The Ups and Downs of Hydroxychloroquine

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As COVID19 continues to spread, the global search for a cure is underway. The development of a preventative vaccine is likely months if not a year away. In the meantime, several therapies have been raised as potential cures with hydroxychloroquine arguably being the most widely known. But will this miracle treatment live up to the hype?

An Old Answer to a New Problem

Hydroxychloroquine was originally developed during World War II as an alternative to the drug chloroquine. Chloroquine was used to treat malaria but its side-effects were problematic and hydroxychloroquine acts as a safer alternative.

Sold under the brand name Plaquenil, hydroxychloroquine is used worldwide as a therapy for rheumatoid arthritis and lupus, and to prevent and treat malaria.

From Bench to Bedside

When the SARS outbreak arose in late 2002 there was a scramble to find an effective treatment. Hydroxychloroquine was eventually identified as a possibility, but by then the threat had passed and treatment development was put on the backburner.

The appearance of a new but related SARS-coronavirus in late 2019 quickly spurred researchers to revisit hydroxychloroquine. Studies using isolated cells showed that treatment with hydroxychloroquine effectively decreased the ability of the SARS-CoV2 virus to infect cells 1,2.

Building on these promising findings clinical investigators began treating COVID19 patients with hydroxychloroquine. Initially results were encouraging. A study led by Dr. Didier Raoult treated patients with hydroxychloroquine or hydroxychloroquine plus the antibiotic azithromycin. Researchers measured SARS-CoV2 levels in patients and found that within 6 days ~50% of patients treated with hydroxychloroquine tested negative for the virus, while all of the patients treated with hydroxychloroquine and azithromycin were negative for SARS-CoV2.

It Really Falls Apart

Unfortunately, concerns about the study were quickly raised that cast doubt on the validity of the findings. These ranged from questions about ethical approval to serious issues about the way data were collected.

Patients were not randomly assigned to different groups which is a standard process for clinical research. In fact, patients who had underlying health issues that prevented them from taking hydroxychloroquine were put into the control group, which creates the risk of bias.

Perhaps most concerning was that of 26 patients treated with hydroxychloroquine, 6 were removed from the study, including 1 who died and 3 who did not improve with treatment. The exclusion of patients from a treatment group because of negative effects calls into question the integrity of the research.

And the Band Played On

Several studies have been published since the initial investigation by French researchers testing hydroxychloroquine for COVID19 patients. Most recently the UK RECOVERY trial involving over 11,000 hospitalized COVID19 patients at 175 hospitals ended early because of findings showing no beneficial effects of hydroxychloroquine3. Although there are differences in timing of treatment, dose of hydroxychloroquine, and even clinical measurements across these studies, one element is consistent: there are no significant benefits with hydroxychloroquine treatment of COVID19 patients.

The disappointing results of hydroxychloroquine studies in COVID19 patients have not entirely stopped the investigation of its therapeutic potential. Proponents of the drug argue that while it may not improve outcomes of COVID19 patients, it may be used to prevent development of the illness.

A study involving researchers in Canada and the United States found that treatment of individuals who were exposed to SARS-CoV2 positive people did not prevent the development of COVID194. These results indicate that if hydroxychloroquine is to be effective, it most likely needs to be applied even before exposure to the virus.

Warning Signs

The use of hydroxychloroquine as a treatment for COVID19 has raised some concern among medical professionals, specifically cardiologists.

Among the most common side-effects of hydroxychloroquine are cardiac arrhythmias. Arrhythmias occur when the normal beating pattern of the heart is disrupted or even stopped. These conditions can be relatively benign, but many increase the risk of developing conditions including heart attacks or heart failure, and some are life-threatening. Interestingly, azithromycin, the antibiotic that is often touted as a critical therapy to provide alongside hydroxychloroquine has its own cardiac risks and heightens the danger of adverse events.

But if hydroxychloroquine is so dangerous, how is it so widely used for the treatment of rheumatoid arthritis, lupus, and as a preventative therapy for malaria without widespread reports of injury? There are some concerns about these claims as the use of hydroxychloroquine for malaria is often used in countries that lack robust drug surveillance systems. This means that adverse events may go unreported.

The main concern about the use of hydroxychloroquine is the patient population that may benefit the most from treatment. The majority of people infected with SARS-CoV2 develop mild or moderate symptoms. Those at highest risk and who would benefit the most from a preventative treatment include individuals with pre-existing cardiovascular disease.

People with rheumatoid arthritis or lupus are screened and monitored for cardiovascular disease to assess and manage risk. Individuals who have cardiovascular disease may receive a treatment other than hydroxychloroquine or the patient may take the drug under the close supervision of a physician.

The increased risk of cardiac complications in COVID19 patients who may benefit from hydroxychloroquine treatment has caused cardiologists to recommend caution in proceeding with this experimental treatment. While investigation of the drug is not precluded, cardiologists and other medical organizations have recommended that treatment only occur in tightly regulated clinical trials and under the close supervision of medical professionals.

Next Steps

The book on hydroxychloroquine as a treatment for COVID19 may not be closed yet, but it is certainly in the final chapters. There remains the possibility that hydroxychloroquine could be used as a preventative therapy, but the associated risks preclude its widespread use outside of the supervision of medical professionals.


  • 1. Yao X, Ye F, Zhang M, et al. Clin Infect Dis. ciaa237. 2020.
  • 2. Liu J, Cao R, Xu M, et al. Cell Discov. 6: 16. 2020.
  • 3. 5 June 2020
  • 4. Boulware DR, Pullen MF, Bangdiwala AS et al. N Eng J Med. 2020.