Source: New England Journal of Medicine

Hydroxychloroquine in Hospitalized Patients with Covid-19


We were surprised by the hydroxychloroquine dose chosen in the Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial conducted by Horby et al. (Nov. 19 issue).1 In this trial, patients received a higher dose of hydroxychloroquine (4 g cumulated over the first 3 days) than that administered in the trial conducted by Lagier et al.2 (600 mg per day), and it was similar to that in the trial conducted by Borba et al.3

In vitro studies show that the effect of hydroxychloroquine is mainly mediated by alkalinization of the phagolysosomes,4 where it can concentrate about 1500 times more than in plasma. This effect can be obtained with low doses of hydroxychloroquine because of its long elimination half-life. High doses may therefore be useless or even deleterious because of the anti-interferon action of hydroxychloroquine,5 which may result in a more severe form of Covid-19.6 

The dose used in the RECOVERY trial, the second highest after that in the trial conducted by Borba et al., arouses concern because it may have been a disease-aggravating factor negating the therapeutic effect.

Alexis Lacout, M.D.
Surgical Medical Center of Tronquieres–Elsan, Aurillac, France

Christian Perronne, M.D., Ph.D.
Versailles Saint-Quentin-en-Yvelines University, Garches, France

Valere Lounnas, Ph.D.
European Molecular Biology Laboratory, Heidelberg, Germany

No potential conflict of interest relevant to this letter was reported.

  1. 1.The RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med 2020;383:2030-2040.
  2. 2.Lagier JC, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis. Travel Med Infect Dis 2020;36:101791-101791.
  3. 3.Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020;3(4):e208857-e208857.
  4. 4.Morrisette T, Lodise TP, Scheetz MH, Goswami S, Pogue JM, Rybak MJ. The pharmacokinetic and pharmacodynamic properties of hydroxychloroquine and dose selection for COVID-19: putting the cart before the horse. Infect Dis Ther 2020;9:561-572.
  5. 5.Gies V, Bekaddour N, Dieudonné Y, et al. Beyond anti-viral effects of chloroquine/hydroxychloroquine. Front Immunol 2020;11:1409-1409.
  6. 6.Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369:718-724.

Related: Perronne in the NEJM: ‘Recovery’ trial contested – is this finally a breach in the denial around hydroxychloroquine?

Low Dose Hydroxychloroquine is Associated with Lower Mortality in COVID-19: A Meta-Analysis of 27 Studies and 44,684 Patients

The AMA Quietly Admits They Lied About Hydroxychloroquine

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk COVID-19 infection includes HCQ & Ivermectin

Peer-Reviewed Journal Reports Hydroxychloroquine Can Reduce Mortality Rates In COVID-19 Patients

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