The Science of Treating Covid-19 with Hydroxychloroquine (HCQ)

Table of Contents

I’ve organized this post as follows:

  • Introductory Thoughts and Background: I explain my journey to this point and my beliefs in regard to scientific inquiry. I also tackle the philosophical differences between the US government’s medical community represented by Dr. Fauci vs. the perspective of myself, the medical community in a number of other countries, and President Trump.
  • Summary: If you don’t have time or desire to read all the gory details, you can read my opinions and conclusions here.
  • Clinical Studies: A summary of the clinical data on the effectiveness of the HCQ + Azithromycin (AZ) + Zinc regimen.
  • Science of Why: Here I tackle some of the theories of why the HCQ regimen is believied to be effective.
  • Natural Alternatives: Combining the “Science of Why” with the effectiveness demonstrated by the “Clinical Studies”, I offer a theory of natural supplements that may be able to replicate some of the effects of HCQ + Zinc without a prescription.
  • Appendix A: An examination of the side-effects of HCQ.

Nothing in this post should be construed as medical advice. These are my opinions for educational and entertainment purposes only. I am not a medical doctor or scientist. I welcome corrections and comments, but please keep it fact-based and constructive. Ad hominem attacks or partisan politics will not be tolerated.

Also, I wrote this post on 9 April 2020, but didn’t hit publish until today (4/19). I had wanted to polish it, but then a bunch of new studies came out. My same basic conclusions remain and I will try to update this post with new data and polish this further as I have time. I feel a bit vulnerable posting this both because I’m guessing I misunderstand some things and am likely missing some things. I also know people have very tribalistic and strong opinions on this subject, quite far out of proportion to their knowledge.

Introductory Thoughts and Background

I’ve been watching Covid-19 closely for a long time. I knew very early on that it was going to be a serious problem. Chinese culture in general and the Chinese Communists in particular have a lesser regard for individual human life and a greater regard for the overall greatness of their nation. When the Chinese shut down the entire city of Wuhan at great economic cost, I instantly knew that they would never take such a step unless they firmly believed it would prevent far greater economic and sociopolitical costs. The size of the cost they were willing to pay made it obvious the severity of the problem, giving lie to their attempts to downplay and obfuscate the infection data and muzzle whistleblowers.

As soon as treatment data began to emerge, I voraciously devoured it as well. (I bought stock in Gilead (Nasdaq: GILD) because they have a drug, Remdesivir, that showed early promise. I’ve since sold GILD because even if Remdesivir is shown to be efficacious, there are far easier to manufacture and cheaper effective treatments, I believe, as you shall see.) The New York Times’ attacks on President Trump (which I now regard as crassly political, dishonest, and extremely harmful to our health) for recommending Hydroxychloroquine (HCQ) in his press briefings only poured fuel on the fire of my research. (See more in Appendix A.)

As I’m just now wrapping up an intense 96+ hour period of research that involved many 4 am mornings, I am amazed at the power of and very grateful to the hive mind of the internet, Twitter in particular. This post is a compilation of human knowledge, experimentation, and testing from all over the world. And I owe my awareness of it entirely to a combination of friends and strangers on Twitter, a tribe of people hungry to know and understand for themselves. I am not a trained scientist or doctor, so I do not have a comprehensive knowledge of human physiology and pharmacology to draw from (though I vacuum up whatever I can informally). So I am utterly dependent upon hints from others for direction in my research. I am especially grateful to Dr. James Todaro, Phil Wilson, and Dr. Vladimir Zelenko. Each of them provided extremely key information found nowhere else.

For those that do not know me, I firmly believe in the scientific method and randomized, double-blind, controlled studies. I am extremely skeptical of the natural supplements world/culture and think it is full of quacks who do not have the faintest understanding of the scientific method and how to evaluate a treatment’s effectiveness However, I also find too many in the medical establishment to be myopically focused on drugs as being the only solutions and not aware of the scientifically sound studies done on the effects of supplements and herbs. (I am also very aware of the ways drug profits distort medical education.) I absolutely adore the significant group of scientists, doctors, and hobbyists whose core medical belief is in the scientific method and who educate themselves from all scientifically-sound sources.

