An EBM Perspective on Hydroxychloroquine and Azithromycin for the Treatment of COVID-19

Medical | Alan Ehrlich, MD| April 27, 2020

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Hydroxychloroquine (with or without azithromycin) has received a lot of media attention for the treatment of COVID-19, but is there evidence that it works?

During a public health crisis, when people are dying, there is often a clamor for bypassing the usual way of evaluating potential treatments. An urgent situation can make a proper placebo-controlled trial problematic, and many patients not in clinical trials will want any treatment that might improve their likelihood of survival despite the risks inherent in such an approach.

Evidence-based approaches use the best available evidence, even if only from a case series, while remembering the limitations of such data. Of all the potential treatments that have been suggested for COVID-19, none has received more media attention than hydroxychloroquine, often with azithromycin. Hydroxychloroquine has in vitro activity against coronaviruses and many COVID-19 patients requiring hospitalization are prescribed hydroxychloroquine with or without azithromycin. The impetus for this approach came from early clinical data in patients with COVID-19 in two small randomized trials in China and two low-quality studies in France.

Chen and colleagues randomized 30 patients who were hospitalized with COVID-19 to hydroxychloroquine sulfate 400 mg once daily for five days vs. placebo (J Zhejiang Univ (Med Sci), 2020). On day seven, 86.7 percent of the hydroxychloroquine group and 93.3 percent of the control group had throat swabs negative for viral shedding by nucleic acid detection (not significant). Only one patient, in the hydroxychloroquine group, progressed to severe infection. Fever and diarrhea rates were similar between the two groups. In another paper released as a preprint, Chen and colleagues conducted a randomized trial of hydroxychloroquine vs. usual care in 62 patients. They found that time to clinical recovery as well as fever and cough improvement were all significantly shortened in the hydroxychloroquine treatment group.

In Marseilles, Gautret and colleagues treated COVID-19 patients with a regimen of hydroxychloroquine 200 mg three times daily for ten days (Int J Antimicrob Agents. 2020 Mar). Patients with pneumonia and a National Early Warning Score (NEWS) of five or higher were also given a broad-spectrum antibiotic such as ceftriaxone. Twenty patients were treated and 16 who refused to enroll in the trial or were ineligible served as controls. Six patients in the hydroxychloroquine group also received azithromycin 500 mg once, followed by 250 mg/day for four doses. There was clearance of nasopharyngeal virus by day six in all patients given hydroxychloroquine/azithromycin, compared to 57.1 percent in the hydroxychloroquine alone group and 12.5 percent of controls. Subsequently, the same authors reported on 80 patients treated with hydroxychloroquine/azithromycin (including the six above) and found that 83 percent had negative nasopharyngeal PCR tests for COVID-19 on day seven (PDF). Finally, another group from France has reported on a series of 11 patients treated with the same hydroxychloroquine/azithromycin protocol and found that eight of 10 surviving patients still had positive nasopharyngeal PCR tests on day six (Med Mal Infect. 2020 Mar).

There is much to criticize about many emerging COVID-related studies that are being fast-tracked in the peer review process and/or quickly released as preprints. Long ethical discussions on this subject could be had in another forum. Some specific concerns with the data discussed in this article include lack of randomized controls, intention-to-treat analysis, clinical outcomes, and confirmation by other relevant publications. In addition, concerns about QT prolongation with hydroxychloroquine and azithromycin must be taken into account for any patient in whom this treatment might be considered. For example, prepublication data suggest QT prolongation cannot be predicted at baseline, and patients therefore require ECG monitoring at multiple points during therapy. In addition, many studies enrolled patients with mild to moderate illness, while the actual usage of the drug tends to be in hospitalized patients. No data we are aware of suggest a benefit from using hydroxychloroquine or hydroxychloroquine/azithromycin prophylactically.

Expect more papers reporting on the efficacy, or lack thereof, of hydroxychloroquine/azithromycin. Until then, clinicians should proceed cautiously and ensure patients understand the lack of proven benefit to date.

For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed

EBM Focus articles provide concise summaries of clinical trials most likely to inform clinical practice curated by the DynaMed editorial team.

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Alan Ehrlich, MD
Executive Editor, DynaMed

This EBM Focus was written by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School. Edited by Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.

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