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Concerns About the Special Article on Hydroxychloroquine and Azithromycin in High-Risk Outpatients With COVID-19

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In May 2020, the Journal published an opinion piece by a member of the Editorial Board, in which the author reviewed several papers and argued that using hydroxychloroquine (HCQ) + azithromycin (AZ) early to treat symptomatic coronavirus disease 2019 (COVID-19) cases in high-risk patients should be broadly applied. As members of the Journal’s Editorial Board, we are strongly supportive of open debate in science, which is essential even on highly contentious issues. However, we must also be thorough in our examination of the facts and open to changing our minds when new information arises. In this commentary, we document several important errors in the manuscript, review the literature presented, and demonstrate why it is not of sufficient quality to support scale up of HCQ + AZ, and then discuss the literature that has been generated since the publication, which also does not support use of this therapy. Unfortunately, the current scientific evidence does not support HCQ + AZ as an effective treatment for COVID-19, if it ever did, and even suggests many risks. Continuing to push the view that it is an essential treatment in the face of this evidence is irresponsible and harmful to the many people already suffering from infection.

Keywords: azithromycin; bias; confounding; hydroxychloroquine; observational studies; randomized trials.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Fox MP, D’Agostino McGowan L, James BD, Lessler J, Mehta SH, Murray EJ. Concerns About the Special Article on Hydroxychloroquine and Azithromycin in High-Risk Outpatients With COVID-19. Am J Epidemiol. 2021 Apr 6;190(4):491-495. doi: 10.1093/aje/kwaa189. PMID: 32860038; PMCID: PMC7499476.

Comment on

 See also

Tony M. Korman, MBBS, FRACP, FRCPAa,b, and James H. McMahon, MBBS, MPH, PhD, FRACPc,d,e

To the Editor:

McCullough et al propose a treatment algorithm for early outpatient treatment of coronavirus disease 2019 (COVID-19), which is not supported by evidence. Early intervention is desperately needed, but unfortunately, no effective treatment is available.

Neither zinc (Zn) nor doxycycline have demonstrated inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro or in animal or human studies. Favipiravir has antiviral activity against SARS-CoV-2 but does not have “proven” therapeutic efficacy in Ebola, Lassa fever, or rabies as claimed. Favipiravir should only be administered as part of clinical trials assessing efficacy and safety.

The Randomized Evaluation of COVID-19 therapy (RECOVERY) trial proved that large clinical trials can be completed rapidly during a pandemic. Dexamethasone was associated with reduced mortality for patients receiving invasive mechanical ventilation or supplemental oxygen but not for patients receiving no respiratory support at randomization. Possible efficacy of prednisone in early disease is unproven speculation that cannot be recommended without further study.

McCullough et al recommended “antivirals” hydroxychloroquine (HCQ) and azithromycin (AZ) “immediately” for high-risk patients, but HCQ did not show antiviral activity in human airway epithelium, and neither HCQ nor HCQ with AZ showed a significant effect on SARS-CoV-2 viral load in macaques. In a meta-analysis (total participants n = 32,943), HCQ was not associated with reduced mortality in hospitalized patients, but HCQ with AZ significantly increased mortality. Observational studies in which HCQ with or without AZ was associated with reduced mortality include important confounders (concomitant corticosteroid use in the HCQ group, more than double the nontreated group). Early treatment of outpatients with mild disease with HCQ with or without AZ has not demonstrated clinical or virological benefit, and no significant reduction of risk of hospitalization.

Facing mounting contrary evidence, the proponents of HCQ with AZ resemble the deluded Black Knight from Monty Python and the Holy Grail whose limbs are progressively cut off but continues to confidently proclaim triumph in the battle.

 2021 Mar; 134(3): e220–e221.
Published online 2021 Feb 23. doi: 10.1016/j.amjmed.2020.08.044
PMCID: PMC7901364
PMID: 33637180


Funding: None.

Conflicts of Interest: TK reports serving as a chairman at a meeting organized by Gilead and a speaker at a meeting sponsored by Janssen (both unrelated to this work and both with no personal payment); JHM reports that Gilead, Viiv, and Merck have supported his institution for the conduct of clinical trials.

Authorship: Both authors had access to the data and a role in writing this manuscript.


1. McCullough P, Kelly R, Ruocco G, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. Am J Med. Accessed August 30, 2020. doi: 10.1016/j.amjmed.2020.07.003 [PMC free article] [PubMed] [CrossRef]
2. Korman TM. Early outpatient treatment of symptomatic, high-risk COVID-19 patients [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: 10.1093/aje/kwaa154 [PMC free article] [PubMed] [CrossRef]
3. The RECOVERY Collaboration Group. Dexamethasone in hospitalized patients with COVID-19 – preliminary report [e-pub ahead of print]. N Eng J Med. Accessed August 30, 2020. doi: 10.1056/NEJMoa2021436 [PMC free article] [PubMed] [CrossRef]
4. Maisonnasse P, Guedj J, Contreras V. Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature. 2020;(585):584–587. doi: 10.1038/s41586-020-2558-4. [PubMed] [CrossRef[]
5. Fiolet T, Guihur A, Rebeaud M, et al. Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis [e-pub ahead of print]. Clin Microbiol Infect. Accessed August 30, 2020. doi: 10.1016/j.cmi.2020.08.022 [PMC free article] [PubMed] [CrossRef]
6. Lee T, MacKenzie L, McDonald E. An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (can’t get no) satisfaction. Int J Infect Dis. 2020;98:216–217. [PMC free article] [PubMed[]
7. Fox MP, D’Agostino McGowan L, James BD, et al. Concerns about the special article on hydroxychloroquine and azithromycin in high risk outpatients with COVID-19 by Dr. Harvey Risch [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: 10.1093/aje/kwaa189 [PMC free article] [PubMed] [CrossRef]


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