If one thinks charitably and without a conspiratorial mindset, the clash between President Trump and Dr. Fauci on the effectiveness of HCQ (as chronicled in the NYT article linked above) is due to Dr. Fauci’s rigid adherence to the medical orthodoxy of requiring a formal controlled, double-blind, randomized study of sufficient sample size before making a recommendation. The assertion of myself, Trump, and the medical communities of China, South Korea, Spain, Italy, and other places is that we do not have the luxury of two months to do a formal study. The data we already have honors the scientific principles behind controlled, double-blind, randomized studies. Because of the lack of formality, the numbers are not precise, but the differences in outcome are large enough to make it obvious that we have a moral imperative to immediately began widespread treatment with the HCQ regimen for those that exhibit Covid-19 symptoms. The side-effects of HCQ are negligible (see Appendix A), despite the NYT’s dishonest attempts to paint the opposite picture. Treating everyone who shows symptoms with the HCQ regimen will quickly get us the large-scale data we need. The pre-HCQ patients are our control group. The urgency of the pandemic mandates that we take that scientifically sound approach even if it is slightly less precise than a formal study. Given the decrease in mortality rate indicated by the HCQ regimen, I do not even think it is morally permissible to have a control group that does not get HCQ at this point.

Summary

There is strong evidence that a 5-day treatment of the malaria/lupus drug HCQ + the antibiotic azithromycin (AZ) (+ sometimes Zinc), when administered quickly after symptom onset, results in a dramatic drop in Covid-19 symptom severity and mortality rate.

The predominant theory of “Why” that I’ve seen is that HCQ transports a surplus of Zinc ions into cells, which inhibits the Covid-19 virus from replicating further. With a balanced diet (especially one rich in shellfish, red meat, eggs, nuts, and/or legumes), your body already has sufficient zinc to be transported across the cellular membrane by HCQ, but zinc supplementation serves as an insurance policy to ensure sufficient levels. AZ then attacks secondary respiratory tract infections that are a result of the virus. (This is very common with the flu virus as well; I had a secondary upper respiratory tract infection from the flu this winter for which my doctor prescribed AZ.) However, there are two other theories for how HCQ/AZ works including a direct attack against the virus that inhibits its replication or through the stimulation of the immune system.

There is also the possibility of a natural, non-prescription, OTC alternative to the HCQ/Zinc combo with three big If’s attached:

  1. If HCQ + Zinc is as effective as it appears from the clinical studies.
  2. If the medical community’s predominant “Theory of Why” HCQ + Zinc works against Covid-19 is correct and the other two theories are incorrect. This is a big If.
  3. If the in vitro (test tube cell cultures) study I reference below gives an accurate picture of how various supplements actually interact in the human body.

If all those “If’s” have a positive answer, then there is a possibility that Zinc + EGCG or Zinc + CQ10 could provide similar results as HCQ + Zinc. However, please read the proper section below for further disclaimers if you are considering taking these supplements.

Clinical Studies

Dr. James Todaro is the best aggregator of research on HCQ + AZ + Zinc that I’ve found. If you’re interested in the subject, you definitely need to follow him on Twitter.

He’s also authored a number of papers and summaries of other research. Here are a few highlights from his overall summary:

In São Paulo, the Prevent Senior hospital had 96 deaths from coronavirus until March 22, 2020. Since the hospital adopted a protocol of early treatment with HCQ, AZ and zinc, it has not registered any additional deaths from COVID-19 and had only one patient in the ICU. April 4, 2020

Of 3005 COVID-19 positive patients at the Méditerranée Infection hospitals (APHM/IHU) in France (as of April 4), 1818 patients have been treated with HCQ and AZ. Below are the outcomes:

COVID-19 patients NOT treated with HCQ+AZ: 1187

Deaths: 28 (2.4%)

COVID-19 patients treated with HCQ+AZ: 1818

Deaths: 5 (0.3%)

I find this French hospital data to be the most compelling because of the huge sample size, large control group, and the relatively randomized nature of the treatments because it included all patients in that hospital system.

Dr. Vladimir Zelenko, a board-certified family practitioner in New York, treated his 700th coronavirus patient with combination therapy of HCQ, AZ and Zinc. Of these patients, 694 recovered with outpatient therapy and, of the 6 requiring hospitalization, only one patient died after, per Dr. Zelenko, not following his treatment protocol. April 3, 2020

The caveat that I would add to Dr. Todaro’s characterization of Dr. Zelenko’s work is that if you read an earlier letter from Dr. Zelenko, you see that Zelenko was very generous in whom he treated with the HCQ + AZ + Zinc regimen. Anyone who showed hints of symptoms of Covid-19 was treated. Given his situation, that was a correct decision in my opinion (and we need all doctors to adopt this procedure because early interdiction with the HCQ regimen is crucial), however, extrapolating a 0.1% mortality rate or assuming that his sample size was 700 Covid-19 patients is not scientifically precise. Given how very contagious Covid-19 is, it is likely many of those had Covid-19, but it’s doubtful they all did. However, if Dr. Zelenko is correct and the one casualty didn’t follow the regimen, it could be argued he has a 0% fatality rate across hundreds of Covid-19 patients. No matter what set of either conservative or generous assumptions you make, Dr. Zelenko’s track record with the HCQ regimen is extremely impressive.

