Could taking hydroxychloroquine for coronavirus be more harmful than helpful?


Andrew McLachlan, University of Sydney and Ric Day, UNSW

A paper published in The Lancet has cast fresh controversy on the use of the malaria drug hydroxychloroquine as a potential treatment for COVID-19.

The study’s authors reported they were “unable to confirm a benefit” of using the drug, while also finding COVID-19 patients in hospital treated with hydroxychloroquine were more likely to die or suffer life-threatening heart rhythm complications.

The publication prompted the World Health Organisation to suspend its testing of hydroxychloroquine to treat COVID-19, while a similar Australian trial has paused recruitment.

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A bit of background

Hydroxychloroquine has been used since the 1940s to treat malaria, but has been making headlines as a potential treatment for COVID-19. US President Donald Trump recently declared he was taking it daily, while Australian businessman and politician Clive Palmer pledged to create a national stockpile of the drug.

The drug alters the human immune system (it’s an immunomodulator, not an immunosuppressant) and has an important role in helping people with rheumatoid arthritis and lupus.

It does have a range of serious possible side-effects, including eye damage and altered heart rhythm, which require monitoring.

We don’t know the patients in this study died because they took hydroxychloroquine.

Laboratory studies suggest hydroxychloroquine may disrupt replication of the SARS-CoV-2 virus that causes COVID-19. It’s also possible hydroxychloroquine could reduce “cytokine storm” – the catastrophic immune system overreaction that happens in some people with severe COVID-19.

A huge global effort is underway to investigate whether hydroxychloroquine is safe and effective for preventing or treating COVID-19, especially to improve recovery and reduce the risk of death. Previous studies have been inconclusive as they were anecdotal, observational or small randomised trials.

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Doubts about hydroxychloroquine’s effectiveness have been increasing, with a large observational study from New York showing it had no benefit in treating people with COVID-19.

The new Lancet study, published last week, has found it could increase the risk of death among COVID-19 patients in hospital. But there’s more to the story.

What did the new study do?

The Lancet study collected real-world data on more than 96,000 hospitalised patients with COVID-19 from more than 600 hospitals across six continents.

About 15,000 patients were treated with hydroxychloroquine (or a closely related drug, chloroquine) alone or in combination with an antibiotic.

Using a global registry the researchers investigated the safety of these treatments. They looked at whether people died in hospital, as well as the risk of developing life-threatening heart rhythm problems (called ventricular arrhythmias).

What did the study find?

Treatment with hydroxychloroquine was associated with increased rates of death in people with COVID-19, even after the researchers adjusted for other factors (age, other health conditions, suppressed immune system, smoking, and severity of the COVID-19 infection) that might increase the risk of death.

About 18% of people who received hydroxychloroquine died in hospital, compared with 9% of people with COVID-19 who did not receive these treatments. The risk of death was even higher (24%) in people receiving hydroxychloroquine in combination with either of the antibiotics azithromycin or clarithromycin.

Hydroxychloroquine (6%) and chloroquine (4%) treatment was also associated with more cases of dangerous heart rhythm problems when compared with untreated people with COVID-19 (0.3%).

Any evidence of benefit, while not the focus of this study, was unclear.

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How can we interpret the results?

This was an observational study, so it can only explore the association between treatments and death – rather than telling us hydroxychloroquine caused these patients to die.

It is unclear why the death rate for patients treated with hydroxychloroquine and chloroquine was double that of those who weren’t, as the cause of death was not reported in this study.

Importantly, the study cannot account for all the factors that might contribute to death in these hospitalised patients and how these factors interact with each other. However, the researchers did a good job of “matching” the characteristics of people who were receiving hydroxychloroquine with those who were not receiving the drug, which makes the results more reliable.

But there may still be other factors, or medicines, that contributed to these findings. So there remains uncertainly about whether hydroxychloroquine causes, or even contributes to, the death of people with COVID-19.

While the Lancet study has seen some hydroxychloroquine trials halted, others are continuing under careful monitoring.

Further, it was not possible to have careful control over the hydroxychloroquine dose people received – or other medicines people might be taking such as antivirals or other medicines for heart conditions (which potentially interact in sick hospitalised patients).

The average dose of hydroxychloroquine in this study was at the upper end of the regular recommended dose range for rheumatoid arthritis and lupus. But the wide range of hydroxychloroquine (and chloroquine) doses in this study makes interpretation of the findings difficult, especially when we know harmful effects are associated with larger doses.

Broader implications

This study provides important information about the safety of hydroxychloroquine in treating vulnerable people with COVID-19 receiving hospital care.

While the implications for using hydroxychloroquine to treat COVID-19 in the community or for prevention of COVID-19 remain unclear, if nothing else this study highlights the need to carefully monitor people receiving the drug.

Some hydroxychloroquine trials are continuing, such as the very large RECOVERY trial in the UK.

This new information must be considered when balancing harm and potential benefit of these trials and will likely result in renewed safety monitoring.

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We’ll need to see results from ongoing high-quality randomised controlled trials to truly know if hydroxychloroquine is effective and safe in treating or preventing COVID-19.

Further questions about what dose should be used, and which patients will benefit most, are topics under active investigation.

You should not take hydroxychloroquine for COVID-19 unless you’re part of a clinical trial. – Andrew McLachlan and Ric Day

Blind peer review

This is a fair and reasonable review of the Lancet paper, its relationship to previous studies, and its impact on ongoing clinical trials.

As stated in the review the Lancet article adds to the body of knowledge, including recent substantial studies in the New England Journal of Medicine and the British Medical Journal, that hydroxychloroquine is without significant effect in treatment trials.

