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>> The world is hunkered down trying to avoid the consequences of the CovID-19 pandemic.
In some places, like Wuhan, Lombardi, Spain, and now New York, the disease has spread
out of control and has caused a great deal of morbidity and mortality.
In desperation, clinicians have tried all kinds of treatments in an effort
to stem the progression of this disease.
One constellation of treatments that's gotten a great deal of attention is the use
of the anti-malarials chloroquine,
and hydroxychloroquine, and the antibiotic azithromycin.
There's not much data to support the use of these drugs,
yet clinicians are talking a great deal about prescribing them to treat COVID-19,
not just for very sick patients but even as a prophylactic measure.
In this special edition of JAMA Clinical Reviews,
we spoke with the noted Pharmacologist Dr. David Juurlink
from the Sunnybrook Health Sciences Centre in Toronto.
Dr. Juurlink is the head of Clinical Pharmacology and Toxicology at Sunnybrook
and spoke with us about these medications, their potential benefits,
and harms when treating COVID-19.
>> From the JAMA Network, this is JAMA Clinical Reviews, interviews and ideas about innovations
in medicine, science, and clinical practice.
Here's your host, Ed Livingston.
>> There's a great deal of concern about COVID-19 and the rapidity
for which it's moving its way through the community and the very high mortality
for patients who are at risk for complications of the disease.
Because of the dramatic course of the disease for those people who get very sick from it,
people have been throwing every medication imaginable at these patients.
It's very, very difficult to know what's working and what's not working.
And you have particular expertise in pharmacology and one of the things we wanted
to specifically talk to you about, hydroxychloroquine, and azithromycin,
which have been specifically recommended for treatment of this disease by some people.
But also, maybe if you could start with a general overview of whatever --
you know, about the medications people are advocating for this drug,
and then maybe hone in on those two drugs.
>> Yeah, I can just quickly review, if you want,
what I understand to be the evidence for using these drugs.
You know, most of it's derived from in vitro studies looking at the ability of drugs
like chloroquine and hydroxychloroquine to inhibit the growth of coronaviruses,
including SARS, as well as the one that's in widespread circulation today.
At the time of this recording, the only clinical data I'm aware of is a study
from China that's extremely thin on details, it's been reported only in a press release,
somewhere in the vicinity of 100 or a few more patients with a variety
of clinical outcomes said to have improved with hydroxychloroquine, but no information
on exactly what was -- was a case series or a clinical trial, or --
so I think we'll have to wait and see what shakes that when that comes to print.
The other is an intriguing study from a group in France, again, very small, open label,
really just a case series that if you look at the figures suggests that the endpoint
in that study was I think viral eradication of day six, the figures look quite impressive.
But when you dig into the paper, which has been released online,
it's not yet been peer reviewed, as far as I know,
there are holes you could drive truck through, and so I think we want to be mindful of the fact
that when we're desperate for a treatment and we have nothing else
to offer except supportive care, it's very tempting to want to use drugs like these.
I, personally, would be inclined to use them, until we've got better data,
but I think the reason we're having this discussion now is
because they do have some toxicities, or at least some safety concerns
that are worth talking about, as we navigate this crisis.
>> I wonder if you could tell us about those toxicities because certainly,
in a desperate situation where a patient is on a downhill course,
it's reasonable to try something that has risk, but discussions that I've heard
over the last couple days include physicians taking these drugs prophylactically.
So, normal healthy people believe that taking hydroxychloroquine and
or as azithromycin might prevent them from getting the diseases that are exposed
to patients, and those people would be particularly prone to the toxicity.
So, could you tell us about the downsides of those drugs?
Are there risks associated with those drugs?
>> Yeah, I think there are several, and we could probably just put them into bins.
The one that I think is foremost on most clinicians' minds is the possibility
of QT prolongation and the risk of Torsades de pointes,
which is obviously a potentially life threatening arrhythmia.
And so, when you dig into the literature on this, it's quite clear that chloroquine
and hydroxychloroquine can do this, but it's very rare.
It's also quite clear that azithromycin can do this, but it's also very rare.
And I would say that in medical circles,
the risk with azithro has been really overstated over the past several years.
What we don't know is what the additive or possibly synergistic risk is when you combine,
say, azithromycin and hydroxychloroquine.
I think given that uncertainty, and given the potential downsides of giving somebody a QT
of 650 and then they -- they drop dead, it's worth being A, mindful of the potential risk;
getting a screening ECG before you decide to put someone on both of these drugs,
and doing what you can to minimize the other factors that might worsen QT prolongation, so --
you know, other drugs that are QT people on.
Antipsychotics, ondansetron, triptans, methadone, that kind of thing,
as well as hypokalemia and hypomagnesemia, those are two other common things that we see
as contributors to QT prolongation.
And so, if I was going to put somebody on these drugs,
I would make sure at baseline their QT is okay, and I would follow them closely
with serial ECGs during the course of therapy, that's I think the --
you know, you sometimes hear it said
that you shouldn't prescribe these drugs together, that's just not true.
