Why we must be cautious about hydroxychloroquine

We have all listened repeatedly to the many confused, confusing, and misleading statements coming from the White House in the midst of this pandemic, unprecedented in its scope and existential threat. Responding to all the misstatements would be a full-time job. However, the barrage of reckless comments made about drug treatments for COVID-19 during a briefing on April 5, 2020, requires immediate and strong correction.

To address this, I will respond—in my role as a physician and researcher specializing in public health—to several selected quotes made by the president during said briefing:

• Hydroxychloroquine, which I think is, you know, it’s a great malaria drug. It’s worked unbelievably. It’s a powerful drug on malaria, and there are signs that it works on this, some very strong signs, and in the meantime, it’s been around a long time. It also works very powerfully on lupus, so there are some very strong powerful signs, and we’ll have to see because again, it’s tested … And if you can, if you have no signs of heart problems, the azithromycin, which will kill certain things that you don’t want living within your body. It’s a powerful drug.

Yes, these drugs have “been around a long time.” (I personally took chloroquine before and during a trip to India in 1981, first as prophylaxis against malaria and then, when I contracted malaria in spite of this, as a treatment for malaria.) But just because a drug is reasonably safe and effective for one disease doesn’t mean it will work for another (for instance, penicillin is great for S. pneumoniae, but it won’t do anything to treat HIV), and malaria is caused by Plasmodium species, which are protozoans, not viruses.

• So it’s a very strong, powerful medicine, but it doesn’t kill people. We have some very good results and some very good tests. You’ve seen the same tests that I have … In France, they had a very good test.

Perhaps the “very good test” from France being referred to is this study. As a small study with no control group, it can’t tell you much. It doesn’t actually assess health outcomes but looks instead at how much virus can be found in patients’ throats—a potentially useful endpoint but hardly the goal of treatment. Moreover, of the 25 phase 3 clinical trials of hydroxychloroquine and/or chloroquine listed at clinicaltrials.gov as of today, only one is listed as “completed.” One study from China on hydroxychloroquine is instructive. It was also small (only 30 patients) but was randomized and looked not only at clearance of virus from throat swabs, but also at how long it took for the virus to clear and at reduction of fever and the progression of computed tomography chest scans—and on these measures there were no differences between the treatment and control groups. Of course, the drug might work, but this study does not support its efficacy.

• The FDA feels good about it. They’ve, as you know, they’ve approved it. They gave it a rapid approval.

These drugs were already approved by the Food and Drug Administration (FDA) (for malaria and lupus and rheumatoid arthritis); as is the case with all approved drugs, they can be legally prescribed (at a prescriber’s discretion) for other conditions. (This is generally referred to as “off-label use.”) Rather than “approve” these drugs, the FDA has issued an Emergency Use Authorization to release them from federal stockpiles in order “to facilitate the availability of chloroquine phosphate and hydroxychloroquine sulfate during the COVID-19 pandemic to treat patients for whom a clinical trial is not available, or participation is not feasible.”

• But we don’t have time to go and say, gee, let’s take a couple of years and test it out, and let’s go and test with the test tubes and the laboratories. We don’t have time. I’d love to do that, but we have people dying today.

Here’s where, as someone who teaches clinical research methods, I actually have some good news to share: it will not “take a couple of years” to “test it out.” We can get reasonable answers quite quickly, provided these unsubstantiated claims don’t prevent patients from giving their consent to participate in randomized trials (which will be the only way to get reliable answers). The reasons this will be quick to study are the same reasons this new disease is so devastating: the incidence of COVID-19 is extremely high, and bad outcomes (respiratory failure, death) are extremely common and happen extremely quickly.

These facts are terrible news to me when I’m wearing my “physician” or “public health” hats, but they are actually good news when I don my “clinical research” hat. The reason so many trials take a long time to yield results is that valid results require large numbers of “clinical outcomes” to occur. In this case, we, unfortunately, will not have to wait too long to get those numbers.

As for concerns about delays imposed by a perceived call to “go and test with the test tubes and the laboratories,” there’s more good news: we already know the clinical pharmacology of these approved drugs, so we can move quite quickly into the phase 3 studies of efficacy (those 25 current trials referenced above) without needing to first go through the preclinical phase 1 and phase 2 studies.

• And a lot of people are saying that when … and are taking it, if you’re a doctor, a nurse, a first responder, a medical person going into hospitals, they say taking it before the fact is good, but what do you have to lose? They say, take it, I’m not looking at it one way or the other, but we want to get out of this. If it does work, it would be a shame if we didn’t do it early. But we have some very good signs. So that’s hydroxychloroquine and as azithromycin, and again, you have to go through your medical people get the approval. But I’ve seen things that I sort of like, so what do I know? I’m not a doctor, I’m not a doctor, but I have common sense.

This quote includes ill-advised recommendations about using this drug as prophylaxis for health care professionals (for which there are no data). Moreover, that “common sense” is not helpful in making these sorts of determinations. The most malignant misstatement in this quote is the president’s oft-repeated “What do you have to lose?” All drugs have side effects, and side effects vary in different populations. (For example, the safety profiles for drugs used to treat children with malaria or young adults with lupus are not necessarily relevant to their use in treating elderly patients with COVID-19 pneumonia and respiratory failure.)

And since we’re deep in the world of anecdotes, let me share an instructive one:

A close friend in his 60s had a severe case of COVID-19 pneumonia. For two weeks, he managed his fever, weakness, cough, and breathlessness at home—keeping himself from exposing others to his infection while carefully monitoring his blood oxygen levels to make sure he was safe. But when his understandably desperate doctor prescribed chloroquine in response to the positive press it had been getting, my friend ended up (for reasons that are not clear) taking twice the recommended dose. He wound up being admitted to the hospital for monitoring of the potential side effect of life-threatening cardiac arrhythmia. He did not, thank God, have an arrhythmia. He spent just two days in the hospital and is currently recovering, but this situation could have turned out differently. It definitely created a situation in which he potentially (and unnecessarily) exposed others (including health care professionals and hospitalized patients) to SARS-CoV-2, the virus that causes COVID-19.

As a longtime contributor to this blog, I have often been admonished that because it is a product of a research-intensive medical school, we must avoid politics. While I appreciate that in principle, we are in a unique crisis moment where politics and public health are enmeshed; my duty as a medical and public health professional takes priority. The U.S. Surgeon General has said that the coming week “is going to be our Pearl Harbor moment.” If we were being led through this devastating pandemic by a figure like Franklin D. Roosevelt, it would be much more reassuring, but we’ve got to play the hand we’re dealt with. That means all of us need to do our best to find real truth in the midst of an avalanche of dangerous nonsense.

KevinMD.com