As of June 2020, hydroxychloroquine (Plaquenil°) had not been shown to be an effective treatment for covid-19 (details in French, > HERE). It had however been shown to provoke sometimes serious, mainly cardiac, adverse effects. New detailed results from comparative randomised trials of hydroxychloroquine in patients with covid-19 were released in July 2020.

Patients hospitalised for severe covid-19: the hydroxychloroquine group of one trial abandoned early, having found no evidence of efficacy. The randomised "Recovery" trial evaluated the addition of various drugs (including dexamethasone and hydroxychloroquine) to usual care in patients hospitalised for covid-19. The trial was not blinded, meaning that the patients and the healthcare professionals involved knew which treatment was being used. The results on dexamethasone have already been reported (> HERE). The detailed results on hydroxychloroquine were released on 15 July 2020, as a step towards publication in a peer-reviewed journal.

The 1561 patients in the usual care + hydroxychloroquine group were compared with 3155 patients who received usual care without hydroxychloroquine (the control group). The hydroxychloroquine regimen set out in the trial protocol consisted of two 800-mg doses of hydroxychloroquine, 6 hours apart, and thereafter 400 mg every 12 hours, with a maximum treatment duration of 10 days regardless of how long the patient remained in hospital. The average age of both groups was 65 years, and about 60% were men. About 25% of the patients enrolled had diabetes or a chronic lung or heart condition. At the time of random treatment allocation, 60% of the patients were receiving oxygen and about 15% were receiving invasive or non-invasive assisted ventilation. The proportions of patients who received the macrolide antibiotic azithromycin or dexamethasone were similar in the two groups.

The primary endpoint was 28-day mortality. In an analysis performed before the end of the trial at the request of the trial’s data monitoring committee, 28-day mortality was 26.8% in the hydroxychloroquine group, versus 25.0% in the control group (no statistically significant difference). The results were similar when the roughly 10% of patients who had not been confirmed by PCR to have Sars-CoV-2 infection were excluded from the analysis. As a result of these findings, enrolment into the hydroxychloroquine group was halted prematurely.

Hydroxychloroquine use appeared to be associated with longer median hospital stays (16 days versus 13 days) and, in patients not receiving invasive ventilation at enrolment, an increased risk of requiring invasive ventilation or of dying.

One episode of torsade de pointes was reported during this non-blinded trial. It occurred in a patient from the hydroxychloroquine group, and resolved without treatment.

Patients hospitalised for mild to moderate covid-19: no evidence of efficacy for hydroxychloroquine, with or without azithromycin. A non-blinded randomised trial in 667 patients hospitalised for mild to moderate covid-19 compared hydroxychloroquine (800 mg per day for 7 days) + usual care, versus hydroxychloroquine (same regimen) + azithromycin (500 mg per day for 7 days) + usual care, versus a control group receiving usual care alone. The average age of the patients enrolled in this trial was 50 years, and about 60% were men. At the time of random treatment allocation, about 40% of the patients were receiving oxygen. The fact that before the trial began about 10% of the patients in each group had taken hydroxychloroquine, and about 35% had had azithromycin, reduces the quality of the evidence provided by this trial.

The primary endpoint was clinical status after 15 days. No difference was found between the three groups on this measure, nor in an analysis confined to the 504 patients with PCR-confirmed Sars-CoV-2 infection. And no differences were found between the groups in terms of length of hospital stay, need for invasive ventilation, or deaths.

The proportion of patients in whom adverse events were reported was higher in the groups that received hydroxychloroquine alone (34% of patients) or in combination with azithromycin (39%) than in the group that received neither drug (23%). Among the 269 patients who had had an electrocardiogram during the trial, about 15% of those who received hydroxychloroquine, with or without azithromycin, had prolongation of the QT interval, versus only one patient among those who received neither drug. An increase in liver enzymes was reported more frequently in patients who received hydroxychloroquine alone (9%) or in combination with azithromycin (11%) than in those who received neither drug (about 3%).

Patients not admitted to hospital: no evidence of efficacy as early treatment for milder disease. A double-blind randomised trial compared hydroxychloroquine versus placebo in 491 non-hospitalised patients who had had covid-19 symptoms for fewer than 5 days, and either had PCR-confirmed Sars-CoV-2 infection or had had contact with someone with confirmed covid-19 during the previous 14 days. The protocol-planned regimen for patients in the hydroxychloroquine group consisted of one dose of 800 mg, followed 6 to 8 hours later by a dose of 600 mg, then a daily dose of 600 mg for the next 4 days.

Half of the patients enrolled in this trial were over 40 years old, and about 55% were women.
Two-thirds of them had no chronic diseases. Clinically, these patients had relatively mild disease. About 9% of the patients were left out of the analysis due to missing data. About 40% of the patients in this trial did not undergo laboratory testing to confirm the diagnosis of covid-19, because testing was unavailable. This reduces the quality of the evidence provided by the trial.

The change in symptom severity over 14 days did not differ between the groups, including in an analysis confined to the 145 patients with confirmed Sars-CoV-2 infection. No statistically significant difference was found in the incidence of hospitalisation or death.

Adverse effects were about twice as common in the hydroxychloroquine group (43%, versus 22% in the control group) and were primarily gastrointestinal disorders. No serious adverse effects were reported during the trial.

Similar results were found in another non-blinded randomised trial in 293 non-hospitalised patients (most of whom were healthcare professionals), with an average age of 42 years, non-severe covid-19, and PCR-confirmed Sars-CoV-2 infection. In this trial, hydroxychloroquine treatment, started within 5 days of the onset of symptoms, was no more effective than usual care at reducing viral load, measured on a nasopharyngeal swab after 7 days of treatment (the primary endpoint), or at reducing symptoms (with a median time to complete resolution of symptoms of about 11 days), or at preventing hospitalisation. No deaths occurred during the trial, and no patients received invasive ventilation. The proportion of patients in whom adverse effects were reported was about eight times higher in the hydroxychloroquine group of this non-blinded trial (72%, versus 9% in the control group). They were primarily gastrointestinal, neurological or cutaneous disorders.

In practice. A substantial amount of data is available as of 24 July 2020 from comparative trials of hydroxychloroquine in the treatment of covid-19, and this drug increasingly appears to have a clearly unfavourable harm-benefit balance in this situation.

©Prescrire 24 July 2020

Sources:

• "Covid-19 et hydroxychloroquine (Plaquénil°) : pas d'efficacité démontrée, y compris dans les formes sans gravité" Application Prescrire, 24 July 2020.
• Horby P et al. "Effect of hydroxychloroquine in hospitalized patients with covid-19: preliminary results from a multi-centre, randomized, controlled trial" 22 June 2020; doi: https://doi.org/10.1101/2020.07.15.20151852. > HERE
• Skipper C et al. "Hydroxychloroquine in nonhospitalized adults with early covid-19. A randomized trial" Ann Intern Med 2020; doi: https://doi.org/10.7326/M20-4207. >  HERE
• Cavalcanti A et al. "Hydroxychloroquine with or without azithromycin in mild-to-moderate covid-19" N Engl J Med 2020; doi: https://doi.org/10.1056/NEJMoa2019014. >  HERE
• Mitjà O et al. "Hydroxychloroquine for early treatment of adults with mild covid-19: a randomized-controlled trial" Clin Infect Dis 2020; doi: https://doi.org/10.1093/cid/ciaa1009. > HERE

For more information:

• "Covid-19: Follow Prescrire's independent, evidence-based analysis of the pandemic" > HERE