Science used to be science. That is to say, politics rarely influenced how we interpreted data. That has all changed during the COVID-19 pandemic. Physicians and patients are so invested in the outcome of various hydroxychloroquine studies that data have taken a back seat to beliefs. Negative hydroxychloroquine studies have generated disbelief, denial, rebuttal, hostility and intimidation.
Flip-Flops in Science:
Please don’t get us wrong. Fashions come and fashions go in medicine as well as in other walks of life. If the prevailing view in the medical community is that hormone replacement therapy (HRT) prevents heart disease and strokes, then we tend to see more positive studies supporting that belief.
Eventually, though, well-conducted randomized controlled trials will reveal the truth. HRT does not prevent heart attacks. In fact, it may increase the risk of blood clots, strokes, other unpleasant cardiovascular events and breast cancer (JAMA, Oct. 2, 2013; Cochrane Database of Systematic Reviews, March 10, 2015).
It took a long time for the truth to come out about HRT. The same thing can be said for dozens of other flip-flops in science. In recent years studies have contradicted the prevailing beliefs that eggs were bad, that hydrogenated margarine was better than butter or that low-fat, high-carb foods would reduce obesity and heart disease. Ultimately, well-conducted clinical trials win out over beliefs every time.
We Hoped Hydroxychloroquine Would Work:
We were more hopeful than most of our colleagues that hydroxychloroquine (HCQ), either alone or with azithromycin, might be able to lead to beneficial outcomes against the coronavirus. Here is one of our first articles:
Are There Compounds That Might Help Control Coronavirus?
There are NO FDA-approved medicines against coronavirus. Thanks to Dr. Roger Seheult, we learned about a few compounds that might help control coronavirus.
We embraced videos by Dr. Roger Seheult. This physician provided a brilliant series of presentations suggesting a mechanism whereby hydroxychloroquine or quercetin could help zinc interfere with viral replication inside human cells. Here are the videos that gave us hope.
and
March 12, 2020 Coronavirus Pandemic Update 35 discusses “Possible COVID-19 Treatments.”
Early Optimism:
Based partly on Dr. Seheult’s discussion of HCQ we were hopeful that the drug might be helpful in the fight against COVID-19. Because the drug is a zinc ionophore it facilitates the passage of zinc into the cell. This gating process allows zinc to act as an antiviral mucking up the replication machinery of SARS-CoV-2. So, from a mechanistic perspective and as a pharmacologist, this seemed like a potentially plausible drug.
By the way, Dr. Seheult did not recommend taking zinc unless a person was zinc deficient.
There were also some very preliminary clinical data out of China and France that supported the potential of the drug to speed healing in patients. These studies were not huge and were not published in highly-regarded medical journals, but they did give us hope.
We agreed with Dr. Seheult when he stated unequivocally that we would need randomized controlled trials to really know whether hydroxychloroquine works against the coronavirus. That did not dampen the enthusiasm for these approaches by lots of Americans.
Negative Hydroxychloroquine Studies Anger Readers:
When the first observational study was published in the New England Journal of Medicine (May 7, 2020) we reported the results. We were unprepared for the backlash. There was a clear shoot-the-messenger reaction. Visitors to this website came up with lots of explanations for the lack of benefit.
Now, another study of the malaria drug hydroxychloroquine against COVID-19 has yielded disappointing results. The research, published in JAMA (May 11, 2020), shows that patients taking hydroxychloroquine, azithromycin or both were neither more nor less likely to die than those who did not.
The investigators analyzed the medical records of patients hospitalized in New York with serious cases of the coronavirus. In all, they considered outcomes for 1,438 patients. Given the excitement that followed announcements of observational studies in France, this is quite a letdown.
The study in JAMA did find that people taking the combination of hydroxychloroquine and azithromycin were more prone to cardiac arrest:
“In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13), but not hydroxychloroquine alone or azithromycin alone.”
Readers React:
Here are just a few of the angry comments we have received for reporting on the negative hydroxychloroquine studies:
Don summed up a lot of comments with this message:
“There’s no profit to be made from wide distribution of this low cost and not patentable drug. This is why testing is rigged to show that it is ineffective: 1. Test primarily on people who are already very ill. 2. When testing on those who are not yet seriously ill, do not combine with zinc and azithromycin, which is the clinical treatment found to be most effective. 3. Use the media to discredit it, and censor dissenting voices.
“The testimony of dozens, if not hundreds of doctors and thousands of patients who have been helped with this drug count for nothing. Sickening, no pun intended. Just because you’re paranoid, doesn’t mean they’re NOT out to get you.”
