Last updated on September 9th, 2020 at 10:52 am
Just when I thought I was out of the hydroxychloroquine pseudoscience, they pull me back in. And here we are, a group of fools is pushing it again. Sigh.
This all started because of an awful study from France published back in March of 2020. At that time, Donald Trump, desperate for a “win” against the coronavirus along with other non-scientists pushed hydroxychloroquine and azithromycin for coronavirus. Of course, me and many others like Orac, who has written several articles about it, found the evidence that hydroxychloroquine, usually with the antibiotic azithromycin, had any effect on COVID-19 was very weak, even non-existent.
And my mind hasn’t been changed in the meantime. And Orac is back calling hydroxychloroquine the “Black Knight,” a reference to a fictional character in the wonderful film, Monty Python and the Holy Grail. Oh, you never saw the movie? Well, I’ll let Orac tell that story:
In the film, King Arthur encounters him guarding a rather pathetic bridge and asks him to join his quest to seek the Holy Grail. The Black Knight refuses and then blocks Arthur’s passage with a menacing, “None shall pass.” The battle is joined, and Arthur, one by one, chops off all of the Black Knight’s limbs in a truly warped comedy sequence. After losing each limb, the Black Knight says things like, “‘Tis but a scratch” and “I’ve had worse.” Before his last leg is chopped off, the Black Knight proclaims (while hopping around), “I’m invincible,” to which Arthur retorts, “You’re a loony.” After losing his last limb, the Black Knight finally concedes, “All right, we’ll call it a draw.” Then, as Arthur crosses the bridge and rides off, the Black Knight yells, “Oh. Oh, I see. Running away, eh? You yellow bastards! Come back here and take what’s coming to ya! I’ll bite your legs off!”
In other words, this damn story about hydroxychloroquine keeps coming back despite having all of its limbs removed. “Tis but a scratch.”
Now, I prefer zombie metaphors (and I believe so does Orac, but I have to give credit to him for the Monty Python reference), because, like many of the tropes we see in the anti-vaccine world, no matter how many times we kill this belief, it keeps coming back. In the world of zombies, one needs to destroy the brain. That’s why I try to present evidence!
Of course this time around, this claim includes demon sperms and alien DNA. I kid you not.
What is hydroxychloroquine?
Chloroquine was approved in October 1949 for treating malaria, and it was the anti-malarial drug of choice for many years. It was replaced by newer and safer anti-malarial drugs such as pyrimethamine, artemisinin, and mefloquine.
Although it is no longer used as an anti-malarial, chloroquine and its derivative hydroxychloroquine have found a new life for the treatment of a number of other conditions. Since the drug mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus. It is unclear how chloroquine works for autoimmune diseases.
In addition, chloroquine is used to control the aquarium fish parasite Amyloodinium ocellatum, so many people have the drug nearby.
Chloroquine has numerous side effects from not-too-serious to dangerous. Common, and not too dangerous, side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Unfortunately, there are more serious and dangerous side effects that include vision problems, muscle weakness, seizures, and low blood cell levels.
What is azithromycin?
Azithromycin is an antibiotic used for the treatment of a number of bacterial infections. Although it’s a generic medicine, it’s well known as Zithromax Z-Pak in the USA and some other countries.
It is often prescribed for middle-ear infections, strep throat, pneumonia, traveler’s diarrhea, and some other intestinal infections. It can also be used for bacterial sexually transmitted infections. Interestingly, it is occasionally used for malaria.
It is unknown why azithromycin might work for COVID-19, but the terrible study mentioned below used it, which started this story.
Hydroxychloroquine and azithromycin treatment
And let’s get to that starting point for this whole bit of nonsense.
The claims about hydroxychloroquine (HC) and azithromycin (HC+AZ) for COVID-19 started with an article published in the International Journal of Antimicrobial Agents, a moderately low impact factor journal. It is my opinion, shared by many, that something of this importance should have been published in a major biomedical journal as a rapid communication. It’s not that we should dismiss it because of where it’s published, but it is somewhat suspicious.
