The Hydroxychloroquine Question: Does It Work?

I am compiling a list of hydroxychloroquine (HCQ) studies found here. It is an on-going project. I also have a list of ivermectin studies. This article discusses what the studies show, and reaches the conclusion that it works if used properly: right dosage, preferably with zinc, and in the right patient population. [Note that studies seem to agree that HCQ with AZT has a higher mortality rate and therefore the combination is not advisable.]

However, not all studies reach the same conclusion. Some well-designed studies show that it works; other studies show that it does not work. How can this be? Essentially, whether or not it works depends on several different factors. If the dose is too high, then the side effects and even the mortality rate is too high. If it is given with zinc, it works better. But it also must be given early, and only to patients which mild to moderate disease. Give it to the wrong category of patients, or too late to any type of patient, and you will have failure. But some persons are uncomfortable with answers that are complex and not entirely certain. They want a simple and definitive answer. This leads to inaccurate coverage of hydroxychloroquine in the media.

Another source of inaccurate coverage is that hydroxychloroquine has become politicized. President Trump tweeted about hydroxychloroquine, and has made positive comments at news conferences. Unfortunately, this has caused his opponents to malign and denigrate the medication, as a way of expressing their dislike for President Trump himself. He didn’t invent the medication. He’s not your doctor prescribing it for you. So the evaluation of hydroxychloroquine by the media has become biased by their dislike (or like) for the President. Instead, they should let the science speak for itself.

The result is that, when particular studies show positive results for hydroxychloroquine, the study is criticized severely. On the other hand, if a study finds a negative result for hydroxychloroquine, it is lauded as definitive proof against the medication. Any study can be criticized. It’s intellectually dishonest to target one study for severe criticism, absolutely dismissing its results, and be entirely uncritical of a study with the opposite finding.

News Media Bias

It is disturbing to read news articles declaring definitively that “science” shows hydroxychloroquine does not work. I’ve read the science, and what it shows is complex.

NBC News (July 30, 2020): “President Donald Trump continues to tout an unproven treatment for the coronavirus. While some treatments have been shown to improve survival or lessen the severity of the disease, leading infectious disease experts, doctors and virologists say it’s time to stop promoting one that hasn’t: hydroxychloroquine.”

There are multiple studies showing that hydroxychloroquine is effective [1 - 6], and a lower mortality rate [1, 4, 6]. It is dishonest to use sweeping phrases like “leading infectious disease experts, doctors and virologists say” as if all were in agreement, especially when multiple studies show effectiveness and many physicians and hospitals continue to use hydroxychloroquine.

The Ohio pharmacy board withdrew a rule barring use of hydroxychloroquine to treat coronavirus because so many physicians and patients objected. It is false to say that all doctors agree that hydroxychloroquine doesn’t work.

And Stephen Hahn, the commissioner of the Food and Drug Administration (FDA), in an interview on July 30, 2020, refused to oppose the use of hydroxychloroquine, and stated it should be left to the decision of physicians and patients. Hahn stated: “We had data that when this drug was combined with others, there was some risk associated with that.” [TheHill.com] The combination to which he refers is azithromycin with hydroxychloroquine. The evidence is sufficient that this combo adds too much risk to justify any additional benefits. But notice that the head of the FDA does not agree that hydroxychloroquine does not work.

A CNN article bemoans the use of hydroxychloroquine in Brazil. The article claims “Globally the debate about hydroxychloroquine — settled by science yet still raging in the mouths of politicians looking for hope to sell….”

No, CNN, science has not settled the debate on hydroxychloroquine. The Henry Ford Hospital study was just published in the August 2020 issue of International Journal of Infectious Diseases (released at the end of July). The article is unfairly titled: “Inside Brazil’s cult of hydroxychloroquine.” Brazil likes hydroxychloroquine because it is widely-available and affordable. As a developing nation, Brazil cannot afford remdesivir and other expensive medications.

The Details

The better studies consider hydroxychloroquine as one of multiple treatments given to Covid-19 patients. Expecting one medication alone to effectively treat a complex and severe disease like Covid-19 is unreasonable. Multiple medications are needed. So the question, “Does it work?” needs to be modified: “Does it work when combined with other treatments? Does it work for certain types of patients, at the right dose, when given early?”

