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.
But a small retrospective study showed 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 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
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.
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.
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
- 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.