Basically, the authors examined the viral load of the patients after they received hydroxychloroquine and an antibiotic. They determined viral loads using a PCR assay.
At the top level, the experimental design is bad. I mean so bad, that I can’t believe anyone would ever consider this paper publishable. Here’s how they set up study:
- 20 patients from the medical center (IHU-Méditerranée Infection, Marseille, France) who received hydroxychloroquine.
- 3 patients who receive hydroxychloroquine and azithromycin
- 16 so-called control patients from another center.
The study is tiny, nowhere near enough to consider any results statistically significant. There was no randomization. It was not double-blinded. The “controls” were not patients who were in the same medical center, who would, presumably, receive the same kinds of treatment. And let’s not forget that in all clinical trials, the control group is blinded to both the patient and the treating physician.
According to a thorough analysis of this study by Skepchick:
That means that you analyze everyone enrolled in the study, regardless of whether they complete the trial or not. This allows the effects of death, non-compliance, cessation of treatment because the side effects are intolerable, etc, to be included and for the impacts of a treatment to be fully considered beyond a narrow group. It gives you more of the drug’s true effect, not simply the effect in the best, most compliant patients.
In the H (hydroxychloroquine) group, participants who stopped taking the drug, died, or went to the ICU were not included. This is hugely problematic because the criteria were not applied uniformly and the outcome in the H group may be the result of only including very robust participants. Patients that are dead or in the ICU and not monitored may have higher viral loads that would not be reflected in the data if these participants are eliminated.
There are two other scientists whom I trust that have ripped this study into little pieces – you can read what they said here.
Hydroxychloroquine and azithromycin – another study
A new study, that has not been peer-reviewed or published as of this date, retrospectively examined 368 male Veteran’s Administration patients based on their exposure to hydroxychloroquine alone, or with azithromycin as treatments in addition to standard supportive management for COVID-19. The two main outcomes were mortality or the need for mechanical ventilation.
About 28% who were given hydroxychloroquine plus usual care died, versus 11% of those getting routine care alone. About 22% of those getting the drug plus azithromycin died too, but the difference between that group and usual care was not considered large enough to rule out other factors that could have affected survival.
Hydroxychloroquine made no difference in the need for a breathing machine, either.
Researchers did not track the adverse effects of the HC+AZ combination but they noted a hint that hydroxychloroquine might have damaged other organs. As I mentioned above, hydroxychloroquine has long been known to have potentially serious side effects, including altering the heartbeat in a way that could lead to sudden death.
The authors concluded that:
In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.
Although this is still a relatively small observational study, it is more powerful than the poorly-designed and statistically insignificant study published by Gautret et al.
There are several metaphors in this photo.
More hydroxychloroquine studies
There have been several studies, recently published, that continue to show robust evidence that hydroxychloroquine along with azithromycin is ineffective in treating the novel coronavirus. Two observational studies clearly showed that the drugs do not work.
The first study, published in JAMA, concluded that:
Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality.
The second study, published in the New England Journal of Medicine, examined 1,376 patients at New York-Presbyterian Hospital-Columbia University Irving Medical Center in northern Manhattan from March 7 to April 8. The researchers concluded:
In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death.
Clinical guidance at our medical center has been updated to remove the suggestion that patients with Covid-19 be treated with hydroxychloroquine. In our analysis involving a large sample of consecutive patients who had been hospitalized with Covid-19, hydroxychloroquine use was not associated with a significantly higher or lower risk of intubation or death (hazard ratio, 1.04; 95% CI, 0.82 to 1.32). The study results should not be taken to rule out either benefit or harm of hydroxychloroquine treatment, given the observational design and the 95% confidence interval, but the results do not support the use of hydroxychloroquine at present, outside randomized clinical trials testing its efficacy.
