCoV-2, severe acute respiratory syndrome coronavirus 2; VA, Veterans Affairs. In the swell of the coronavirus disease 2019 (COVID-19) pandemic, the world rushed to find therapies and prophylactic treatments, and hydroxychloroquine (HCQ) became an early front-runner (1, 2). HCQ is a common antimalarial and antirheumatologic drug with immunosuppressive functions. Results of early in vitro studies suggested HCQ might be repurposed to treat infections with a strong immune component (1, 3, 4), such as COVID-19. This was appealing, considering its low cost and widespread availability. The US Food and Drug Administration issued an emergency use authorization for HCQ on March 28, 2020 (5), prior to the com pletion of a randomized controlled trial, only to revoke it less than 3 months later, following concerns about HCQ-associated adverse events reported from observational studies (6, 7). At about the..