The Antimalarial Plaquenil Showed No Benefit and Caused More Adverse Effects in a Human COVID-19 Trial!

The antimalarial hydroxychloroquine (marketed as Plaquenil) did not improve symptoms of the disease caused by the novel coronavirus (SARS-CoV-2), COVID-19, compared with standard care and even caused more adverse effects. This was demonstrated in 150 patients in China in a randomized controlled clinical trial.

Whether antimalarial drugs work in COVID-19 treatment is one of the world’s leading debates. Following laboratory studies and a small number of positive case reports, many doctors and hospitals began treating COVID-19 patients with chloroquine and hydroxychloroquine without question, despite studies reporting contrary findings. Some doctors even began recommending hydroxychloroquine prophylactically, before exposure to the virus. In Turkey, the Ministry of Health also recommends hydroxychloroquine prophylaxis for healthcare workers immediately after contact with a COVID-19 patient. With more than 1 million healthcare workers in Turkey, the challenges of this recommendation are clear. Results from more comprehensive human trials—that is, stronger scientific evidence—are also beginning to show that the efficacy of antimalarial drugs against coronavirus infection is not what was assumed, bringing this recommendation from Turkey’s Ministry of Health into question. Later in this article, we also briefly discuss how hydroxychloroquine use conflicts with the pathophysiology of coronavirus infection.

Note: Hydroxychloroquine is a less toxic derivative of chloroquine.

The lead author, Wei Tang, together with specialists in respiratory and critical care medicine at Ruijin Hospital in Shanghai, China, enrolled patients with COVID-19 from 16 treatment centers in China in February.

No Additional Benefit

The primary endpoint defined at the start of the study, after 28 days of follow-up, was the negative conversion rate of the SARS-CoV-2 test. Conversion rates were similar in patients receiving or not receiving hydroxychloroquine: 85.4% with hydroxychloroquine plus standard care and 81.3% with standard care alone (P = .341). Negative SARS-COV-2 conversion rates were also similar on days 4, 7, 10, 14 and 21.

There is another reason these results are striking: earlier nonrandomized studies, in which patients were not selected randomly, and unblinded clinical studies had claimed a substantial reduction in viral load with hydroxychloroquine.

A Large Difference in Adverse Effects

Adverse effects occurred in 30% of the hydroxychloroquine arm versus 8.8% of controls. Diarrhea was the most common, occurring in 10% of patients receiving hydroxychloroquine and in none of the controls.

Two patients in the hydroxychloroquine arm had serious adverse effects (grades 3 and 4): one had disease progression and the other an upper respiratory tract infection. Patients received a high loading dose of 1200 mg daily for 3 days, followed by a maintenance dose of 800 mg daily for the remaining days. The total duration was 2 weeks for mild or moderate disease and 3 weeks for severe disease.

No Benefit in Relieving COVID-19 Symptoms

Hydroxychloroquine and standard care had similar effects on symptom relief by day 28. Symptoms actually improved more in the standard-care arm, but the difference was not statistically significant: 59.9% with hydroxychloroquine plus standard care versus 66.6% with standard care alone.

The median patient age was 46 and 55% were men. Almost all had mild or moderate disease; two had severe disease.

Confusing Aspects of Hydroxychloroquine Studies

In this and many other COVID-19 trials, most patients take other medicines alongside the experimental drugs, making it difficult to determine the effect of a single drug. For example, 89% of patients in this Chinese study were receiving another treatment.

Furthermore, because studies have so far enrolled fewer patients than would be ideal, it is difficult to say that randomization has been adequate. The groups therefore differ at baseline—for example, in symptom burden at diagnosis or median age.

This study does not completely rule out the possibility of a clinical benefit from hydroxychloroquine. If there is one, it seems related to the drug’s anti-inflammatory properties.

Is the Pathophysiology of Coronavirus Infection Being Ignored When Hydroxychloroquine Is Recommended?

During the incubation period and the early, nonsevere stage of coronavirus infection, an adaptive immune response is needed. Treatments that activate immunity should therefore be considered at this stage. If the immune system can develop antibodies early, that is favorable; if it cannot, the infection progresses. However, one property of hydroxychloroquine is moderate immune suppression, which may explain why it causes more adverse effects without helping recovery.

- Related Topic: HOW DOES THE IMMUNE SYSTEM RESPOND to the Novel Coronavirus (SARS-Cov-2)? Where Is the Problem?

Different Results in Other Studies

These unfavorable findings on hydroxychloroquine’s antiviral activity contradict earlier encouraging in-vitro laboratory findings and recently reported data from a nonrandomized study of 36 COVID-19 patients.

However, as many experts had already emphasized, the earlier 36-patient trial has since been questioned.

Despite no clear evidence of benefit, hydroxychloroquine appears in many countries’ COVID-19 treatment guidelines. The US Food and Drug Administration (FDA) has granted "authorization," rather than approval, for treating critically ill adults with COVID-19.

By contrast, the Infectious Diseases Society of America recently concluded that no specific treatment could be recommended for COVID-19 patients because of insufficient data.

Clearly, larger clinical trials with random patient selection, as in this Chinese study, are needed to determine whether hydroxychloroquine is effective against COVID-19. However, this trial, the largest and most comprehensive to date, has begun to suggest that, contrary to expectations, hydroxychloroquine is ineffective against COVID-19 and may cause more adverse effects.

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