You can prescribe them together if you're a mindful of this potential consequence.
>> What about other complications from the drugs?
>> Most of them are going to be in the antimalarials, the Mefloquine series.
So, hypoglycemia is one to be aware of, this can happen with chloroquine and hydroxychloroquine.
I think it's quite rare, but it certainly happens.
And it seems to have at least two mechanisms, one is that it seems
to enhance insulin sensitivity that -- something about these drugs interferes with in
on a gradation at the receptor level,
and so you actually get increased insulin sensitivity and improved glucose uptake.
But there's also clearly a component of enhanced insulin release as well,
and so I think before starting these, you'd want to be mindful
of the possibility of hypoglycemia.
It might be more likely in someone with diabetes, especially someone who's
on [inaudible] or say, metformin.
And I would watch for the usual symptoms, diaphoresis, tremor, confusion,
that sort of thing, and be prepared to manage it.
And -- and if I did encounter a patient who had symptomatic hypoglycemia with one
of these agents, I think -- other than just getting them out of trouble acutely
with some dextrose, it might be worth giving them a dose of octreotide, say 100 micrograms
of octreotide, that's a very, very safe drug that turns off,
temporarily, pancreatic insulin secretion.
And to the extent that pancreatic insulin secretion is playing a role
in the hypoglycemia, you can shut that down.
Another set of side effects to be mindful of are central nervous system effects
with chloroquine and hydroxychloroquine.
So, that can be subtle -- you know, a bit of disorientation, or clouding of the sensorium,
but it could also manifest as frank psychosis, someone who becomes restless, and agitated,
and paranoid in the early days of treatment with these drugs, that's the anti-malarial,
until proven otherwise, and the drugs should be stopped and --
and these will normally subside with time.
What else to mention?
Drug interactions, this is an interesting one.
So, I guess the chief drug interaction we've already talked about is the potential
for additive or synergistic QT prolongation, when you add say hydroxychloroquine to azithro,
but it's not widely appreciated that both chloroquine and hydroxychloroquine can interfere
with the liver's metabolism of other drugs, and they do that especially
by inhibiting an enzyme called CYP-2D6 and not to get to pointy headed about it,
but this is the enzyme that turns codeine into morphine, turns tramadol into its metabolite,
and so in theory, if someone was on codeine or tramadol, adding chloroquine
or hydroxychloroquine could interfere with the activation of those drugs
and actually precipitate opiate withdrawal.
We know that if someone is on metoprolol or Carvedilol,
those are drugs that are metabolized by 2D6.
But when you add hydroxychloroquine, you can increase concentrations
of those drugs, so I'd be cautious.
If a doctor wants to put a patient on hydroxychloroquine and that patient is on --
you know, 100 twice a day of metoprolol, I would be wary,
and I might empirically cut back the metoprolol a little bit
in anticipation of its accumulation otherwise.
Hemolysis is more of a theoretical concern.
So, there are patients who got -- quite common to have G6PD deficiency, especially in the U.S.,
especially in the -- the African-American population
where most of the deficiencies are mild.
I think this is something to sort of be mindful of but I think that even in patients
with more severe variants, it's not generally very common for drugs like chloroquine
or hydroxychloroquine to precipitate significant oxidative hemolysis,
you see it more with primaquine, or maybe dapsone, or sulfamethoxazole, just --
again -- something to be aware of.
And if you did have somebody who is known to, for example, have a severe variant of G6PD
and you were going to start one of these drugs,
probably sensible to keep an eye on their CBC and LDH.
Final point I suppose -- I guess two final thoughts,
the first is pregnancy, this always comes up.
And so, I'm not aware of any concerns regarding the use of chloroquine,
or hydroxychloroquine, or azithromycin in pregnancy.
I think you wouldn't withhold them.
If it one day becomes clear that these are truly effective therapies that improve outcomes
in a meaningful way, I don't think we would withhold them from someone who's pregnant
because of safety concerns about the drugs, themselves.
Last point is the possibility of overdose and so this is my toxicologist hat talking.
The chloroquine and hydroxychloroquine can be very, very difficult to manage in overdose.
You know, when you get up to 2 grams or more in an average adult, people can get quite sick.
Obviously, the higher the dose, the more serious the poisoning, but it's characterized
by seizures, and cardiovascular collapse, shock, arrhythmias,
hypokalemia that can be quite profound, and generally be indicative
of the severity of the poisoning.
So, do keep that possibility in mind and I would be mindful of --
you know, in someone who's got a history of self-harm or risk factors for it,
I would be reluctant to send them home with a month's worth of hydroxychloroquine.
Last point just to mention this, it's a retinopathy is something with both chloroquine
and hydroxychloroquine that we screen for in patients who are on, say,
hydroxychloroquine long term for rheumatoid arthritis or lupus,
that's not something you're going to see in the course of a weeks' worth of therapy.