Although these are observational studies and not a gold standard randomized, double-blinded, placebo-controlled clinical trial, it does strongly indicate that hydroxychloroquine, with or without azithromycin, is nearly worthless for treatment of COVID-19.
I, and many others, have written that hydroxychloroquine was a bogus treatment for COVID-19 since mid-late March 2020. It’s not that I had some secret inside knowledge, it’s just that the evidence supporting the claims about this drug was incredibly weak. It was just slightly above the level of evidence that we see for things like homeopathy.
In another recent study published in the New England Journal of Medicine, David R. Boulware, M.D., M.P.H. et al. examined the results from a double-blind, placebo-controlled, randomized clinical trial that tested the effect of hydroxychloroquine on preventing a COVID-19 infection. They found that the drug was no better than a placebo.
Boulware et. al. launched the trial in mid-March 2020, enrolling more than 800 adults who were either healthcare workers or first responders who were at a higher risk of exposure to the virus.
The researchers concluded:
After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure.
The analysis found not even a hint of benefit based on race, occupation, age, or comorbidities. In other words, it was useless no matter the risk of serious complications.
Furthermore, and I am somewhat amused by this, the study found no benefit from the use of zinc and vitamin C, which were used in the placebo group.
Let me be clear about this – in this randomized, placebo-controlled, double-blind clinical trial, which is the gold standard of medical research, they found nothing.
So, unless there is some amazing new evidence from a large placebo-controlled, randomized, double-blinded clinical trial that shows overwhelming evidence that hydroxychloroquine has even a tiny benefit in treating or preventing COVID-19, this story should be over.
But, like true zombies, it’s never over.
Not the alien you were looking for.
And back to that demon sperm and aliens
Over the past few days, two new efforts to push hydroxychloroquine for COVID-19 – one that was laughably weird and the other seemed reasonable on the surface, but failed to meet any standard of science.
Let’s talk about the physician who pushed hydroxychloroquine (and subsequently tweeted by Trump) and demon sperm. And here come the zombies.
On 27 July 2020, the right-wing conspiracy website Breitbart “News” released a video that featured a group of doctors who called themselves “America’s Frontline Doctors” that spread across social media. According to the New York Times:
…a group of people calling themselves “America’s Frontline Doctors” and wearing white medical coats spoke against the backdrop of the Supreme Court in Washington, sharing misleading claims about the virus, including that hydroxychloroquine was an effective coronavirus treatment and that masks did not slow the spread of the virus.
The video did not appear to be anything special. But within six hours, President Trump and his son Donald Trump Jr. had tweeted versions of it, and the right-wing news site Breitbart had shared it. It went viral, shared largely through Facebook groups dedicated to anti-vaccination movements and conspiracy theories such as QAnon, racking up tens of millions of views. Multiple versions of the video were uploaded to YouTube, and links were shared through Twitter.
Facebook, YouTube and Twitter worked feverishly to remove it, but by the time they had, the video had already become the latest example of misinformation about the virus that has spread widely.
That was because the video had been designed specifically to appeal to internet conspiracists and conservatives eager to see the economy reopen, with a setting and characters to lend authenticity. It showed that even as social media companies have sped up response time to remove dangerous virus misinformation within hours of its posting, people have continued to find new ways around the platforms’ safeguards.
Remember, they have nothing going for them to support their claims about COVID-19, but I guess the right-wing anti-science crowd ate it up.
But there’s even more. The star of this zombie hoard of nutjobs was a Houston physician and religious minister, Dr. Stella Immanuel. The Daily Beast wrote:
A Houston doctor who praises hydroxychloroquine and says that face masks aren’t necessary to stop transmission of the highly contagious coronavirus has become a star on the right-wing internet, garnering tens of millions of views on Facebook on Monday alone. Donald Trump Jr. declared the video of Stella Immanuel a “must watch,” while Donald Trump himself retweeted the video.
Before Trump and his supporters embrace Immanuel’s medical expertise, though, they should consider other medical claims Immanuel has made—including those about alien DNA and the physical effects of having sex with witches and demons in your dreams.
Immanuel, a pediatrician and a religious minister, has a history of making bizarre claims about medical topics and other issues. She has often claimed that gynecological problems like cysts and endometriosis are in fact caused by people having sex in their dreams with demons and witches.
She alleges alien DNA is currently used in medical treatments, and that scientists are cooking up a vaccine to prevent people from being religious. And, despite appearing in Washington, D.C. to lobby Congress on Monday, she has said that the government is run in part not by humans but by “reptilians” and other aliens.
Hey, I’ve already claimed that I’m part of the reptilian conspiracy, so maybe she’s right.
I don’t have the inclination to deal with their claims or watch the video, but once again, they can yell and scream about demon sex and alien DNA, they failed to bring one femtogram of evidence that hydroxychloroquine has anything but zombies.
An appeal to authority claim
Next up is an op-ed piece that showed up on Newsweek and has zombified across social media. Yes, zombified is a word.
The article, “The Key to Defeating COVID-19 Already Exists. We Need to Start Using It,” was written by Harvey A. Risch, MD, Ph.D., who is a Professor of Epidemiology at Yale School of Public Health. He also touts hydroxychloroquine to treat COVID-19.
Now, Dr. Risch seems like an accomplished researcher, stating that he has over 300 peer-reviewed articles to his name. PubMed lists only 289 at this time, but close enough. But here’s the thing I found curious – the vast majority of his research is in cancer. And that sends off the Appeal to False Authority Bat Signal almost immediately.
In the Newsweek article, Dr. Risch states:
I am referring, of course, to the medication hydroxychloroquine. When this inexpensive oral medication is given very early in the course of illness, before the virus has had time to multiply beyond control, it has shown to be highly effective, especially when given in combination with the antibiotics azithromycin or doxycycline and the nutritional supplement zinc.
On May 27, I published an article in the American Journal of Epidemiology (AJE) entitled, “Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis.” That article, published in the world’s leading epidemiology journal, analyzed five studies, demonstrating clear-cut and significant benefits to treated patients, plus other very large studies that showed the medication safety.
He is referring to an article published in the American Journal of Epidemiology, a fairly low impact-factor journal. Like his opinion piece in Newsweek, the peer-reviewed article was essentially another opinion piece.
He made it seem like it was a “review,” but it did not meet the standards of a meta-review or systematic-review, either of which is considered the most important piece of evidence for science-based medicine. And curiously, he either ignored or criticized all of the clinical evidence that showed that hydroxychloroquine does not work, while giving a lot of credence to easily debunked “evidence” that shows it does work.
In a published reply to Dr. Risch’s article, Dr. Vincent Fleury wrote (and I’ll quote liberally since it is behind a paywall) several key criticisms.
Dr. Fleury started by writing:
A major error is found in the article : Early Outpatient Treatment of Symptomatic, High_Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis, by Harvey Risch, which highlights how the work by Prof. Raoult should be read and considered.
Well, that’s not a good start. Then Dr. Fleury laid out a few key points:
Risch posited that based on the observed number of fatalities among at-risk patients in other studies, one would expect 20% of the 1,466 patients in these 2 cohorts to have died (i.e., approximately 293 patients rather than 7), and therefore the bitherapy of hydroxychloroquine plus azithromycin is 41 times more efficacious than standard of care. After the initial online publication of Dr. Risch’s article, it came to light that 405 of these 1,466 patients were the at-risk patients in Dr Zelenko’s cohort; the remaining 1,061 comprised the whole sample in the study by Million et al. (3). However, as shown in their Table 2, not all of the 1,061 patients had at least 1 comorbid condition that was a risk factor. Adding the numbers of patients with each chronic condition reveals that less than 45% of the total treated sample had such a condition. In addition, because patients often have more than 1 comorbid condition (e.g., obesity and diabetes or obesity and hypertension), the number of patients who were really at risk is presumably far lower. 56 patients are even mere asymptomatic contacts of documented cases.
In other words, the cohorts are flooded with so many confounding factors, it was impossible to determine if there was a difference between those patients who received hydroxychloroquine and those who hadn’t. Those individuals who were claimed to be at risk because of some comorbidity did not have any comorbidities, so their risk of harm was always going to be lower with or without hydroxychloroquine.
That is some bad science there.
Dr. Fleury goes on to criticize, again, the research from D Raoult (which we discussed above) that has been thoroughly dismissed by the whole scientific community.
Another reply to Risch’s opinion piece states:
In his accepted manuscript, Risch (1) criticizes the NIH and the FDA because “these reviews have omitted the two critical aspects of reasoning about these drugs: use of hydroxychloroquine combined with azithromycin or with doxycycline, and use in the outpatient setting.”
We would like to highlight the uncritical appraisal he made on the available evidence and our surprise that such a viewpoint could be accepted in this journal.
Wow, that’s harsh.
Risch’s article ignores all of the valid scientific criticism of the Raoult study that started this nonsense, plus the subsequent evidence that showed that hydroxychloroquine has no (or at best, a very minor) effect on the course and outcomes from COVID-19.
I do not know how someone like Dr. Risch gets a forum to push his beliefs, but I wish it didn’t happen.
Conclusion
I never thought that hydroxychloroquine and azithromycin would have any effect on COVID-19 for lots of reasons. The evidence was weak and I was concerned that there was no biological plausibility that the drugs could have an effect on coronavirus infections.
Even though this COVID-19 pandemic feels like the zombie apocalypse, we ought to ignore zombie claims whether they are from Donald Trump, a bunch of right-wing physicians that think that demon sperm is an issue, or from an apparently legitimate epidemiologist who seems to have gone off the rails.
We still don’t have any evidence supporting even a modest effect on the course and outcomes from a COVID-19 infection. And now we have a better study that shows that it does nothing.
But I, and many others, will stand up to the zombie hoard and try to keep killing them so that this hydroxychloroquine myth doesn’t get out of hand. Well, it may be too late, but for some of us, we avoid that hydroxychloroquine zombie bite.
Citations
- Fleury V. Commentary: Comment on “Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis”. Am J Epidemiol. 2020 Jul 20:kwaa155. doi: 10.1093/aje/kwaa155. Epub ahead of print. PMID: 32685969.
- Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20;:105949. doi: 10.1016/j.ijantimicag.2020.105949.
- Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, Labella A, Manson D, Kubin C, Barr RG, Sobieszczyk ME, Schluger NW. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 May 7;. doi: 10.1056/NEJMoa2012410. [Epub ahead of print] PubMed PMID: 32379955; PubMed Central PMCID: PMC7224609.
- Peiffer-Smadja N, Costagliola D. RE: EARLY OUTPATIENT TREATMENT OF SYMPTOMATIC, HIGH-RISK COVID-19 PATIENTS THAT SHOULD BE RAMPED-UP IMMEDIATELY AS KEY TO THE PANDEMIC CRISIS. Am J Epidemiol. 2020 Jul 20:kwaa151. doi: 10.1093/aje/kwaa151. Epub ahead of print. PMID: 32685975.
- Risch HA. Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis. Am J Epidemiol. 2020 May 27:kwaa093. doi: 10.1093/aje/kwaa093. Epub ahead of print. PMID: 32458969.
- Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, Weinberg P, Kirkwood J, Muse A, DeHovitz J, Blog DS, Hutton B, Holtgrave DR, Zucker HA. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020 May 11;. doi: 10.1001/jama.2020.8630. [Epub ahead of print] PubMed PMID: 32392282; PubMed Central PMCID: PMC7215635.
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