What’s the Deal with HCQ? Updated.

What does the Data on HCQ say? 

Updated: October 23, 2020

๐—ง๐—ต๐—ฒ๐—ฟ๐—ฒ ๐—ถ๐˜€ ๐—ฎ ๐—น๐—ผ๐˜ ๐—ผ๐—ณ ๐—ฐ๐—ผ๐—ป๐—ณ๐˜‚๐˜€๐—ถ๐—ผ๐—ป ๐—ผ๐—ป ๐—ต๐˜†๐—ฑ๐—ฟ๐—ผ๐˜…๐˜†๐—ฐ๐—ต๐—น๐—ผ๐—ฟ๐—ผ๐—พ๐˜‚๐—ถ๐—ป๐—ฒ (๐—›๐—–๐—ค) ๐—ฎ๐—ป๐—ฑ ๐˜„๐—ต๐—ฒ๐˜๐—ต๐—ฒ๐—ฟ ๐—ถ๐˜ ๐˜„๐—ผ๐—ฟ๐—ธ๐˜€. Compounded with the new Americaโ€™s Frontline Doctors group and the retracted Lancet study, I thought I could do an easy to understand review of the data so far, and why evidence is more than just data.

 

Image: University of Canberra Library

So far there have been at least half a dozen systematic reviews published on HCQ. Every single one suggests that HCQ is ineffective as a treatment or prophylaxis for Covid-19. Almost all of them state that adverse side effects were more commonly seen with HCQ.
The gold standard in systematic reviews are done by an international group called ๐—–๐—ผ๐—ฐ๐—ต๐—ฟ๐—ฎ๐—ป๐—ฒ ๐—–๐—ผ๐—น๐—น๐—ฎ๐—ฏ๐—ผ๐—ฟ๐—ฎ๐˜๐—ถ๐—ผ๐—ป. They have undertaken a full review of the data on HCQ and this should be published shortly. If you want to understand what goes into one of these reviews, have a read of their protocol publication (see link in references below).
๐™๐™๐™š ๐™ฃ๐™š๐™ญ๐™ฉ ๐™ก๐™š๐™ซ๐™š๐™ก ๐™ช๐™ฃ๐™™๐™š๐™ง ๐™ฉ๐™๐™ž๐™จ ๐™ž๐™จ ๐™ฌ๐™๐™–๐™ฉ ๐™ฌ๐™š ๐™˜๐™–๐™ก๐™ก ๐™๐˜พ๐™๐™จ – ๐™ฅ๐™ง๐™ค๐™จ๐™ฅ๐™š๐™˜๐™ฉ๐™ž๐™ซ๐™š, ๐™ง๐™–๐™ฃ๐™™๐™ค๐™ข๐™ž๐™ฏ๐™š๐™™ ๐™˜๐™ค๐™ฃ๐™ฉ๐™ง๐™ค๐™ก๐™ก๐™š๐™™ ๐™ฉ๐™ง๐™ž๐™–๐™ก๐™จ.

๐—ง๐—ต๐—ฒ  ๐—ฅ๐—˜๐—–๐—ข๐—ฉ๐—˜๐—ฅ๐—ฌ ๐˜€๐˜๐˜‚๐—ฑ๐˜†  ๐˜„๐—ฎ๐˜€ ๐˜„๐—ต๐—ฎ๐˜ ๐—ฟ๐—ฒ๐˜€๐˜‚๐—น๐˜๐—ฒ๐—ฑ ๐—ถ๐—ป ๐—›๐—–๐—ค ๐—ฏ๐—ฒ๐—ถ๐—ป๐—ด ๐—ฑ๐—ถ๐˜€๐—ฐ๐—ผ๐—ป๐˜๐—ถ๐—ป๐˜‚๐—ฒ๐—ฑ ๐˜๐—ผ ๐—ฏ๐—ฒ ๐˜‚๐˜€๐—ฒ๐—ฑ ๐—ฎ๐˜€ ๐—ฎ ๐˜๐—ฟ๐—ฒ๐—ฎ๐˜๐—บ๐—ฒ๐—ป๐˜ ๐—ณ๐—ผ๐—ฟ ๐—–๐—ผ๐˜ƒ๐—ถ๐—ฑ-๐Ÿญ๐Ÿต. This was a large and robust randomized controlled trial led by the U.K. The study recruited a total sample size of 15,000 of which 1542 hospitalized patients were given HCQ and 3132 randomized to standard of care. This study showed us HCQ was not effective in reducing mortality, duration of hospitalization or any disease outcomes. In fact, they showed that HCQ was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death.