A global survey by Sermo of 6,227 verified physicians found that hydroxychloroquine (HCQ) and azithromycin (AZ) were the most used treatments (outside of analgesics) in the treatment of COVID-19. Out of 15 drug options, HCQ was also voted the most effective therapy. April 2, 2020

The US FDA issued an Emergency Use Authorization for hydroxychloroquine and chloroquine in treatment of novel-coronavirus. March 29, 2020

In a trial by Dr. Didier Raoult in South France of 80 patients treated with HCQ and AZ, 98% of patients had negative viral cultures on day 5 and 93% with negative PCR tests on day 8. When compared with prior studies by F Zhou et al (The Lancet) and KKW To et al (The Lancet) that demonstrated 50% and 30% of patients with viral shedding by day 20, respectively, Raoult et al shows that viral shedding times may substantially decrease with early HCQ and AZ treatment in COVID-19. This suggests that early treatment may decrease the spread of novel-coronavirus infection. March 27, 2020

Unpublished data from an open-label, multicenter, non-randomized trial in China of 197 patients showed that COVID-19 positive patients treated with chloroquine for 10 days had a higher rate of negative PCR testing by day 10 compared to controls (91.4% vs 57.4%, P < 0.001) and a shorter duration of fever (P = 0.003). Video and results slide here. March 26, 2020

Dr, Hu Bijie, Shanghai Combined Task Force on COVID-19 on treatment options for COVID-19 states: 

In regard to the use of antiviral drugs, anti-HIV medication Lopinavir/Ritonavir, and a broad spectrum anti-viral drug, Abitor, the overall result compared to placebo group showed no significant difference…We truly felt hydroxychloroquine is the specific drug of choice for COVID-19. March 20, 2020

The National Task Force for COVID-19 in India recommends hydroxychloroquine for prophylaxis in “Asymptomatic healthcare workers involved in the care of suspected or confirmed cases of COVID-19.” March 21, 2020

There are a number of other studies and evidences in favor of HCQ that are linked in the document above, including a number of newer studies.

I’d finally note that there many pieces of evidence (including this one) that it is essential to treat Covid19 with HCQ + AZ + Zinc very early, in the first day or two of presenting symptoms. Doctors must not wait for a several-day test result. Once the cytokine storm starts or ventilator is needed, the chances of getting ahead of the virus has grown very small.

Science of Why

There are at least three groups of theories for how HCQ/AZ/Zinc works against Covid-19. The first is that of Direct Attack in which HCQ and/or AZ bind directly to the virus or change the acidity of the ACE2 receptors (which is where the virus typically binds on a human), either of which prevents the virus’ further replication. The second theory is one I understand the least and involves, best I can determine, a stimulation of the immune system. The third theory is that of Zinc Transport in which HCQ transports more zinc ions through the cell membranes with the zinc inhibiting the virus’ replication.

I find the Zinc Transport theory most widely supported by the clinical evidence, while Direct Attack is best supported by in vitro studies. The truth is, all three mechanisms might work together to fight Covid-19. At the point, we really don’t know.

Direct Attack

Once again, Dr. James Todaro provides excellent summaries of the available evidence:

A Nature article in Cell Discovery demonstrated that hydroxychloroquine is effective in inhibiting SARS-CoV-2 infection in vitro by blocking the transport of SARS-CoV-2 from EEs to ELs—a requirement to release viral genome. Authors conclude that “In combination with its anti-inflammatory function, we predict that the drug [hydroxychloroquine] has a good potential to combat the disease.” March 18, 2020

Energetics based modeling of hydroxychloroquine and azithromycin binding to the SARS-CoV-2 Spike (S)Protein-ACE2 Complex shows that hydroxychloroquine may increase the acidity of the ACE2 system in the interaction between the ACE2 and SARS-CoV-2 spike that results in degradation of the spike, and potentially the discontinuation of the virus’ ability to spread further. Azithromycin on the other hand, may more directly block the binding interaction between SARS-CoV-2 spike and ACE2 complex. March 23, 2020