The solution to Covid-19, if we ever find one, is extremely likely to be a set of medications and treatments, varying for different patient populations and different stages of the disease. It is unlikely that one medication alone will simply cure Covid-19. And that is not the direction of the research either. Consider the MATH+ Protocol, which looks at different stages of Covid-19 and has a different set of medications, at different doses, for those stages.

Another issue is the need, in developing nations, for low cost and widely-available medications. Hydroxychloroquine and ivermectin both qualify. And we see that in South America, for example, both medications are popular with physicians as well as politicians. They have a certain efficacy, and they are available and affordable. Remdesivir can cost as much as $3000.00 US dollar per course of treatment. That is out of the reach of many nations, especially when they might have to treat millions of persons. So the question is not even whether hydroxychloroquine is the best treatment, but whether it does in fact work better than other affordable available medications.

Finally, one cannot simply look at whether hydroxychloroquine worked in a study or not, but on the details of how the drug was used. Hydroxychloroquine does not work if given late in the progress of the disease. It has shown greater efficacy when combined with zinc. It has shown greater side effects when combined with azithromycin (so don’t use the two together).

A USA Today article by Dr. Marc Siegel takes a positive look at hydroxychloroquine:

Dr. Siegel writes: “The Henry Ford Health System in Detroit has just released a large retrospective study in which the drug was given very early in the hospitalization. I spoke with its chief academic officer, neurosurgeon Steven Kalkanis. ‘We stand behind our recent Henry Ford study where we looked at 2,500 patients and we found that the use of hydroxychloroquine alone cut the death rate in half (from 26% to 13%),’ he told me. According to Dr. Kalkanis, the study screened heavily for those with preexisting conditions, including cardiac disease. He said the key to success is using the drug early in the course of the illness, before significant inflammation occurs.” [USA Today]

Studies in which the drug is given early, at a moderate dose of 200 mg twice a day, show that the drug is effective. Two studies combining HCQ with zinc also had a good result. But it isn’t the right medication for every Covid-19 patient. And studies using a much higher dose found much higher side effects and higher mortality.

The Studies

1. Arshad, Samia, et al. “Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.” International Journal of Infectious Diseases (2020).
This is the Henry Ford Hospital study.
https://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext

In the Arshad study, done at the Henry Ford Hospital in Detroit, hydroxychloroquine was given to hospitalized Covid-19 patients very promptly. They tried hydroxychloroquine alone, with azithromycin, and azithromycin alone, as well as a control group. HCQ alone has the lowest mortality rate (13.5%) as compared to 26.4% for the control group. That’s about half the mortality of the control. Azithromycin did not improve the performance of hydroxychloroquine, and did not out-perform hydroxychloroquine.

The Henry Ford study was severely criticized by news media outlets for making them look like liars.

2. Kadnur, Harshith B., et al. “Hydroxychloroquine Pre-Exposure Prophylaxis for COVID-19 Among Healthcare Workers: Initial Experience from India.” (2020).
https://papers.ssrn.com/sol3/Delivery.cfm/THELANCET-D-20-12512.pdf?abstractid=3622350&mirid=1

The government of India has recommended the use of hydroxychloroquine as a prophylaxis for its healthcare workers. Many doctors and nurses take the drug, once a week, to reduce their risk of infection. The Kadnur study found that the use of HCQ for prophylaxis reduced risk of Covid-19 infection by 87%. Why isn’t the United States using hydroxychloroquine to reduce the risk to our healthcare workers?

An 87% reduction in infections is likely to translate into a similar reduction of mortality. What’s wrong with an 87% reduction in death of doctors and nurses? But the media have decided that hydroxychloroquine doesn’t work. The study was not an RCT, but at this point an RCT might not be moral, as we know that the drug is effective. So we can’t expose healthcare workers to a deadly disease and only give them a placebo. The above study used the healthcare workers who decided not to take HCQ as the control. That’s fair. But they did have a higher death rate.