If someone is on the stuff, prophylactically, which I think is not a good idea yet,
no evidence to support that, and they stay on it for a long time,
that would obviously be a consideration.
So, it's one reason why I, for example,
if I had access to the drug would not be taking it prophylactically,
I'd be worried about a retina, this is not a reversible complication.
>> That's really very helpful because I think most clinicians are not very familiar
with these drugs, they're not used that often.
Well, azithromycin is used a lot but not the chloroquines.
So, there are three potential scenarios.
You've just said that based on what you know, it's probably not wise
to use these drugs prophylactically.
I think we can agree that when patients are in the intensive care unit
and have a rapidly downhill course that to use these drugs in the effort
to treat the disease is probably reasonable.
What about treating otherwise healthy patients who have COVID-19?
Given what you know about the evidence supporting its use, which we stipulate as thin,
and also the complication profile, which most clinicians are not all that familiar with,
what are your -- I want to preempt your answer by saying, we recognize this as an opinion,
it's not a medical recommendation.
But given what you know about the potential benefits and risks of these drugs,
what's your opinion sitting here today, March 24th, 2020, about the use of this drug
for patients that aren't that sick but have COVID-19?
>> You've prefaced your question with it but I'm going to plant a big flag here saying
that my opinion a week or two or a month or two from now could be very different,
depending on what the evidence shows.
If someone has just tested positive and is minimally symptomatic, I got to say,
I would be inclined to sit back and not use it.
My inclination to use it would go up as the intensity of the person's symptoms goes up.
So, if you have someone who's got some mild coryza and a temp of 38.1 or Fahrenheit,
you say 100.5, or say 101, if that's all they've got, recognizing that as far
as we can tell right now, most people do just fine and they coast through this,
I would be inclined not to use it.
But if someone were actively getting sicker, or if they had comorbidities that I was worried
about might put them at risk for a worse outcome, my inclination to use these drugs,
in combination, would go up, not because I know they're going
to help, but because I think they might.
And in the absence of another therapy, I think it's worth a shot until we have more data.
>> Thank you for that, this is really helpful.
Do you have any other thoughts about these drugs or any other drugs in reference to COVID-19?
>> I do have a concern that, especially -- and not to get political, but as --
you know, it's been promoted by the president as is something that we all hope
that it proves useful, there are reports of pharmacies running out of this stuff
of hydroxychloroquine in particular, no one is going to run out of Z paks, but there are people
with lupus, and RA, and ankylosing spondylitis, and sarcoid, and other conditions who are
on hydroxychloroquine long term, and who could become quite sick
if they aren't able to access the drugs.
So -- you know, if massive stockpiling happens at a societal level,
there are some important considerations for people
who have valid chronic indications for drugs like these.
>> That's a really important point because I did get an email yesterday that one
of the local health systems notified all their clinicians that these drugs are not available,
and that they're backordered, and they don't know
when they will be available, so this is already happening.
>> Yeah, I did see one of the producers -- I forget which one, maybe two of them --
have indicated a commitment to ramp up production of the drug.
So, I mean -- these are ancient drugs, they shouldn't be hard to produce.
So, hopefully, that concern recedes into the background in the near future.
>> I really thank you for taking the time to talk with us today
because this is real full information.
>> Well, I appreciate the opportunity.
Thanks very much, Ed.
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>> The COVID-19 pandemic has been frightening for all of us to deal with.
Clinicians are desperate to find treatments
for a disease we've never faced before and have no idea how to control.
For reasons that are not clear, many clinicians have zeroed in on chloroquine,
hydroxychloroquine, and the antibiotic, azithromycin.
Medications, for which there is very little evidence,
to suggest that they're effective in treating COVID-19.
As Dr. Juurlink explained, these are not benign drugs, and they have a myriad
of complications and drug interactions.
Perhaps it's reasonable to use these medications to treat critically ill patients
who are deteriorating, but it's probably not a good idea to treat otherwise healthy patients
who test positive for COVID and definitely a bad idea to use these medications prophylactically.
A viewpoint written by Dr. Andrew Khalil from the University of Nebraska
in Omaha entitled Off-Label Drug Use, Compassionate Use,
and Randomized Trials During Pandemics was published online in JAMA on March 24th, 2020.
Take a look at this viewpoint to learn more about the appropriate and inappropriate use
of medications and times like we are currently experiencing with the COVID-19 pandemic.
I'd like to thank Dr. David Juurlink for speaking with us
about medications used for COVID-19.
Today's episode was produced by Jesse McQuarters.
Our audio team here at JAMA includes Shelly Stefans, Daniel Mauro, Lisa Harden,
and Mike Berkowitz [assumed spellings],
the deputy editor for electronic media here at the JAMA Network.
I'm Ed Livingston, deputy editor for Clinical Reviews
and Education at JAMA, thanks for listening.