The Recovery study also had another arm on dexamethasone – a commonly available corticosteroid that is fairly inexpensive. There is a reason why I mention this arm and the results, keep reading! In this study, 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Dex resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen, but not among those receiving no respiratory support. The hypothesis being that at this stage has more to do with immunopathological (inflammatory immune) response vs active viral infection.
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The SOLIDARITY trial conducted by the WHO evaluated the effects of four potential drug regimens for Covid-19 in 11,266 adult patients across more than 30 countries, one of which was HCQ. HCQ was found to have little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients.

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Several other RCTs have shown similar results with HCQ in different populations (hospitalized, non-hospitalized in early disease, mild-to-moderate disease). See links in references below.
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On pre-exposure prophylaxis, a recent RCT was published on 1483 health care workers who were randomized to HCQ 1x or 2x weekly vs placebo. There was no difference in the development of confirmed or probably Covid-19.

There have been several retrospective, single-arm (ie no comparator/placebo), observational or case series studies done, likely over a 100 at this point. These studies have their role in science, but are unable to provide any certainty or causality. Majority of these showed no benefit with HCQ. A few, however, showed the opposite. ๐—ข๐—ป๐—ฒ ๐˜€๐˜‚๐—ฐ๐—ต ๐˜„๐—ฎ๐˜€ ๐˜๐—ต๐—ฒ ๐—›๐—ฒ๐—ป๐—ฟ๐˜† ๐—™๐—ผ๐—ฟ๐—ฑ ๐˜๐—ฟ๐—ถ๐—ฎ๐—น.
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๐—ง๐—ต๐—ฒ ๐—›๐—ฒ๐—ป๐—ฟ๐˜† ๐—™๐—ผ๐—ฟ๐—ฑ ๐˜€๐˜๐˜‚๐—ฑ๐˜†– a retrospective observational study where they reviewed medical records of 2451 patients who received treatment for Covid-19. Remember that this isnโ€™t a study where they first recruited individuals, then randomized and gave them different medicines. They had no contact with these patients, simply looked back at their records. This study showed a decrease in mortality with HCQ. However, 77% of the patients in the group that received HCQ also received steroids (whereas only 36% received a steroid in the non-HCQ arm).

Remember above how I said the other arm of the Recovery study showed that dexamethasone was shown to be effective in patients with severe disease? This is why that little piece of information is important. This is a huge discrepancy in the groups and it makes it difficult to gauge whether it was the steroid that was actually helpful in these patients or HCQ. Unfortunately, we will not know that from the results of this study.

๐™„๐™ฃ ๐™ฉ๐™๐™š ๐™ฆ๐™ช๐™š๐™จ๐™ฉ ๐™ฉ๐™ค ๐™œ๐™š๐™ฉ ๐™™๐™–๐™ฉ๐™– ๐™ค๐™ช๐™ฉ, ๐™ฉ๐™๐™ค๐™ช๐™จ๐™–๐™ฃ๐™™๐™จ ๐™ค๐™› ๐™จ๐™ฉ๐™ช๐™™๐™ž๐™š๐™จ ๐™ฌ๐™š๐™ง๐™š ๐™ž๐™ฃ๐™ž๐™ฉ๐™ž๐™–๐™ฉ๐™š๐™™ ๐™ž๐™ฃ ๐™– ๐™ซ๐™š๐™ง๐™ฎ ๐™™๐™ž๐™จ๐™ค๐™ง๐™™๐™š๐™ง๐™ก๐™ฎ ๐™›๐™–๐™จ๐™๐™ž๐™ค๐™ฃ. ๐™ˆ๐™ค๐™จ๐™ฉ ๐™ค๐™› ๐™ฉ๐™๐™š๐™จ๐™š ๐™–๐™ง๐™š ๐™ฅ๐™ค๐™ค๐™ง๐™ก๐™ฎ ๐™™๐™š๐™จ๐™ž๐™œ๐™ฃ๐™š๐™™ ๐™–๐™ฃ๐™™ ๐™ก๐™–๐™˜๐™  ๐™จ๐™˜๐™ž๐™š๐™ฃ๐™ฉ๐™ž๐™›๐™ž๐™˜ ๐™ซ๐™–๐™ก๐™ž๐™™๐™ž๐™ฉ๐™ฎ ๐™™๐™ช๐™š ๐™ฉ๐™ค ๐™š๐™ž๐™ฉ๐™๐™š๐™ง ๐™ซ๐™š๐™ง๐™ฎ ๐™จ๐™ข๐™–๐™ก๐™ก ๐™จ๐™–๐™ข๐™ฅ๐™ก๐™š ๐™จ๐™ž๐™ฏ๐™š๐™จ ๐™ค๐™ง ๐™ฅ๐™ค๐™ค๐™ง ๐™ข๐™š๐™ฉ๐™๐™ค๐™™๐™ค๐™ก๐™ค๐™œ๐™ฎ. ๐™๐™๐™ž๐™จ ๐™ž๐™จ ๐™– ๐™๐™ช๐™œ๐™š ๐™ข๐™ž๐™จ๐™จ ๐™ž๐™ฃ ๐™ฉ๐™š๐™ง๐™ข๐™จ ๐™ค๐™› ๐™›๐™ช๐™ฃ๐™™๐™ž๐™ฃ๐™œ, ๐™ง๐™š๐™จ๐™ค๐™ช๐™ง๐™˜๐™š๐™จ ๐™–๐™ฃ๐™™ ๐™ฉ๐™ž๐™ข๐™š.

