Are hydroxychloroquine and azithromycin the key against COVID-19?

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Summary:

I am really interested in reading your opinions on this study. I am not a medical student but I am really interested in medicine.

Main Question or Discussion Point

Hydroxychloroquine and azithromycin have been reported (By SEOM, Sociedad Española de Oncología Médica, by US President and others) to be a promising combination to treat COVID-19.

A study leaded by French doctor Didier Raoult has yielded the following results:

Captura de pantalla (1008).png




Why could such a combination work?

I've been reading that hydroxychloroquine has been proven to be effective against lupus, rheumatic disorders and malaria while azithromycin has been proven to be effective against infections caused by H. influenzae, M. catarrhalis, or S. pneumoniae.

Thank you.
 

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  • #2
Ygggdrasil
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Summary:: I am really interested in reading your opinions on this study. I am not a medical student but I am really interested in medicine.

Hydroxychloroquine and azithromycin have been reported (By SEOM, Sociedad Española de Oncología Médica, by US President and others) to be a promising combination to treat COVID-19.

A study leaded by French doctor Didier Raoult has yielded the following results:

View attachment 259448



Why could such a combination work?

I've been reading that hydroxychloroquine has been proven to be effective against lupus, rheumatic disorders and malaria while azithromycin has been proven to be effective against infections caused by H. influenzae, M. catarrhalis, or S. pneumoniae.

Thank you.
Just because a drug works for one condition, doesn't mean it will work for another. Lupus and rheumatic disorders are autoimmune diseases, so one would expect that drugs that are effective against these conditions to be drugs that suppress the immune system -- definitely not something that one would expect to be useful against a virus. Similarly, azithromycin is an antibiotic that is effective against bacterial infections, but bacteria are different than viruses and generally antibiotics are not prescribed to treat viral infections. Similarly, malaria is caused by a single-celled parasite, which is very different than a virus.

While there is evidence from experiments in test tubes that hydroxychloroquine and azithromycin can inhibit viral replication, how they do so is not very well understood (indeed, the mechanism of how hydroxychloroquine affects malaria, lupus and rheumatoid arthritis is not understood either).

Here's a citation for the paper describing the study of hydroxychloroquine and azithromycin as a COVID-19 treatment, for those who wish to look more carefully at the study, its methodology, and its data:

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
https://www.sciencedirect.com/science/article/pii/S0924857920300996?via=ihub

The study has been criticized for some methodological flaws, however:
Three statisticians published a review of the French study that argued that the way it was designed made the treatments look better than they actually are. They pointed to the lack of randomization, as well as an inappropriate control group composed partly of people who refused to take the drug. They also noted that the study dropped some patients from the analysis — the small study of 42 patients actually only included data from 36.
https://www.statnews.com/2020/03/27/we-dont-know-hydroxychloroquine/

These issues are especially significant for hydroxychloroquine as it is associated with some severe side effects, which would affect which people would choose to take the drug as well as those who would drop out of the treatment group (likely due to these side effects).

Furthermore, a recent randomized trial from China suggests that hydroxychloroquine is not effective against COVID-19:
a second study emerged last week from Shanghai University in China of 30 patients hospitalized for Covid-19. Whether patients received hydroxychloroquine or not, their body temperature returned to normal a day after hospitalization, and the time it took for levels of the virus to become undetectable was comparable. Unlike the study from France, the patients in this study were randomly assigned to either hydroxychloroquine or the control group, which makes the results more reliable.
https://www.statnews.com/2020/03/27/we-dont-know-hydroxychloroquine/

So, while the Raoult paper provides some positive data suggesting that the drug could be effective, it by no means provides definitive data, and data from a larger, better designed trial would be needed to make a better judgement about the therapy's efficacy.
 
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  • #3
morrobay
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What about chloroquine phosphate alone?
 
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Lupus and rheumatic disorders are autoimmune diseases, so one would expect that drugs that are effective against these conditions to be drugs that suppress the immune system -- definitely not something that one would expect to be useful against a virus.
This thinking seems to be too simplistic. The anti-rheumatic mechanism of quinolones simply isn't known; the main hypothesis is that quinolones function mainly in lysosomes.

There is a hypothesis that coronaviruses as well as many other viruses in bats are kept at bay due to the high levels of free radicals produced presumably in the bat cell mitochondria. Does some of this make its way to their lysosomes, strengthening the bat immune system against viruses? Do quinolones lead to any (partially) similar effects in human lysosomes? These are all open questions.

In any case, in actual practice on the ICU quinolones are being used, with clinically varying results. Neglecting the possible efficacy of the treatment in potential use cases based on a single RCT would be throwing out the baby with the bathwater.
 
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The study has been criticized for some methodological flaws, however:
I agree, this study has several severe limitations.

First and most importantly is the small sample size, only 6 patients were treated with the combination (Hydroxychloroquine and Azithromycin), and only 14 with the single drug (Hydroxychloroquine only). In drug studies this is a very, very, small sample. Unfortunately, small samples are plagued with a statistical effect that basically means that any effects that you do detect are inflated substantially by simple random statistical variation, simply by the fact that you did detect them. This is indicated by the 100% response rate, such a response rate is statistics, not reality.

Second is the “look elsewhere effect” which is another statistical phenomenon that inflates the significance of small samples when you are running multiple trials. Currently globally many doctors are trying many different treatments. With all of those doctors running small trials someone somewhere is essentially guaranteed to randomly get 6 responders in their treatment group. This one cannot be avoided in the context of coronavirus. But it means that the first paper on a successful treatment is not the important one. Look for the second paper from a different institution or multiple institutions with a much larger number of patients. That will be the informative paper.

Third, this was a non-randomized study design. That can cause problems, and importantly the patients who served as controls did not receive a placebo. That means that some of the effect will be the placebo effect.

Finally, six of the original Hydroxychloroquine group were excluded from the study. These are patients that began the treatment but whose data were not included in the study because they did not finish the course of treatment. Three did not finish because they were admitted to the ICU and one did not finish because they died. One did not finish because they left the hospital and another did not finish because of nausea. Of the four who died or went to the ICU, I think that it is fair to say that the treatment was ineffective, but their data was excluded.

Overall, I would say that this is a promising initial result and certainly warrants further investigation, but I would not consider it confirmed. If infected I would not make demands for these medicines, but I would definitely ask my doctor about it to see if there have been any follow-up studies demonstrating the effectiveness or in-effectiveness at another institution. Also, a discussion about the dosages and side-effects is important. If needed (God forbid), use it only after discussion with a trusted physician who knows your individual medical history. It may very well turn out to be effective, although I would expect true response rates closer to 50% than to 100%.

The CDC is likely to have the most up to date information, and does reference the above study. Hopefully all healthcare providers are reading the CDC guidance regularly. They seem to have the same attitude that I do. This is definitely worth further investigation, but it is not a recognized treatment yet:

https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html
 
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  • #6
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What about chloroquine phosphate alone?
According to the CDC hydroxychloroquine has "higher in-vitro activity against SARS-CoV-2 and ... wider availability in the United States compared with chloroquine". Also, in the paper posted above by @Ygggdrasil "Hydroxychloroquine clinical safety profile is better than that of chloroquine (during long-term use) and allows higher daily dose and has fewer concerns about drug-drug interactions"
 
  • #7
morrobay
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From an abstract in Journal of Microbial Chemotherapy: In addition to hydroxychloroquine having antivirus replication potential. It is an immune suppressant and so may halt the uncontrolled cytokine release during transition from symptoms to acute respiratory distress.
 
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More Deaths, No Benefit from Malaria Drug in VA Virus Study
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.
 
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  • #9
Tom.G
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The US National Institutes of Health:
https://covid19treatmentguidelines.nih.gov/therapeutic-options-under-investigation/
recommends against the use of the following drugs for the treatment of COVID-19:
  • The combination of hydroxychloroquine plus azithromycin (AIII) because of the potential for toxicities.
One of the other toxicities I've seen referred to is in the EKG of heart electrical activity. (QT interval as I recall)

Here is a link to the study @Keith_McClary referenced, above.

The Veterans Health Administration:
(I can't get COPY to work here!)
Look at page 22 of this retrospective study showing that giving hydroxychloroquine plus azithromycin doubles the death rate from 11% to 22%. (Sounds like the wrong direction!)
https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf

EDIT: Here is a study published in JAMA (Journal of the American Medical Association).

https://jamanetwork.com/journals/ja...mp;utm_campaign=ftm_links&utm_term=042420

It indicates that though there is an antiviral effect, the required dosage is high enough to increase the risk of death.
The major complication, even in short regimens, is the potential for QTc interval prolongation, favoring fatal arrhythmias such as ventricular tachycardia and torsades de pointes.18 The in vitro antiviral activity of CQ was first identified in the late 1960s.19,20 Two studies have shown anti–SARS-CoV activity, with high concentrations needed for antiviral effect.9,11
Cheers,
Tom
 
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  • #10
chemisttree
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The US National Institutes of Health:
https://covid19treatmentguidelines.nih.gov/therapeutic-options-under-investigation/


One of the other toxicities I've seen referred to is in the EKG of heart electrical activity. (QT interval as I recall)

Here is a link to the study @Keith_McClary referenced, above.

