As of 23 March 2020, we were unable to identify any published results of randomised trials of hydroxychloroquine in patients with SARS-CoV-2 infection, i.e. covid-19. However, the results of a randomised trial in 30 patients were published in Chinese in early March in a university journal (Chen J et al. "A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)" Journal of Zhejiang University March 2020: 6 pages).

The trial included only 30 patients, randomly assigned to one of two groups. There were no major differences in baseline characteristics between the groups. Patients with a history of cardiac disease were ineligible for the trial. On average, the patients were about 50 years old and had had symptomatic covid-19 for 6 days, without respiratory distress. The control group received standard care. The intervention group also received 400 mg of hydroxychloroquine once daily for 5 days.

After a 2-week follow-up, the health of all the patients had improved, with no notable difference between the groups. No patients died. The PCR-based test for the presence of the virus in a throat swab became negative after a median of 4 days in the hydroxychloroquine group, versus 2 days in the control group. Median time to resolution of fever was about 1 day in both groups. On day 3 after enrolment, radiological improvement was observed (on chest CT) in 5 patients in the hydroxychloroquine group, versus 7 patients in the control group. The health of one patient in the hydroxychloroquine group worsened, versus none in the control group. The differences between the groups are not statistically significant.

In summary, these results do not show hydroxychloroquine to have efficacy in this situation, nor do they rule it out, due to the trial's low statistical power. Given the limitations of PCR testing of throat swabs and the observation that this test tends to rapidly become negative in patients with covid-19, with or without hydroxychloroquine, this does not appear to be a particularly relevant endpoint for evaluating treatment efficacy. Similarly, studies without a control group recruited in the same way as the treated group do not provide meaningful results.

In this Chinese randomised trial and in a study conducted in Marseille that received a great deal of media coverage in mid-March 2020 (with additional results released on 27 March 2020), the health of several patients deteriorated, all of whom had been exposed to hydroxychloroquine. This observation can be interpreted as a safety signal, suggesting that hydroxychloroquine – a drug used as a weak immunosuppressant in some autoimmune conditions – may actually exacerbate covid-19. Before patients are routinely exposed to this drug, other larger randomised comparative trials are warranted to investigate this hypothesis, such as the ongoing European "Discovery" trial (see the analysis of the Marseille study, 23 March 2020 > HERE).

Hydroxychloroquine is a derivative of the antimalarial drug chloroquine. Proposed treatment protocols for patients with covid-19 use relatively high doses of chloroquine or hydroxychloroquine. The main adverse effects of short-course treatment with chloroquine or hydroxychloroquine are:

• headache, psychotic episodes, agitation;
• seizures;
• gastrointestinal disorders (nausea, vomiting, diarrhoea);
• tinnitus, hearing disorders;
• rash and other skin disorders;
• myopathy and neuromyopathy, muscle weakness, atrophy of proximal muscle groups;
• cardiomyopathy, cardiac conduction disorders, ventricular arrhythmia, and QT prolongation.

Overdose is fatal, mainly due to the drugs' rapid cardiac effects, resulting in hypotension and arrhythmia, circulatory collapse, seizures, hypokalaemia, cardiac arrest, coma, and death.

A great many other drugs increase the risk of QT prolongation, which can lead to potentially fatal torsade de pointes. They include neuroleptics, antihistamines used for allergies, some angina treatments, and macrolide antibiotics, including azithromycin. Hypokalaemia increases the risk of torsade de pointes; it is caused in particular by drugs such as diuretics, laxatives, and beta-2 agonists used in asthma or chronic obstructive pulmonary disease. Drugs that slow the heart rate, such as beta-blockers, some calcium-channel blockers, and some drugs used in Alzheimer's disease, also increase the risk of torsade de pointes.

©Prescrire 30 March 2020

See also:

• "Covid-19 and drug trials: what to make of the initial results?" (23 March 2020) > HERE
  

Source:

"Covid-19 et hydroxychloroquine : prudence" Application Prescrire; 30 March 2020.

For more information (in French), see www.prescrire.org > Dans l'actualité

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