Hydroxychloroquine and azithromycin for coronavirus – UPDATED with new studies

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Because of an awful study from France published on 20 March 2020, Donald Trump and other non-scientists pushed hydroxychloroquine and azithromycin for coronavirus. Of course, this old dinosaur 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. 

And now we have information that Donald Trump is taking hydroxychloroquine prophylactically (or maybe he has the disease and not saying it). This happened despite the lack of effectiveness, the lack of any data that it can be used as a prophylactic, and the strong evidence that it can cause serious harm.

And now, new observational studies now show that hydroxychloroquine and azithromycin had no positive effect on the course or outcomes from severe cases of COVID-19. Let’s take a look. 

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 pyrimethamineartemisinin, 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 ocellatumso 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

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:

  1. 20 patients from the medical center (IHU-Méditerranée Infection, Marseille, France) who received hydroxychloroquine.
  2. 3 patients who receive hydroxychloroquine and azithromycin 
  3. 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

Update 18 May 2020

Two new observational studies published recently continue to establish that hydroxychloroquine along with azithromycin does 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.

Despite this information, Donald Trump is taking it. Please don’t follow his lead, he’s a moron about anything in medicine or science.

Update 3 June 2020

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 about at the level of evidence that we see for things like homeopathy

In a new 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. 

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, I think I’m done with this story. But who knows, maybe Trump will claim it cures cancer. 

 

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.

Certainly, anything President Trump claims should be immediately dismissed as being useless in medicine, even if he is taking it, a stunning development.

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 nothing. 

Of course, there are amateur scientists, who lack any training in study design, statistics, and the scientific method, want to dismiss this new study based on political expediency rather than actually reading the study. 

Right now, we have nothing, except anecdotes and one really terrible study, to support any claim that hydroxychloroquine and azithromycin have any effect on COVID-19. However, like I’ve said a million times, I am not dogmatic about science – bring published evidence that it works, and I’ll take a look.

But it better be in the form of a large epidemiological or clinical study published in a respected, peer-reviewed journal. Something that Donald Trump has no ability to read. 

Citations



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The Original Skeptical Raptor
Chief Executive Officer at SkepticalRaptor
Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!