Explainer: What’s the fuss about (hydroxy)chloroquine and COVID-19?

(Disclaimer: This article was written with information available as of April 22, 2020.)

What are we talking about and why?

We’re talking about chloroquine and hydroxychloroquine. These drugs are improved versions of quinine – a medicine derived from the bark of the cinchona tree. Quinine has been used to treat malaria for centuries.

Chloroquine (CQ) is a version of quinine that was synthesized during the time of World War II. It was developed because quinine in its natural form posed many problems, writes Public Radio International.  Malaria was rampant among soldiers, quinine was in short supply as people had to rely on the plant’s growth, and the problem was exacerbated by countries cutting off each other’s quinine supply as a war tactic.

Later, hydroxychloroquine (HCQ) was developed as a version that causes lesser side effects.

Currently, chloroquine and hydroxychloroquine are used to treat malaria as well as some autoimmune diseases like lupus and rheumatoid arthritis.

But now, these drugs have captured international headlines as their combination has emerged as one of the potential frontrunners amongst treatments being tested for COVID-19.

Donald Trump has been one of the many politicians touting the benefits of hydroxychloroquine, calling it a ‘game changer’ in a press conference in March 2020. Credit: AP Archive

Wait…malaria and autoimmune conditions? And now possibly COVID-19 too? Aren’t these very, very different types of diseases? How do the medications work?

Yes, they are very different. Malaria is a disease caused by Plasmodium parasites which spread through mosquito bites. Autoimmune conditions like lupus and rheumatoid arthritis differ, but they’re based on one’s immune system attacking their own body cells. And COVID-19 is caused by a virus called SARS-CoV-2.

So, here’s the shocker: despite the fact that quinine and its variations have been around for so long, scientists don’t fully understand how they work. However, the most widely accepted explanation has to do with CQ and HCQ’s ability to enter cells and increase the pH of some regions of those cells, making the regions less acidic and more basic. This change in pH interferes with important processes of the cells.

Science communicator Hank Green hosts an episode on the YouTube channel SciShow, in which he elaborates on the science behind the drugs as we know it.

Scientists suggest that this mechanism is what makes the drugs useful in treating some diseases. In malaria, the drugs interfere with important processes within Plasmodium parasites, eventually killing the parasitic cells. In autoimmune conditions, the drugs enter the immune system cells that have gone rogue and are attacking the body’s own cells. Here, too, they reduce the pH of the over-reacting immune cells, changing the way they function, and ultimately calming down the body’s overall immune response.

And COVID-19? Where does it fit in?

As with many issues surrounding a never-seen-before pathogen like SARS-CoV-2, the short answer is: scientists don’t know yet, and are still figuring it out.

One informed guess is that the drugs may reduce the acidic nature of human cells, making it difficult for the virus to enter human cells in the first place.

Another likely explanation is that the drugs may work by reducing the body’s out-of-proportion immune response to the virus. This may be important – from what we know about COVID-19 so far, some patients are dying not just because of the virus per se, but because the virus triggers such a strong immune response that the body’s healthy cells get fatally damaged in the process too.

How did scientists even think about CQ and HCQ as potential treatments?

When researchers began looking for treatments for COVID-19, their Plan A was to look at medicines that are already available in the market, since it is quicker than discovering and developing new, unknown treatments from scratch.

One of their first sources of inspiration was to look at treatments that were being developed for other coronaviruses – which led them to SARS-CoV-1 (the virus that caused the 2002-04 SARS epidemic), as well as MERS-CoV (the virus that caused periodic MERS outbreaks since 2012).

One of the first suggestions of using CQ and HCQ as an antiviral treatment dates back to 2003. In a paper published in The Lancet, researchers argued that these old drugs could see a ‘revival’. Chloroquine’s use as an antimalarial drug was stagnating with the emergence of chloroquine-resistant malaria. At the same time, the drugs were showing promise in clinical trials looking to treat a viral condition instead – HIV. The authors had argued that chloroquine could be a consideration to combat the SARS virus too.

Over time, this suggestion led to different experiments which in turn examined the promise of these drugs in treating coronaviruses like SARS and MERS. These studies involved petridish cell cultures as well as mice.

However, none of these studies moved on to the human trial stage since the SARS and MERS outbreaks ended up being tackled using other public health measures.

Now, the current studies looking at CQ and HCQ to treat COVID-19 are building on the work of such past research.

So where are we now? What’s the progress on CQ and HCQ in treating COVID-19 so far?

The first human studies to suggest promising benefits of these drugs in treating COVID-19 came from China and France. On one hand, the papers should be taken with a grain of salt (the Chinese article was preliminary and did not provide the data backing its conclusions; the French paper only tested a small group of patients).