๐—จ๐—ป๐—ณ๐—ผ๐—ฟ๐˜๐˜‚๐—ป๐—ฎ๐˜๐—ฒ๐—น๐˜† ๐˜๐—ต๐—ฒ ๐—Ÿ๐—ฎ๐—ป๐—ฐ๐—ฒ๐˜ ๐˜€๐˜๐˜‚๐—ฑ๐˜† ๐—ณ๐—ถ๐—ฎ๐˜€๐—ฐ๐—ผ ๐˜„๐—ฎ๐˜€ ๐˜ƒ๐—ฒ๐—ฟ๐˜† ๐˜‚๐—ป๐—ณ๐—ผ๐—ฟ๐˜๐˜‚๐—ป๐—ฎ๐˜๐—ฒ, ๐˜‚๐—ป๐—ฒ๐˜๐—ต๐—ถ๐—ฐ๐—ฎ๐—น ๐—ฎ๐—ป๐—ฑ ๐—ถ๐—ป๐—ฒ๐˜…๐—ฐ๐˜‚๐˜€๐—ฎ๐—ฏ๐—น๐—ฒ. It had to do with a company by the name of Surgisphere, who were collecting data for this study (and several others). When the publication came out in pre-print, there were several discrepancies in data. For example, in the study, data collected from patients in many countries exceeded the total number of Covid-19 patients in the country. To add to this, the company refused to release basic information, such as which hospitals participated in the study, citing contractual privacy. This is inherently incorrect because in typical situations, hospitals generally want to be recognized for their research (especially pivotal ones like this!) and are typically named in the publication as a general practice. They also named several European cities as sites of clinical trials, but when the major hospitals in these cities were contacted, all of them stated they did not participate in these studies. So, then that begs the question – where did this supposed data come from? And this, right here, is the reason why the study was retracted.

๐™๐™๐™ž๐™จ ๐™ž๐™จ ๐™ฌ๐™๐™–๐™ฉ ๐™ง๐™š๐™–๐™ก ๐™จ๐™˜๐™ž๐™š๐™ฃ๐™˜๐™š ๐™ก๐™ค๐™ค๐™ ๐™จ ๐™ก๐™ž๐™ ๐™š. ๐™„ ๐™ง๐™š๐™จ๐™ฅ๐™š๐™˜๐™ฉ ๐™‡๐™–๐™ฃ๐™˜๐™š๐™ฉ ๐™–๐™จ ๐™– ๐™Ÿ๐™ค๐™ช๐™ง๐™ฃ๐™–๐™ก, ๐™„ ๐™—๐™š๐™ก๐™ž๐™š๐™ซ๐™š ๐™ค๐™ฉ๐™๐™š๐™ง ๐™ง๐™ค๐™—๐™ช๐™จ๐™ฉ ๐™–๐™ฃ๐™™ ๐™ซ๐™–๐™ก๐™ž๐™™ ๐™™๐™–๐™ฉ๐™– ๐™ฉ๐™๐™–๐™ฉ ๐™จ๐™๐™ค๐™ฌ๐™จ ๐™ƒ๐˜พ๐™Œ ๐™ž๐™จ ๐™ž๐™ฃ๐™š๐™›๐™›๐™š๐™˜๐™ฉ๐™ž๐™ซ๐™š, ๐™—๐™ช๐™ฉ ๐™„ ๐™–๐™ข ๐™ฉ๐™๐™š ๐™›๐™ž๐™ง๐™จ๐™ฉ ๐™ฉ๐™ค ๐™จ๐™–๐™ฎ ๐™ฉ๐™๐™–๐™ฉ ๐™ฌ๐™๐™–๐™ฉ ๐™๐™–๐™ฅ๐™ฅ๐™š๐™ฃ๐™š๐™™ ๐™ฌ๐™ž๐™ฉ๐™ ๐™ฉ๐™๐™ž๐™จ ๐™จ๐™ฉ๐™ช๐™™๐™ฎ ๐™›๐™ง๐™ค๐™ข ๐™จ๐™ฉ๐™–๐™ง๐™ฉ ๐™ฉ๐™ค ๐™›๐™ž๐™ฃ๐™ž๐™จ๐™ ๐™ฌ๐™–๐™จ ๐™จ๐™๐™–๐™™๐™ฎ, ๐™š๐™ซ๐™š๐™ฃ ๐™ฉ๐™๐™ค๐™ช๐™œ๐™ ๐™ฉ๐™๐™š ๐™ง๐™š๐™จ๐™ช๐™ก๐™ฉ๐™จ ๐™›๐™ž๐™ฉ ๐™ข๐™ฎ ๐™ฃ๐™–๐™ง๐™ง๐™–๐™ฉ๐™ž๐™ซ๐™š. ๐™๐™๐™š ๐™ง๐™š๐™จ๐™ช๐™ก๐™ฉ๐™จ ๐™ค๐™› ๐™– ๐™จ๐™ฉ๐™ช๐™™๐™ฎ ๐™ข๐™š๐™–๐™ฃ ๐™ฃ๐™ค๐™ฉ๐™๐™ž๐™ฃ๐™œ ๐™ž๐™› ๐™ฉ๐™๐™š ๐™ข๐™š๐™ฉ๐™๐™ค๐™™๐™ค๐™ก๐™ค๐™œ๐™ฎ ๐™ž๐™จ ๐™ฅ๐™ง๐™ค๐™—๐™ก๐™š๐™ข๐™–๐™ฉ๐™ž๐™˜. ๐™๐™๐™ž๐™จ ๐™ž๐™จ ๐™˜๐™ง๐™ž๐™ฉ๐™ž๐™˜๐™–๐™ก๐™ก๐™ฎ ๐™ž๐™ข๐™ฅ๐™ค๐™ง๐™ฉ๐™–๐™ฃ๐™ฉ.

