There has recently been suggestion that a combination of two medications (azithromycin, a macrolide antibiotic) and hydroxychloroquine (a drug which targets malaria parasites, and which is also used in rheumatic disease like rheumatoid arthritis and lupus) may help COVID-19.
There was a recent French study that’s getting a lot of enthusiasm in some quarters. (President Trump was pushing the idea that these were helpful several days ago, before the new study. One man took a form of chloroquine used to disinfect fish tanks, and it killed him, while also putting his wife into critical condition in the ICU.)
It will be great if these help, but I would suggest caution and modesty in interpreting the results. Why? Several reasons.
Not a randomized trial
The “study” was a case series–it was several patients treated with the meds. But, there was no control group–there was no placebo control. And there was no blinding–the doctors knew who was getting the treatment (i.e., everybody.)
We have learned through sad experience that our clinical experience can mislead us. (There’s a joke I tell med students: “What’s the definition of clinical experience?” Answer: It’s making the same mistake over and over with increasing levels of confidence.)
Every patient treated also had water during the treatment period. But we don’t turn around and assume that water made them better.
You need randomized-controled trials (RCT) to know if treatments work. Physicians bled patients for over two thousand years, and they (and their patients!) were convinced it helped. They had mountains of clinical experience. But they were, in the main, very wrong. (There are a few things that bleeding might help temporarily, but they’re few and far between.)
Not yet published or peer reviewed
The findings have not been published yet, and peer review has not vetted them. Peer review is important for weeding out bad work, and spotting potential errors. It probably will be published, but it will be interesting to see how much peer review makes them dial back their enthusiasm to what can be justified by the science (i.e., not much).
The patients tested were not very sick
One article on the trial reported this:
Dr Philippe Gautret, who was part of the team behind Raoult’s latest findings, admitted that they only used the combination of drugs on “patients who had not been showing signs of being seriously ill after admission” to the hospital.
So…color me unimpressed. These people weren’t terribly ill. They weren’t the ones on respirators likely to die. If you keep the sickest people out of the trial, of course it’s going to look like the medication helps.
Better studies have been negative so far
A small randomized-controlled trial on hydroxychloroquine showed no significant difference in treatment or placebo.
It was a small study and wasn’t powered to detect all effects–so there might still be benefit. But thus far, it is not a “game changer” or overwhelming.
Note:
One week after hospitalization, 86.7% of patients in the experimental group and 93.3% of patients in the usual care group tested negative. This difference was not statistically significant
This isn’t a statistically significant difference, but more people tested negative for virus in the non-treatment group than the treatment group. People treated also took four days to clear virus on average; the non-treatment group took only two days. Again, not statistically significant, but not suggesting even a “trend” toward significance.
But, don’t worry–the WHO is doing actual randomized controlled trials (though without placebo and blinding) world-wide on several treatments. That’s the best way to get good data in a hurry.
We’ve tried it in other viruses
Part of the reason hydroxychloroquine is an idea is that it causes problems for the virus in vitro. (That’s Latin for “in glass”–it means in a test tube or petri dish.) We want it to work in vivo–“in life,” or in a living body.
However, it has consistently failed to have the same effect when it’s put into actual, you know, humans. We don’t care about killing viruses in a test tube; we want to kill it in human bodies:
Studies in cell culture have suggested chloroquine can cripple the virus, but the doses needed are usually high and could cause severe toxicity. “Researchers have tried this drug on virus after virus, and it never works out in humans,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen.
Think of it this way–if you pour straight bleach into a test tube of COVID-19 virus, I guarantee you that it will kill all the virus. However, drinking bleach to cure the virus is not going to kill the virus in you, and would probably have several other nasty toxicity-related side effects as well.
(Don’t worry, CBS News has your back with a great article called “Coronovirus cannot be cured by drinking bleach or snorting cocaine.”)
That this warning is necessary makes you think that perhaps our species is too dumb to survive. DON’T DRINK BLEACH. It essentially melts through your throat and esophagus. It’s a good way to die very, very painfully over several days.
“The clinical notes of the young woman commenced with the memorable words ‘Overdose of bleach’, raising the interesting medical question as to the correct therapeutic dose of bleach.”