On the other hand, such anecdotal tip-offs have led researchers to begin large-scale clinical trials around the world. For example, in China alone, at least 13 trials are being conducted to test HCQ in COVID-19, according to the WHO.

One of the most recent players in the the clinical trials field is Novartis. The Swiss-based pharmaceutical company announced on April 20 that it is initiating a large-scale, randomized, double-blind, placebo-controlled experimental trial: the gold standard of testing the safety and effectiveness of a treatment.

“We felt like there was just a lot of noise out there regarding whether it would be beneficial for this population of patients that [it] could really be helpful for,” said John Tsai, the chief medical officer of Novartis, in an interview with STAT News.

“So we wanted to embark on a rigorous, scientifically led approach to address the unanswered question, which is whether the use of hydroxychloroquine can help patients with COVID-19.”

Meanwhile, the WHO is also sponsoring a megatrial called SOLIDARITY – a global, speeded-up trial that studies patients in over 100 countries to collect data while administering the drugs on eligible patients. The combination of CQ and HCQ as a treatment will be compared with three other promising treatments that have caught the public eye – remdesivir; a combination of lopinavir and ritonavir; and a combination of lopinavir, ritonavir and interferon beta-1a.

Until researchers learn more information from such clinical trials, there will be no consensus on whether CQ and HCQ should be administered to patients. Governments around the world are left to decide whether they should allow doctors and other healthcare professionals to prescribe unproven drugs to patients who need it the most – an emergency measure called compassionate use.

Such decisions are informed by limited, less substantiated non-clinical trial studies that are emerging in the meantime. The most recent example comes from a retrospective study that has been submitted to the New England Journal of Medicine for peer review as of April 22.

The study found that HCQ may not be making any significant difference on patients’ need for breathing support, as reported by Reuters. But patients who took HCQ may have had more than double the risk of death as compared to the placebo group (those who took nothing).

Why is that? And what could go wrong in allowing doctors to prescribe promising but unproven medicines against COVID-19? Are we being too safe and slow when we’re waiting for clinical trial results, which could take weeks or months? After all, CQ and HCQ are already being prescribed for patients with malaria and autoimmune conditions, right?

Clinical trials don’t just set out to prove the effectiveness of therapeutics in treating diseases. They are also done to ensure the drug is safe, and doesn’t cause more harm than good.

For example, in the case of CQ and HCQ, the treatment’s potential risks lie in its mechanism. Recall that the drugs enter cells and lower their acidity, thus impacting the functioning of the cells. However, the drugs are indiscriminate and can cause this harm in helpful, unaffected cells too.

This is one of the reasons why even for patients with malaria and autoimmune diseases, the drugs are monitored very carefully – high doses of the drugs can cause toxic side effects like irregular heartbeats (already, there is some evidence suggesting that CQ and HCQ could cause potentially fatal damage to the heart as a side effect).

HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains – Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents)…..

— Donald J. Trump (@realDonaldTrump) March 21, 2020

….be put in use IMMEDIATELY. PEOPLE ARE DYING, MOVE FAST, and GOD BLESS EVERYONE! @US_FDA @SteveFDA @CDCgov @DHSgov

— Donald J. Trump (@realDonaldTrump) March 21, 2020

The uncertainties surrounding HCQ have not stopped some leaders from promoting its benefits and advocating for its widespread use.

Meanwhile, in the same way that panic buying masks and food meant that they ran out for those who needed them the most, hyping up a treatment before testing it makes it difficult to access for those patients who already use the drugs for malaria and autoimmune diseases.

The other harm of promoting promise before proof also happens when the media sensationalism ends up influencing the clinical trial design in the first place. In the case of CQ and HCQ, the WHO was initially not going to include it as one of the treatments being tested in its SOLIDARITY megatrial, as written by science journalists Kai Kupferschmidt and Jon Cohen in Science magazine. However, the WHO ended up including the drugs in the megatrial after the treatment received “significant attention in countries”.

As summarized by Hank Green, host and science communicator on the YouTube channel SciShow, “I think everyone really, really hopes that they [the drugs] will work. I mean, how amazing would it be if we already have something on hand that kicks this virus’ butt? Something that we understand, and that is inexpensive to manufacture?”

“But until we know for sure, we should not get our hopes up too much. We have to let healthcare professionals and medical researchers test this stuff carefully and rigorously.”

(Featured image credit: National Institute of Allergy and Infectious Diseases (NIAID) on Wikimedia Commons. The image is from an electron microscope. It shows SARS-CoV-2 [round gold objects] emerging from the surface of human cells isolated from a patient in the U.S. and cultured in the lab.)