Linda adds this comment:
“I have seen many doctors say they’ve had major success treating patients with hydroxychloriquine together with azithromycin and zinc. Also that dosage depends on weight. But that it has to be administered early and before patients need hospitalization. It was already too late for these patients.”
LaRae is also upset:
“Wait a minute…The information stated in your article states that the patients given hydroxychloroquine were sicker than the patients not given the drug. Sorry but this shows me this study is not valid. Hmmm, sounds to me like there was an agenda in debunking a low cost drug to treat Covid-19.
“Also, I don’t think you can discount the numerous accounts by renowned doctors who have stated publicly that gave their patients hydroxychloroquine and feel that it saved their patient’s lives.”
Connie is quite angry:
“I don’t trust any study on Covid that was done in New York. I don’t care what medical journal is posting it. Cuomo banned the use of the drug so how were they even able to do this? Further study is needed and if a patient wants to try the drug it should be given.”
S.J. expresses a belief shared by many:
“Another study skewed by the people administrating the trial. It has been told that hydroxychloroquine helps get ZINC into the cells, which then stops the replication of the virus. Wow, none of these participants were given zinc along with the hydroxychloroquine. This is just another bogus report, because this is old and cheap. Everything has to be new and expensive these days. What a sham.”
Terry adds:
“It is a Political tactic to downplay HCQ, because it is a cheap drug that the Pharmaceutical Co.’s cannot profit from like the drug that they are pushing, Remdesivir that costs tens of thousands of dollars. For detail info look up Dr. Judy Mikovits and/or “Doctors in Black” for some definitive info that is being destroyed.”
Merita makes a point that many people believe:
“Once again, this study was with hospitalized patients. Evidence has shown the importance of administering the combination of the drugs before they are that ill.”
What’s Going on with Negative Hydroxychloroquine Studies?
Much has been made of the fact that maybe the patients getting the drugs were sicker or that they did not get the drugs fast enough. The French study that reported positive results did not administer the drugs substantially faster. Ditto in China. The drugs were given within 24-48 hours of admission in the NEJM study. Any faster would have been challenging in any hospital setting.
A study in which patients were given the HCQ + azithromycin before they entered the hospital would have been impossible to administer. Who would oversee such a trial. In order to compare the effectiveness of the drugs, investigators have to be able to compare results with people who do not get the medications.
If the drug(s) were as promising as everyone (including myself) had hoped, we should have seen a positive signal. There should have been some clear indication that there was less intubation and fewer deaths in the HCQ group as predicted by Didier Raoult.
Here is the key issue: Many people do get better even when seriously ill with COVID-19 whether they get HCQ or not. When a doctor administers HCQ and/or azithromycin and sees improvement, is that due to the drug(s) or is that the natural course of the disease for that patient?
When a patient is intubated or dies without HCQ/Z-pak is that because he did not get the drug or because he was headed downhill regardless? And if a patient dies while taking HCQ/Z-pak was that because the drug was started on day 2 instead of day 1 or because he was just sicker or because the drug(s) didn’t work?
The only way to answer such questions is with large observational studies like the JAMA and NEJM studies and ultimately with randomized controlled trials.
What about zinc? Here is a critical point. Dr. Seheult does not suggest that people need extra zinc unless they are zinc deficient. As far as I can tell, Dr. Didier Raoult, the French physician who really started the hydroxychloroquine + azithromycin protocol, did not administer zinc either. Neither did the Chinese researchers who reported positive benefit from hydroxychloroquine. We have seen no published studies that demonstrate zinc supplements are crucial for the effectiveness of HCQ with or without azithromycin.
What Does the Future Hold for HCQ, Azithromycin and/or Zinc?
Although the two observational studies published in the New England Journal of Medicine and JAMA have not produced promising results, we remain hopeful. There are literally dozens of studies underway. Some are large observational studies. Others are randomized controlled trials (RCTs). These are the gold-standard studies we need to rule out bias or confounding variables.
At least two of the RCTs will be testing the preventive power of HCQ. In other words, people who were exposed to patients with COVID-19 will be randomized to receive either HCQ or placebo before they themselves get sick. This way we will learn if the drug can prevent the disease in the first place. Wouldn’t it be wonderful if the results were positive!
We remain agnostic on the outcome of future research. If negative hydroxychloroquine studies are contradicted by positive results, we will be extremely happy. We will send out special health alerts announcing the good news as fast as humanly possible.
If, on the other hand, there are additional negative hydroxychloroquine studies we will report them objectively. Science should not be politicized.
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