— Theodore Dalymple, If Symptoms Persist (Monday Books, 2010).
But, at any rate, test tube does not equal real life.
The research folks aren’t impressed
From the above article:
Professor Francois Balloux of University College, London, tried to dampen talk that the drug could be a silver bullet.
“No, (this is) not ‘huge’ I’m afraid,” he said on Twitter.
“This is an observational study (i.e. not controlled) following 80 patients with fairly mild symptoms. The majority of patients recover form #COVID19 infection, with or without #Hchloroquine and #Azithromycin treatment.”
Treatments have side effects
Very few treatments in medicine have no risk of side effects. Anything that can cause good effects can probably cause bad effects.
Hydroxychloroquine is an immune suppressant — that’s why we use it in rheumatic disease. So it could be that suppressing the immune system is a bad idea in an infectious disease. Or, it could be a good thing if part of the damage is from an over-reaction by the immune system (e.g., cytokine storm).
Hydroxychloroquine also has significant potential heart toxicity. We have seen cases in COVID-19 (even without hydroxychloroquine on board) of relatively young people starting to improve, only to suddenly crash due to an inflammation of heart muscle. I’ve read anecdotal reports from ICU physicians who describe young patients who are sometimes left with a very poorly-functioning heart (ejection fraction < 10%; normal is 50-60%) afterwards.
A history of heart disease is also correlated with poor outcomes.
So introducing a cardio-toxic drug is not without its potential downsides.
Ignore people telling you to get this
There are restrictions in Alberta on prescribing these medications. If you think you have COVID-19, your family doc or whoever is not able to prescribe this combination (nor should they).
There is a limited supply of hydroxychloroquine (Plaquenil is the trade name). It is an important drug in the treatment of lupus and rheumatoid arthritis. A “run” on this drug will threaten the health of those patients.
The only way you’re going to get this experimental treatment is in the context of a clinical trial, or perhaps if you’re hospitalized. So don’t run out and try to stock up. Here’s the Alberta College of Pharmacists:
This week, pharmacists have identified to ACP an increased demand for some drugs (e.g., Kaletra®, hydroxychloroquine) due to reports of them being prescribed as treatments for COVID-19. The prescribing and dispensing of drugs used to treat COVID-19 for the purpose of stockpiling for personal use is not appropriate.
Information we have received demonstrates the diligence of many pharmacists in assessing the appropriateness of drug therapy, and we commend them for this. We have heard stories of pharmacists receiving prescriptions for these drugs for groups of family members, for personal family members, and in other instances from specialties where these drugs are not normally used. Thank you to all of you who have been diligent in your assessments and have intervened by not dispensing these prescriptions.
ACP recognizes and appreciates the extraordinary efforts of pharmacists and pharmacy technicians during these unprecedented and challenging times. Your diligence will support appropriate use, improved health, and the continued availability of these drugs for those who need them most.
Are these docs heroes?
Not really. They’re doing bad science, and they’re sensationalizing things. As one expert noted:
Statistician Tim Morris of the university’s clinical trials unit was even more scathing.
“If hydroxychloroquine turns out to be useful,” he tweeted, “it’s a shame that this group will be praised as heroes and prophets instead of held to account for the misinformation and self-promotion they’ve been churning out at a critical time.”
The rules of science and medicine don’t just disappear in a crisis. If anything, we have to adhere to them more strictly, since in emotional and stressful times, we’re more likely to go with our gut rather than our brain. And our gut has proven to be a poor predictor of what works.
As Nobel Prize-winning physicist Richard Feynmann wisely observed:
The first principle is that you must not fool yourself—and you are the easiest person to fool. So you have to be very careful about that. After you’ve not fooled yourself, it’s easy not to fool other scientists. You just have to be honest in a conventional way after that….I’m talking about a specific, extra type of integrity that is not lying, but bending over backwards to show how you’re maybe wrong, that you ought to do when acting as a scientist. And this is our responsibility as scientists, certainly to other scientists, and I think to laymen.[1]
If that’s true of scientists, it’s doubly true of medical scientists in a pandemic.
[1] Richard Feynman, “Cargo Cult Science,” Caltech Commencement Address, 1974, http://calteches.library.caltech.edu/51/2/CargoCult.htm.
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