Immune Stimulation

Mike Coudrey tweets:

Hydroxychloroquine works by activating the innate immune system signaling pathways of IFN-β, AP-1, & NFκB. These signaling pathways help inhibit the anti-inflammatory environment exuded by the virus to evade immune detection, and induce apoptosis in virus infected cells. IFN-β has been shown to reduce viral replication of COVID-19 by 99% in vitro, which is one of the signaling pathways Hydroxychloroquine activates. HCQ has also been shown to increase extra-cellular ROS (reactive oxygen species) production, a byproduct of mitochondrial processes and also a cellular response to a viral infection. ROS is generated by the immune system to act as a potent destroyer of invading pathogens. In some studies, it was shown that HCQ inhibited HIV-1 replication by > 75%. It was also shown to inhibit replication of HPV, HSV-1+2, Zika, DENV, & COVID-19.

This study and this study may be relevant to this theory. I wish someone could fill me in more on how this theory fits with the other two and fill in my gaps in understanding.

Zinc Transport

A key insight from Dr. Zelenko’s letter (and which I’ve seen reported elsewhere as well) about Zinc is contained in this summary of his rationale for prescribing this particular mix:

The rationale for my treatment plan is as follows. I combined the data available from China and South Korea with the recent study published from France (sites available on request). We know that hydroxychloroquine helps Zinc enter the cell. We know that Zinc slows viral replication within the cell. Regarding the use of azithromycin, I postulate it prevents secondary bacterial infections. These three drugs are well known and usually well tolerated, hence the risk to the patient is low.

With some searching and a little help from Phil Wilson’s tweets, I found the body of research to which Dr. Zelenko was referring. There is a class of substances called ionosphores which transport ions across cell membranes. HCQ and chloroquine are both Zinc-ionosphores. Zinc ions inside the cell membranes are effective at inhibiting SARS-Coronaviruses (as well as other kinds of viruses like poliovirus and flu virus).

One of the strongest evidences I’ve seen for the truth of this theory of how HCQ + Zinc works (along with yet another strong medical endorsement of HCQ) is the following comment from Dr. Anthony Cardillo, an ER doctor and the CEO of Mend Urgent Care in Los Angeles:

What we’re finding clinically with our patients is that it really only works in conjunction with Zinc. So the HCQ opens the zinc channel, the zinc goes into the cell, it then blocks the replication of the cellular machinery [the RNA transcription of the virus]. So it has to be used in conjunction with Zinc… Every patient I’ve prescribed it to has been very, very ill and within 8 to 12 hours, they were basically symptom-free. So clinically I am seeing a resolution… I’m seeing people taking it alone [without Zinc] and it not having efficacy.

Finally, St. Luke’s Clinic in Poland appears to be yet another medical source of many that agrees with the Zinc Transport theory.

Natural Alternatives

An in vitro (test tube, not clinical in humans) study indicates that natural supplements CQ10, EGCG, and QCT all act as Zinc-ionosphores, performing the same function that it is believed HCQ performs in transporting Zinc ions into cells. This knowledge has three strong caveats of which I am aware:

  1. It was an an in vitro study, not a clinical study. Some things that work in vitro end up not working in a human body because in vitro cannot replicate all the processes that occur in a human body.
  2. The probable effectiveness of these depends entirely upon the theory of why HCQ is effective being correct. It has been my observation and opinion that often the weakest link in medical research is having a firm and sure understanding of the “why” of a treatment. We can objectively test and measure results, but the incredible complexity of the human body often leads to making educated guesses and shifting understandings of the “why” medical treatments work or why they do not work in certain situations.
  3. There has been zero (to my knowledge) actual testing of Zinc + EGCG/CQ10 for treating Covid-19.

If you decide to take Zinc + EGCG or Zinc + CQ10, it should only be:

  1. Prophylactic (preventative): As a “lottery ticket” prophylactic with zero side effects. If taken as a prophylactic, it should not give a false sense of security. You can still catch Covid-19, spread it to others, and die, even if we were to make the unwarranted assumption that one of these combos is just as effective as the HCQ regimen.
  2. Therapeutic (treatment of Covid-19 symptoms): This should only be done if you are utterly unable to get a doctor to prescribe HCQ + AZ. (SpeakWithAnMD.com may be willing to provide a prescription via telemedicine. If you try them, please leave a comment letting us know your results.) Given the clear data showing efficacy of HCQ, it would be medical malpractice to sub in anything else speculatively if HCQ is available.