๐—œ ๐˜„๐—ฎ๐—ป๐˜ ๐˜๐—ผ ๐—ฒ๐—ป๐—ฑ ๐˜๐—ต๐—ถ๐˜€ ๐—ฏ๐˜† ๐˜๐—ฎ๐—น๐—ธ๐—ถ๐—ป๐—ด ๐—ฏ๐—ฟ๐—ถ๐—ฒ๐—ณ๐—น๐˜† ๐—ฎ๐—ฏ๐—ผ๐˜‚๐˜ ๐˜๐—ต๐—ฒ ๐—ผ๐—ฝ-๐—ฒ๐—ฑ ๐—ฏ๐˜† ๐—›๐—ฎ๐—ฟ๐˜ƒ๐—ฒ๐˜† ๐—ฅ๐—ถ๐˜€๐—ฐ๐—ต ๐—ถ๐—ป ๐—ก๐—ฒ๐˜„๐˜€๐˜„๐—ฒ๐—ฒ๐—ธ. I wonโ€™t spend much time on this as Science Based Medicine has done a great deep dive on this. But three important things to remember:

1- the data included in this op-ed were poor quality evidence and primarily uncontrolled studies or case series.
2- He mentions repeatedly about his article in the American Journal of Epidemiology. Risch forgets to mention that he sits on the editorial board of this journal. This is hugely problematic, because he has a lot of say on what does and does not get published in this journal.
3- Most importantly, he claims this is all due to HCQ being politicized because of it being low cost. In fact, dexamethasone – shown to be effective in certain populations – is also low cost and actually lower in cost compared to HCQ.
๐—ฆ๐—ฎ๐—ณ๐—ฒ๐˜๐˜†
I want to briefly mention the side effect profile of HCQ. Yes, HCQ has existed for many years, but remember that every drug has a risk-benefit profile. A medicine is considered useful for a particular situation when the benefits outweighs the associated risks in that specific situation. HCQ can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia. This is accentuated when given with other drugs that also cause these side effects, such as azithromycin (often given together with HCQ for Covid-19). HCQ is being touted for high-risk individuals, but this is where it gets dangerous because these side effects are much more pronounced in those with heart or kidney issues. The flip side of the safety equation is that it takes away access to HCQ by way of drug shortages for those who need it, specifically for certain autoimmune diseases where the benefits outweigh the risks.

 

 

References:
Hierarchy of evidence:
 
Systematic reviews:
 
 
 
 
 
 
 
RCTs
 
 
 
 
Overall review:
 
Ford study:
 
Data shows Covid-19 studies disorderly:
 
Retracted Lancet study:
 
Havery Risch article in Science Based Medicine:
 
Safety: