As the COVID-19 pandemic rages in our various cities, it is important to remember that as of today there are no proven effective therapies.
Still it is very difficult to watch people die despite your care. With about a thousand lives already lost to SARS-CoV-2 in the United States, everybody is scrambling to find therapeutics for prevention, cure, and mitigation of COVID-19. Safe and efficacious therapeutics.
Social media and physician list-serves are full of anecdotes from those who are using various medications “off label” presumably with success. In fact, there is very little in the way of randomised control trials for many of these therapeutics in regards to COVID-19.
We need to remember that supportive care is care. When there is no proven therapy for COVID-19, the next best thing is to NOT kill people with unproven arrhythmia-inducing drugs. Even if President Trump did not tout the potential efficacy of chloroquine last week at one of his televised coronavirus task force briefings and then reinforce his endorsement by Twitter several days later for the hydroxychloroquine plus azithromycin combination, hydroxychloroquine, along with off-label use antivirals are already being used in multiple countries in an attempt to treat COVID-19. Yet deaths are soaring.
The president’s touted hydroxychloroquine efficacy is so exaggerated to the point that nurse practitioners, dentists, doctors of all kinds are prescribing it for self, family and friends as prophylaxis or to have “just in case”. So disappointing. We could do better.
Sadly, there is the story of the couple in Arizona who self-medicated with chloroquine sulfate resulting in death, and there are those who are poisoning themselves inadvertently in Nigeria with chloroquine. The chloroquine as cure craze in Nigeria though started before this past week as previously stated.
In either case, hydroxychloroquine seems to have shot up to become the first-line COVID-19 trial medication on many US hospital guidelines. The “French study” that seemingly had everyone excited last week was nonrandomised. It had twenty-six people in the treatment arm. That is those who got hydroxychloroquine. By the time of the analysis, that number was twenty. Why? Because one died, three others decompensated requiring ICU transfer, one had nausea, and one left the hospital.
So right off the bat, four patients, maybe five did not do well with hydroxychloroquine. But the study conveniently leaves them out when it comes to comparing the treatment group to those who did not receive hydroxychloroquine. Then six of the remaining twenty patients in the treatment arm are given azithromycin in addition. The study then concludes that at day 6 45% of the treatment group had PCR detectable SARS-CoV-2 versus 89% of the control. A big difference in number yes, but a poor study all the same.
As physicians, we spent countless hours in medical school and residency learning how to read scientific literature. This one is a poor study. Single site. Small. Authors with conflict of interest (board of editors) so no wonder they were able to get their “study” published. And then not to mention the number of patients “lost to follow-up”. The lack of clinical data points. Where do I stop? The madness that people are so eager to prescribe themselves and their loved ones these drugs.
Let us pause a second and study these medications. Chloroquine (and hydroxychloroquine) were developed in the 1940s as antimalarial agents. Now, in several parts of the world Plasmodium falciparum, the protozoan responsible for malaria is resistant to chloroquine. Hydroxychloroquine, on the other hand, found life as an immunomodulating medication in the setting of rheumatologic diseases such as systemic lupus erythematous. Both have in vitro antiviral properties. One hypothesis is that they can inhibit the angiotensin-converting enzyme (ACE2) receptors that are necessary for viral entry. Another is that their immunomodulating capability can attenuate the cytokine storm that occurs in severe COVID-19 infections.
To be fair, most people do tolerate these medications well. Some patients will experience nausea, vomiting, diarrhoea. Those with pre-existing renal dysfunction will not clear them as well leading to potentially toxic levels in the body. Both medications have the capability of prolonging the QTc interval thus causing cardiac arrhythmias like torsades de pointes or even worse sudden cardiac death. This especially in those who are prone by their genetics, those who are on other medications with torsadogenic potential (for example, the azithromycin in the French study, LPV/r another of interest medicine), or who have electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia).
I wonder how many of the clinicians (or self-medicating patients) do a risk-benefit analysis – weighing the potential of developing COVID-19 ARDS versus the potential of hydroxychloroquine arrhythmia.
And what about that other medicine? Azithromycin. This is an antibacterial macrolide which inhibits RNA translation (and thus protein synthesis) by binding to the 50S ribosomal subunit. So what are its antiviral properties? There are no in vivo studies looking at these antiviral properties yet people are willing to add this QTc prolonging drug to another QTc prolonging drug (hydroxychloroquine) to see if it works?
All of this while we still wait to find out if hydroxychloroquine (with or without the azithromycin) is indeed efficacious in the setting of COVID-19 disease. And if it is, in what dose, for what duration, and at what time in the clinical course would it be best to initiate?
What happened to “First Do No Harm”?
Let us not forget that now the rush for these medications has led to a drug shortage for patients who actually have proven benefit from them for their rheumatologic conditions. How did we get here?
Well today, a pilot study is making the rounds, though not exaggerated by the media and not yet touted by the President of the United States who apparently “really gets this stuff”. This pilot study out of China enrolled 30 treatment-naive COVID-19 patients and randomized them 1:1 to get hydroxychloroquine or conventional/supportive care. The percentage negative viral load at day 7, the median time to normalization of body temperature, and radiologic progression were comparable between the two groups. Their conclusion is that hydroxychloroquine is no better than supportive care. This study is also not reassuring. Almost all the patients received inhaled alpha-interferon, an antiviral agent. Could it be that’s what was effective?
UGH! We still need more data.
The bottom line is that we don’t have a cure. Here in the United States, we have barely begun to confront COVID-19. We still need to flatten the curve, social distance, and very importantly “wash our hands”. All of us. And we should not forget that providing oxygen and ventilator support to patient’s with COVID-19 is doing something. Yes, several reports so far on hydroxychloroquine seem promising but that’s not enough for all of us to jump on the bandwagon.
I would like us not to anchor on hydroxychloroquine as the cure. That would be a premature closure in the search for effective therapeutics to treat COVID-19. There are still so many other options to explore, the right way, in a clinical trial, for efficacy. Let us all not practice shot-gun medicine.
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