Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial


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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure.

METHODS: We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19-compatible illness. We measured hydroxychloroquine whole-blood concentrations.

RESULTS: We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was .72 (95% CI, .44-1.16; P = .18) and for twice-weekly was .74 (95% CI, .46-1.19; P = .22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82-120) with once-weekly and 200 ng/mL (IQR, 159-258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19-compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P = .08).

CONCLUSIONS: Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19-compatible illness among healthcare workers.

CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov NCT04328467.

Original languageEnglish (US)
Pages (from-to)E835-E843
JournalClinical Infectious Diseases
Issue number11
Early online dateOct 17 2020
StatePublished - Jun 1 2021

Bibliographical note

Funding Information:
This work was supported by Jan and David Baszucki, Steve Kirsch, the Rainwater Charitable Foundation, the Alliance of Minnesota Chinese Organizations, the Minnesota Chinese Chamber of Commerce, and the University of Minnesota Foundation. M. R. N., R. R., and M. F. P. are supported by the National Institute of Allergy and Infectious Diseases (grant numbers K08AI134262, K23AI138851, T32AI055433). S. M. L. is supported by the National Institute of Mental Health (grant number K23MH121220). C. P. S. is supported by a combined Fogarty International Center Global Fellows Scholarship/National Institute of Neurological Disorders and Stroke grant (D43TW009345). K. A. P. and E. C. O. were supported through the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota. M. L. A. is supported by National Institutes of Health grants T32GM007347 and F30CA236157. T. C. L. and E. G. M. receive research salary support from the Fonds de Recherche du Qu?bec-Sant?. In Manitoba, research support was received from the Manitoba Medical Service Foundation and Research Manitoba. Rising Pharmaceuticals in the United States provided a donation of the hydroxychloroquine tablets. The REDCap software was supported by the National Institutes of Health's National Center for Advancing Translational Sciences (grant number UL1TR002494).

Publisher Copyright:
© 2020 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.


  • COVID-19
  • healthcare workers
  • hydroxychloroquine
  • pre-exposure prophylaxis
  • Canada
  • SARS-CoV-2
  • COVID-19/drug therapy
  • Health Personnel
  • Humans
  • Hydroxychloroquine/therapeutic use
  • Pre-Exposure Prophylaxis

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Journal Article
  • Research Support, N.I.H., Extramural


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