Hydroxychloroquine: There are Arguments and Counterarguments, but You Can't Have it Both Ways

I have had several exchanges with the folks that argue that hydroxychloroquine (HCQ) is an effective treatment for COVID-19, and in this post I want to go over some of the arguments and counterarguments that have been bouncing around the internet, and try to make sense of them within a logical framework.
 
Other posters and I have pointed out to the HCQ proponents that the best-designed studies have not found any effects of HCQ administered alone or with antibiotics (1, 2, 3, 4, 5, 6,and 7). In response to this, the HCQ proponents argue that these studies used HCQ doses that were too high and even (they claim) toxic for the study participants. Some HCQ proponents have suggested that these high doses were administered on purpose to make the HCQ groups in the studies fail, and they infer a nefarious purpose behind this, such as the study authors selling out to Big Pharma to discredit a cheap treatment for COVID-19 (HCQ) in favor of vastly more expensive treatments. Why did these studies use these high doses?
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There was nothing nefarious about choosing those high doses. It was done according to scientific rationales based on mathematical models that incorporate parameters such as the absorption, distribution, metabolism, and excretion of HCQ, and its activity against the virus in cell culture, coupled to the understanding that administering a short course of HCQ for a viral infection (which requires rapid drug penetration into tissues for effective prompt antiviral activity), is different from dosing HCQ for chronic conditions like rheumatoid arthritis or lupus. Specifically, not only is HCQ a weak antiviral, but HCQ has what is called a large volume of distribution. This is a pharmacokinetic parameter that describes the amount of a drug present in plasma in relation to the amount present in the rest of the body. Drugs (such as HCQ) with a high volume of distribution take longer to reach therapeutic concentrations in the blood, and require a loading dose to quickly reach the therapeutic concentration, followed by maintenance doses to sustain these therapeutic concentrations.
 
The dosing in these studies was carefully engineered based on knowledge of known toxicity of chloroquine overdoses and other considerations to achieve high HCQ concentrations while minimizing toxic side-effects. The high doses actually favored HCQ. If these studies had used the low doses that HCQ proponents advocate in social media, the studies would have been open to the criticism that the doses the studies used were not high enough for HCQ to be effective!
 
I want to also dispel the notion that HCQ is being shot down because it is a cheap therapy from which Big Pharma will not profit. One of the trials that did not find an effect of HCQ, the Recovery Trial, did find an effect of steroids in reducing mortality for patients with COVID-19 receiving respiratory support, and steroids are generic cheap medicines which are now being used successfully to save the lives of COVID-19 patients. If Big Pharma could control the outcome of the HCQ arm of the study, why would it allow the steroid arm of the trial to succeed depriving them of millions of dollars they could have earned with their expensive therapies? Make no mistake: If HCQ alone or with antibiotics had been found to be effective, we would have seen it in the Recovery trial and the rest of similarly well-designed clinical trials.
 
Further evidence against HCQ as a single agent that I’ve mentioned before, includes: 1) People who suffer from lupus and were taking HCQ when the pandemic started, were not protected from COVID-19 compared to those lupus patients that were not taking HCQ, and 2) HCQ does not protect macaque monkeys or hamsters against COVID-19. Additionally, as I have also mentioned before, HCQ has been found to have no antiviral action in cells from the human airways, which is probably due to the inability of HCQ to block a specific pathway of viral entry into these cells.
 
Under the massive weight of the evidence some of the HCQ proponents have reluctantly admitted that HCQ alone does not work against COVID-19, but they claim that this is irrelevant because HCQ was not coadministered with zinc. The so called “zinc hypothesis” of HCQ action states that it is zinc that has the antiviral action (it prevents replication of the virus), and that the role of HCQ is to facilitate the entry of zinc into the cells. HCQ proponents claim that the clinical trials using HCQ alone are silly because HCQ is being used in a fashion that won’t be effective (i.e. without zinc).
 
All the clinical trials I mentioned above with HCQ as a single agent or with antibiotics, but no zinc, were designed and commenced in the early phase of the pandemic when zinc was not part of the argument. The initial trials that brought HCQ to the attention of the world and the initial hypothesis of HCQ action did not involve zinc. Scientists were testing the hypothesis that was current at the time. This is perfectly reasonable and understandable. However, at least one clinical trial did analyze a subset of patients who were taking zinc supplements (scroll down to table S8) and found that this did not make a difference in the treatment outcome. But because this was not part of the treatment of the formal study protocol, this result is not conclusive. There are several ongoing clinical trials that include hydroxychloroquine and zinc, so we are waiting for those results to decide if the combination of HCQ and zinc works
 
Finally, I need to address an issue that I have seen played out over and over in social media. HCQ proponents dismiss again and again any HCQ trial that does not combine the drug with zinc, but at the same time cheer and defend the results of trials that find a positive effect for HCQ even if it was not used with zinc, such as the one from Dr. Raoult’s lab or the one from the Henry Ford Health System. And when these trials are criticized for having biases that compromise their interpretation (which they do: big time), HCQ proponents lash out at the critics and insult them calling them stooges of the establishment who have sold out to Big Pharma interests that want to shoot down HCQ even if it kills tens of thousands of Americans.
 
If HCQ does not have an antiviral activity of its own and just acts as a facilitator for zinc to enter the cell and stop viral replication (like the zinc hypothesis proposes), then trials that use HCQ alone SHOULD NOT work. You can, of course, argue that other effects of HCQ besides getting zinc in can produce some positive results, but they would certainly be far from stellar. The fact that trials such as the one from Dr. Raoult’s lab or the Henry Ford Health System found impressive results with HCQ alone actually raises a huge red flag, because they indicate the extent of the biases that compromised the interpretation of the results. This is why we can’t rely on observational studies like these to come to meaningful conclusions.
 
My message to HCQ proponents is that science is about discriminating between alternative hypotheses. If you argue that the best trials found no effect because you need to administer HCQ with zinc in order for the therapy to work, you can’t argue at the same time that HCQ has great effects on its own. You can’t have it both ways.
 
Yin Yang Image by Gregory Maxwell and the image of hydroxychloroquine by Fvasconcellos are in the public domain and were modified