Hydroxychloroquine and Zinc: Avoid Falling in Love with the Story

One of the things you learn as a scientist is to be skeptical of stories. By stories I mean narratives that scientists have put together to try to explain certain observations, to explain how some things work, or to suggest new ways of doing things that may be more effective than the old approaches. And the way you learn to be skeptical of stories is through the experience of witnessing countless numbers of them crash and burn over the years. We scientists try to discover reality, but the problem is that reality is often more complicated and nuanced than we can imagine. The English biologist Thomas Huxley once encapsulated this in his famous dictum: The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact.
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Because scientists are human, they tend to fall in love with their ideas and bring to the front in their arguments all the evidence that suggests those ideas are true while overlooking evidence that indicates the opposite. But thankfully these biases are countered by experience. As a scientist, I have lost track of how many times I thought I understood how things worked only to have my ideas disproved by the next experiment. As a scientist, I have also lost track of the number of times I became enamored of a beautiful idea proposed by a scientist only to read later that another scientist had performed an experiment that refuted it. After years of being exposed to this process, you tend to be wary of anything new that sounds too good, and this experience is a fundamental part of the development of a skeptical scientific mindset.
 
I remarked before that one of the problems we have in science communication is that now people without training as scientists have access to information intended only for experts. The vast majority of these people do not have the experience I outlined above. As a result of this, I am witnessing many of these individuals become infatuated by unverified hypotheses to the point of aggressively defending them in social media and arguing that these hypotheses have been proven to be true by what is nothing but substandard evidence.
 
A case in point is the hypothesis that hydroxychloroquine (HCQ) and/or its combination with zinc is effective against COVID-19.
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Hydroxychloroquine (HCQ)
HCQ and its parent compound chloroquine (CQ) have been used for decades against malaria. But the original interest in using HCQ against COVID-19 was generated as a result of studies that indicated CQ had antiviral activity against various viruses including SARS-Cov, a virus related to SARS-Cov-2 which produces COVID-19. More recent studies found that HCQ does indeed have antiviral activity against SARS-Cov-2. Unfortunately, this antiviral activity was evaluated in cultured green monkey kidney (Vero-E6) cells. When HCQ was tested in human airway cells or animal models, no such activity was found. Thus the initial rationale that got scientists interested in using HCQ against COVID-19 has evaporated. If we knew at the start of the pandemic what we now know about HCQ’s lack of antiviral activity against SARS-Cov-2, HCQ would never have been tested against COVID-19. This lack of antiviral activity probably explains why HCQ has not been found to be effective against COVID-19 in the best designed trials (1, 2, 3, 4, 5, 6, 7, 8, 9).
 
Nevertheless, HCQ proponents claim that other effects of HCQ such as its anti-inflammatory actions can produce a protective effect against COVID-19. HCQ does indeed have well-documented anti-inflammatory action in diseases such as lupus or rheumatoid arthritis. However, the onset of this action is slow taking several weeks to months for patients to begin to see improvements, with the full effects taking as much as a year or more. In comparison, the time frame of HCQ treatment in COVID-19 is a couple of weeks at most. And in case you are wondering, studies indicate that patients with lupus or rheumatoid arthritis who were taking HCQ were not protected from COVID-19. There is some evidence that in patients with COVID-19 treated with HCQ there is a faster onset of anti-inflammatory action, but it is not clear why HCQ would be better than other anti-inflammatory agents or why the anti-inflammatory properties of HCQ did not make a difference in the best designed trials.
 
Zinc and HCQ
Another hypothesis for a possible HCQ action against COVID-19 involves the trace element, zinc. HCQ proponents claim that HCQ taken with zinc is a very effective therapeutic for COVID-19. Zinc has been found to have antiviral action in cell culture because it inhibits the enzyme necessary for the replication of the virus’ genetic material. Additionally, zinc deficiency compromises normal immune function and there is some evidence that zinc deficiency results in a worse COVID-19 outcome. So giving zinc to people with COVID-19 seems like a good idea to correct any zinc deficiency. In fact one of the treatments that the president received when he was infected with COVID-19 was zinc supplements (but not HCQ).
 
So you may ask, if a COVID-19 patient is receiving zinc, why also coadminister HCQ?
 
Some HCQ proponents argue that in physiological conditions zinc is a charged molecule that has trouble getting across cell membranes, and HCQ in a cell culture study was found to act like a zinc ionophore. This means it increases zinc uptake into cells. Therefore the claim is that you administer HCQ with zinc to “help” zinc get inside the cells where it can inhibit the virus. In this view, it is zinc that has the antiviral action while HCQ only helps it get into cells. The issue with this notion is that zinc has no problems getting across cell membranes. There are zinc transporters in the membranes of cells that can let zinc in (and out) just fine. In fact, 99.9% of the zinc in the body is inside the cells.
 
Regardless, HCQ proponents argue that HCQ is necessary to drive the uptake of an excess amount of zinc to produce antiviral effects. In the cell culture study mentioned above (and bearing in mind that these are cell culture results with all of their caveats), a concentration of 10 micromolar HCQ outside the cells increased intracellular zinc slightly above two times the normal amount. Whether this is enough to antagonize viral replication is an open question. However, the majority of the intracellular zinc was targeted to a compartment called a lysosome (which is where HCQ accumulates). The problem is that viral replication takes place elsewhere in the cell (the cytosol). How can zinc trapped in the lysosome affect extralysosomal viral replication? And increasing the HCQ concentration outside the cell to push in more zinc is problematic. In humans, HCQ plasma concentrations greater than 15 micromolar are associated with mortality (reference: download pdf).
 
An additional complicating factor is that the majority of the zinc both inside and outside the cells is not free. It is bound to proteins. Zinc is used as a signaling molecule by cells and if its levels are allowed to increase in an uncontrolled fashion, they can be toxic. Cells control their internal free zinc levels and try to keep them as low as possible.
 
I am greatly skeptical about the effectiveness of HCQ against COVID-19, because I consider that the best evidence we have indicates it doesn’t work. I am also skeptical about the zinc story. There are too many questions and a lot of it remains unproven. The effect of zinc alone may be to correct a deficiency as opposed to a pharmacological effect, and HCQ may have no role in the process. But as I have stated before, I want to save lives, not be right. If HCQ alone is found to work against COVID-19 in some specific dose modality or temporal dosing regimen, then that’s great. If zinc combined with HCQ is better than HCQ alone, then that’s great too. But we need well-designed clinical trials to prove this (which excludes observational studies).
 
In the meantime we will all be best served if we maintain a reasonable level of skepticism. My message to HCQ proponents is: Avoid falling in love with the story.
 
Heart image by Mozilla used here under a Creative Commons Attribution 4.0 International (CC BY 4.0) license was modified from to include the words of hydroxychloroquine and zinc with the heart on a white background.