Finally, please note that while they try to decaffeinate EGCG (it’s a green tea extract), it’s often been reported to keep people awake if taken in the evening, so plan your timing accordingly.

I’d also add that here are a number of other scientifically-proven (if my memory is serving me correctly) immune-boosting supplements that you can take that I am taking right now (and often use to fight off viruses and other illnesses).

  • Vitamin D (I take 10k IU at night before bed for the other benefit of boosting testosterone production per Tim Ferriss)
  • Garlic (Fresh clove quarter, peeled and chopped, and then swallowed with water is best, but take supplements if you can’t. High-allicin garlic or garlicin is best when it comes to supplements. If you can’t find that, get a garlic-oil-based supplement.)
  • Vitamin C
  • Probiotics (look for number of strains and number of billion CFUs to get rough measure of effectiveness)

Appendix A: Side Effects of HCQ

I’ll start this section by again linking a New York Times article that made me furious. Before I saw that, I assumed the press was being biased against Trump and downplaying HCQ only in the vacuum of formal pro-HCQ evidence, but that they’d be relatively honest once the science became more clear. However, this article was so dishonest about the side effects of HCQ (which I already knew as such from my independent research from medical sources) that it really torpedoed my expectation that they’d be more honest in the future. They were launching all out disinformation war against HCQ.

The combination of huge drug profits being at stake–HCQ is a very old drug with no patents and many generics while new drugs would be insanely profitable–and partisan politics of the right wing being the first to advocate for HCQ, makes this a very fraught issue with lots of agendas in the Americas. In Asia and Europe, both of these are non-issues because neither host many research-based drug companies or have the insane left/right divide on this issue. And we see the practical results of that with HCQ + AZ + Zinc being very standard in Asia and Europe but far too unused in the Americas.

But enough background, let’s move on to the actual evidence on side effects of HCQ. More from Dr. Todaro:

A review of available clinical evidence on chloroquine and hydroxychloroquine in the treatment of COVID-19 in patients with or without diabetes concluded that these therapies had minimal risk and should be carefully considered for clinical use as experimental drugs. March 22, 2020

And then also see Wikipedia’s article which gives excellent perspective and debunking of the NYT’s (and common press) lies about HCQ side effects. Here’s a key excerpt:

Hydroxychloroquine was approved for medical use in the United States in 1955. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. In 2017, it was the 128th most commonly prescribed medication in the United States, with more than five million prescriptions.

This is an unfinished section. I will try to give more perspective when I have time.

Join the Conversation

5 Comments

  1. Knew I had to read your work. You’ve always written thoughtful and thorough write ups in the past. Sad that if someone makes up stuff all the time, he won’t be believed, even when he may be right and it may save lives. Glad you’ve studied this critically.

  2. Hans Thank you!!! really appreciate your diligence . VERY helpful Shalom Al Longenecker

  3. I have quoted this article a couple of times, as a source of alternative studies to the recent VA retrospective. Both times, commenters have attacked you, as a writer, rather than the content. People often resort to ad hominem attacks, when they run out of arguments. These were made before any content/logical/scientific argument had taken place!

    This seems to be a new-ish way of responding to content that people can’t really argue with. It took me by surprise, how people became aggressive so quickly.

    Thanks for the sources!

    1. There is a place for respecting expert authority. Untrained laypeople are much quicker to misunderstand key issues or fail to understand key issues. However, when those experts cannot quickly explain in an objective, fact-based way the specific problems with the amateur research, there’s something wrong.

      And if all these extremely angry, rude trolls who lob reflexive authority-based ad hominem attacks (against us non-experts who organize the experts’ data) cannot point to a proper debunking of the methodological problems with the experts’ studies we cite, there is also something very wrong afoot.

      Like I explained in the intro, I am not prone to conspiratorial thinking and I still don’t wish to speculate on what all is going on here (whether political or drug profit motive), but something really stinks about all of this.

  4. I was able to obtain a prophylactic prescription for Hydroxychloroquine and zinc. Azithromycin not written or dispensed bc I have no diagnosed infection.

    I set up the appointment on Monday $59, was called a couple of hours later. Dr asked some basic and some more specific health questions, asked about my profession and potential exposure.. approved Rx.

    Next day recieved a call from the pharmacy to confirm mailing address and to take payment – $75 for 40 tablets.. plus $10 for 45 Zinc tabs.

    Recieved the prescription via UPS on Friday.

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