The high death rate is concerning but not unprecedented, given that a clinical trial in Brazil was halted because of adverse effects on the heart. However, recent media reports suggest the data may have to be revised due to misclassification of the participating hospitals. – Ian Musgrave

Research Checks interrogate newly published studies and how they’re reported in the media. The analysis is undertaken by one or more academics not involved with the study, and reviewed by another, to make sure it’s accurate.The Conversation

Andrew McLachlan, Head of School and Dean of Pharmacy, University of Sydney and Ric Day, Professor of Clinical Pharmacology, UNSW

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Donald Trump is taking hydroxychloroquine to ward off COVID-19. Is that wise?

Teresa G. Carvalho, La Trobe University

The White House’s confirmation that US President Donald Trump has been taking hydroxychloroquine every day for the past two weeks, with his doctor’s blessing, has reignited the controversy over the drug. It has long been used against malaria but has not been approved for COVID-19.

Trump said he has “heard a lot of good stories” about hydroxychloroquine, and incorrectly claimed there is no evidence of harmful side-effects from taking it. His previous claims in March that the drug could be a “game changer” in the pandemic prompted many people, including Australian businessman and politician Clive Palmer, to suggest stockpiling and distribution of the drug to the public.

But the dangers of acting on false or incomplete health information were underlined by the death of an Arizona man in March after inappropriate consumption of the related drug chloroquine. It’s important to know the real science behind the touted health benefits.

How do these medicines work?

Hydroxychloroquine is an analogue of chloroquine, meaning both compounds have similar chemical structures and a similar mode of action against malaria. Both medications are administered orally and have common side-effects such as nausea, diarrhoea and muscle weakness. However, hydroxychloroquine is less toxic, probably because it is easier for the body to metabolise.

Chloroquine and hydroxychloroquine are listed by the World Health Organisation as an essential medicine. Both drugs have been used to treat malaria for more than 70 years, and hydroxychloroquine has also proved effective against auto-immune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The US Food and Drug Administration has approved both chloroquine and hydroxychloroquine for treating malaria, but not for COVID-19.

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We don’t know exactly how these drugs work to combat the malaria parasite. But we know chloroquine disrupts the parasite’s digestive enzymes by altering the pH inside the parasite cell, presumably effectively starving it to death.

Malaria parasites and coronaviruses are very different organisms. So how can the same drugs work against both? In lab studies, chloroquine hinders replication of the SARS coronavirus, apparently by changing the pH inside particular parts of human cells where the virus replicates.

This offers a glimmer of hope that these pH changes inside cells could hold the key to thwarting such different types of pathogens.

Is it OK to repurpose drugs like this?

Existing drugs can be extremely valuable in an emergency like a pandemic, because we already know the maximum dose and any potential toxic side-effects. This gives us a useful basis on which to consider using them for a new purpose. Chloroquine is also cheap to manufacture, and has already been widely used in humans.

But we shouldn’t be complacent. There are significant gaps in our understanding of the biology of SARS-CoV-2, which causes COVID-19, because it is a brand new virus. There is a 20% genetic difference between SARS-CoV-2 and the previous SARS coronavirus, meaning we should not assume a drug shown to act against SARS will automatically work for SARS-CoV-2.

Widely used, but with common side effects.
Gary L. Hider/Shutterstock

Even in its primary use against malaria, long-term chloroquine exposure can lead to increased risks such as vision impairment and cardiac arrest. Hydroxychloroquine offers a safer treatment plan with reduced tablet dosages and lessened side-effects. But considering their potentially lethal cardiovascular side-effects, these drugs are especially detrimental to those who are overweight or have pre-existing heart conditions. Despite the urgent need to confront COVID-19, we need to tread carefully when using existing medicines in new ways.

Any medication that has not been thoroughly tested for the disease in question can have seriously toxic side-effects. What’s more, different diseases may require different doses of the same drug. So we would need to ensure any dose that can protect against SARS-CoV-2 would actually be safe to take.

The evidence so far

Although many clinical trials are under way, there is still not enough evidence chloroquine and hydroxychloroquine will be useful against COVID-19. The few trials completed and published so far, despite claiming positive outcomes, have been either small and poorly controlled or lacking in detail.

A recent hydroxychloroquine trial in China showed no significant benefits for COVID-19 patients’ recovery rate. A French hydroxychloroquine trial was similarly discouraging, with eight patients prematurely discontinuing the treatment after heart complications.

The fascination with chloroquine and hydroxychloroquine has also adversely affected other drug trials. Clinical trials of other possible COVID-19 treatments, including HIV drugs and antidepressants, have seen reduced enrolments. Needless to say, in a pandemic we should not be putting all our eggs in one basket.

Then there is the issue of chloroquine hoarding, which not only encourages dangerous self-medication, but also puts malaria patients at greater risk. With malaria transmission season looming in some countries, the anticipated shortage of chloroquine and hydroxychloroquine will severely impact current malaria control efforts.

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Overall, despite their tantalising promise as antiviral drugs, there isn’t enough evidence chloroquine and hydroxychloroquine are safe and suitable to use against COVID-19. The current preliminary data need to be backed up by multiple properly designed clinical trials that monitor patients for prolonged periods.

During a pandemic there is immense pressure to find drugs that will work. But despite Trump’s desperation for a miracle cure, the risks of undue haste are severe.

This article was coauthored by Liana Theodoridis, an Honours student in Microbiology at La Trobe University.The Conversation

Teresa G. Carvalho, Senior Lecturer in Microbiology, La Trobe University

This article is republished from The Conversation under a Creative Commons license. Read the original article.