3. Bernaola, Nikolas, et al. “Observational Study of the Efficiency of Treatments in Patients Hospitalized with Covid-19 in Madrid.” medRxiv (2020).

Click to access 2020.07.17.20155960.full.pdf

HCQ treated patients were 17% more likely to have a better outcome than treatment with antivirals or other medications. Prednisone (15%) was also an effective medication in this study, almost as effective as hydroxychloroquine (17%).

HCQ was substantially more effective when combined with zinc supplementation, reducing mortality 55.1%. This study, and the Zelenko study both used zinc with the hydroxychloroquine because HCQ is a zinc ionophore, it carries zinc into the infected cell, and then the zinc ions interfere with the virus’ replication.

This was a meta-analysis, which combined the results from multiple studies of HCQ. The problem is that the dosing and other factors vary from one study to another. Overall, HCQ worked about as well as standard care with the same mortality rate, but with more side effects and longer hospitalization. This is a tenable treatment for developing nations, which need affordable widely-available medications. They can improve on the result from this meta-analysis by choosing the factors that provided the best results. They would not obtain the same result as a meta-analysis, as they are not using an average of all the studies as the treatment regimen.

6. Scholz, Martin, Roland Derwand, and Vladimir Zelenko. “COVID-19 outpatients–early risk-stratified treatment with zinc plus low dose hydroxychloroquine and azithromycin: a retrospective case series study.” (2020).
https://www.preprints.org/manuscript/202007.0025/v1/download

A lower rate of hospitalization and a lower rate of death was found with use of HCQ plus zinc. One fifth as many patients died who used hydroxychloroquine as compared to controls. Patients on HCQ were 81.8% less likely to be hospitalized.

Summary

The evidence to date shows that hydroxychloroquine can be an effective medication. It needs to be given with zinc, without azithromycin, and only to patients with mild to moderate disease, as early as possible. The effective dosing seems to be 200 mg twice a day, with an initial loading dose of 400 mg twice for the first day. Once hyper-inflammation begins, hydroxychloroquine does not do well. It is not for patients with severe disease. More studies are needed of the combination of hydroxychloroquine and zinc as a prophylaxis and as a treatment for early mild Covid-19.

Many physicians are still using hydroxychloroquine, and for good reason. It is one of many different medications that can be effective for some patients, in some circumstances. Physicians should be able to choose which medications to give to their patients.

In these two videos, Dr. Mobeen Syed interviews a researcher Adam Gaertner and Dr. Paul Marik. Both of them mention that they think hydroxychloroquine works if used appropriately. Marik mentions that the dosing must be low (200 mg bid) and it should be given with zinc.

Finally, take a look at this list of studies on hydroxychloroquine.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

Consider supporting Covid.us.org with a one-time or recurring donation via PayPal

3. Bernaola, Nikolas, et al. “Observational Study of the Efficiency of Treatments in Patients Hospitalized with Covid-19 in Madrid.” medRxiv (2020).

Click to access 2020.07.17.20155960.full.pdf

[HCQ treated patients 17% more likely to have a better outcome than treatment with antivirals.]

4. Carlucci, Philip, et al. “Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients.” medRxiv (2020).
https://www.medrxiv.org/content/10.1101/2020.05.02.20080036v1
[HCQ was substantially more effective when combined with zinc supplementation, reducing mortality 55.1%.]

5. Ghazy, Ramy Mohamed, et al. “Effectiveness and Safety of Chloroquine or Hydroxychloroquine as a mono-therapy or in combination with Azithromycin in the treatment of COVID-19 patients: Systematic Review and Meta-Analysis.”
https://tinyurl.com/y5ezx46y
[HCQ worked about as well as standard care with the same mortality rate, but with more side effects and longer hospitalization. This is a tenable treatment for developing nations, which need affordable widely-available medications.]

7. Fauci, Anthony S., H. Clifford Lane, and Robert R. Redfield. “Covid-19 — navigating the uncharted.” New England Journal of Medicine, March 26, 2020, 382:1268-1269.
https://www.nejm.org/doi/full/10.1056/nejme2002387

8. Cao, Bin, et al. “A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19.” New England Journal of Medicine, May 7, 2020, 382:1787-1799.
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

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