The Veterans Health Administration:
(I can't get COPY to work here!)
Look at page 22 of this retrospective study showing that giving hydroxychloroquine plus azithromycin doubles the death rate from 11% to 22%. (Sounds like the wrong direction!)
https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf

Cheers,
Tom
Also from that study...

The nationwide study was not a rigorous experiment.
 
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  • #11
chemisttree
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The Veterans Health Administration:

(I can't get COPY to work here!)

Look at page 22 of this retrospective study showing that giving hydroxychloroquine plus azithromycin doubles the death rate from 11% to 22%. (Sounds like the wrong direction!)

https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf



Cheers,

Tom
I’m sorry but that is NOT what the study shows. This retrospective study shows absolutely nothing! Some of the important points illustrating the nonsensical information in this study:

1). From the study:

Because the number of female patients in this cohort (17) was too small to permit robust statistical analyses, we evaluated the remaining 368 male patients in this study. Patients were categorized into three different groups: those treated with hydroxychloroquine (HC, n=97), treated with hydroxychloroquine and azithromycin (HC+AZ, n=113), or unexposed to hydroxychloroquine (no HC, n=158) (Table 1). All patients received standard supportive management. There were significant differences among the three groups in baseline demographic characteristics, selected vital signs, laboratory tests, prescription drug use, and comorbidities
This is a male only study. There were significant differences for EVERYTHING THAT MATTERS! Demographics, vital signs, lab tests, comorbidities as determined by prescription drug use. Two thirds were black. Two thirds of the ‘control’ group (no HC) were actually taking azithromycin! All were clinically obese. The treatment group had significantly lower initial pulse ox and significantly higher temperatures (>38.1C). About a quarter of all had congestive heart failure. The study states:

Baseline demographic and comorbidity characteristics were comparable across the three treatment groups. However, hydroxychloroquine, with or without azithromycin, was more likely to be prescribed to patients with more severe disease, as assessed by baseline ventilatory status and metabolic and hematologic parameters. Thus, as expected, increased mortality was observed in patients treated with hydroxychloroquine, both with and without azithromycin.
Whats it called when you select test and control subjects non-randomly? Selection bias!

Despite propensity score adjustment for a large number of relevant confounders, we cannot rule out the possibility of selection bias or residual confounding.
In fact, their previous statement that the treatment group was, at least in part, selected because of their more severe symptoms, practically guarantees a worse outcome for the treatment group.

2). Conflicting statements.

There were significant differences among the three groups in baseline demographic characteristics, selected vital signs, laboratory tests, prescription drug use, and comorbidities....
...As baseline characteristics corresponding to clinical severity varied across the three groups of patients and could have influenced the non-randomized utilization of hydroxychloroquine and azithromycin, ....
VS

Baseline demographic and comorbidity characteristics were comparable across the three treatment groups.
Sounds like a masseuse wrote this!

3). No control for time of treatment with respect to onset of symptoms. We DO know that their symptoms had progressed to the point that all subjects required hospitalization. This is important since antivirals need to be given EARLY, not when things are bad enough to require hospitalization.

4). NO DATA REGARDING DOSAGE. Who even tries to evaluate something like this when such a fundamental variable is unknown?

5). Politics with my science?

Among the myriad therapeutics advanced as potential repurposing candidates for Covid-19, the antimalarial and immunomodulatory drug hydroxychloroquine has captured great attention following an open- label, non-randomized, single treatment center study that reported efficacy of hydroxychloroquine and a potential synergistic effect with the macrolide antibiotic azithromycin,
in improving viral clearance in Covid-19 patients. The resulting spotlight and public interest has led to its soaring utilization in Covid-19, drug shortages impacting its use in labeled indications, and stockpiling by countries.
They think public interest led to all that? Not the virus itself or the recommendations of the doctors in China?
https://pubmed.ncbi.nlm.nih.gov/32074550/
 
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  • #12
Tom.G
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Thanks for the critique on the report @chemisttree! Obviously I didn't read the whole thing before posting the link. I'm glad that someone with a sufficient background payed attention to it.

Cheers,
Tom
 
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Luckily we still have intravenous disinfectant therapy......
 
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  • #15
nrqed
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Luckily we still have intravenous disinfectant therapy......
But it won't help, the virus is obviously caused by climate change :-)
 
  • #16
jim mcnamara
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In case you missed it the answer is no - the drugs are not shown to be beneficial.
Well, let's give up on this thread. Thread closed. Thanks to everyone for participating.
 
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