key: cord-0784130-28ftx8dw
authors: Peiffer-Smadja, Nathan; Costagliola, Dominique
title: RE: EARLY OUTPATIENT TREATMENT OF SYMPTOMATIC, HIGH-RISK COVID-19 PATIENTS THAT SHOULD BE RAMPED-UP IMMEDIATELY AS KEY TO THE PANDEMIC CRISIS
date: 2020-07-20
journal: Am J Epidemiol
DOI: 10.1093/aje/kwaa151
sha: 13a7f65a69d159dd75ababb32ac9bc6aba166477
doc_id: 784130
cord_uid: 28ftx8dw

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In his accepted manuscript, Risch (1) criticizes the NIH and the FDA because "these reviews have omitted the two critical aspects of reasoning about these drugs: use of hydroxychloroquine combined with azithromycin or with doxycycline, and use in the outpatient setting"

We would like to highlight the uncritical appraisal he made on the available evidence and our surprise that such a viewpoint could be accepted in this journal.

Gautret el al (2) led an open label single arm clinical trial to prove the efficacy of hydroxychloroquine alone in hospitalized patients (EudraCT Number: 2020-000890-25). In the paper reporting the trial, there was an ad-hoc untreated comparison group comprising 16 patients who refused to take part in the trial, who had non-inclusion criteria or who were hospitalized in other clinical centres. Among the 26 patients treated with hydroxychloroquine, six were excluded from the analysis without justification. We do not know if they also received azithromycin, but given the severity of the disease among the 4 of them who progressed (three to ICU, one death), it is quite likely that several of them received the combination. Among the 20 remaining patients, six were treated with the combination and the claim of the efficacy of the combination is based on the analysis of these 6 participants. Risch reports the p-value of the test done by the authors who compared the three groups. However, this test is not appropriate to claim that the combination is more effective than hydroxychloroquine alone. The appropriate test would compare the results of the 14 participants who received hydroxychloroquine alone to the 6 who received the combination, and this test is not significant (p=0.39).

Risch stated that the only valid criticism against this trial is the lack of randomization. He rejects the criticism about the "small study size", saying that size matters only when no evidence is found. But no evidence is found in this study as shown above. Besides, a larger The only other published study discussed (3) was led on both outpatients and hospitalized patients, with a low proportion of at-risk participants. Risch and the authors conclude to efficacy, however a study with no control group for a disease for which natural history is not completely understood cannot conclude to efficacy. All the other studies reviewed are unpublished, poorly designed studies whose quality is even lower than the papers discussed above, but the limited space available prevents us from providing a detailed critical analysis. 

Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France

Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non-human primates

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19