What’s the Deal with HCQ? Updated.
What does the Data on HCQ say?
Updated: October 23, 2020
𝗧𝗵𝗲𝗿𝗲 𝗶𝘀 𝗮 𝗹𝗼𝘁 𝗼𝗳 𝗰𝗼𝗻𝗳𝘂𝘀𝗶𝗼𝗻 𝗼𝗻 𝗵𝘆𝗱𝗿𝗼𝘅𝘆𝗰𝗵𝗹𝗼𝗿𝗼𝗾𝘂𝗶𝗻𝗲 (𝗛𝗖𝗤) 𝗮𝗻𝗱 𝘄𝗵𝗲𝘁𝗵𝗲𝗿 𝗶𝘁 𝘄𝗼𝗿𝗸𝘀. Compounded with the new America’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 𝗖𝗼𝗰𝗵𝗿𝗮𝗻𝗲 𝗖𝗼𝗹𝗹𝗮𝗯𝗼𝗿𝗮𝘁𝗶𝗼𝗻. 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).
𝙏𝙝𝙚 𝙣𝙚𝙭𝙩 𝙡𝙚𝙫𝙚𝙡 𝙪𝙣𝙙𝙚𝙧 𝙩𝙝𝙞𝙨 𝙞𝙨 𝙬𝙝𝙖𝙩 𝙬𝙚 𝙘𝙖𝙡𝙡 𝙍𝘾𝙏𝙨 – 𝙥𝙧𝙤𝙨𝙥𝙚𝙘𝙩𝙞𝙫𝙚, 𝙧𝙖𝙣𝙙𝙤𝙢𝙞𝙯𝙚𝙙 𝙘𝙤𝙣𝙩𝙧𝙤𝙡𝙡𝙚𝙙 𝙩𝙧𝙞𝙖𝙡𝙨.
𝗧𝗵𝗲 𝗥𝗘𝗖𝗢𝗩𝗘𝗥𝗬 𝘀𝘁𝘂𝗱𝘆 𝘄𝗮𝘀 𝘄𝗵𝗮𝘁 𝗿𝗲𝘀𝘂𝗹𝘁𝗲𝗱 𝗶𝗻 𝗛𝗖𝗤 𝗯𝗲𝗶𝗻𝗴 𝗱𝗶𝘀𝗰𝗼𝗻𝘁𝗶𝗻𝘂𝗲𝗱 𝘁𝗼 𝗯𝗲 𝘂𝘀𝗲𝗱 𝗮𝘀 𝗮 𝘁𝗿𝗲𝗮𝘁𝗺𝗲𝗻𝘁 𝗳𝗼𝗿 𝗖𝗼𝘃𝗶𝗱-𝟭𝟵. 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.
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.
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.
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. 𝗢𝗻𝗲 𝘀𝘂𝗰𝗵 𝘄𝗮𝘀 𝘁𝗵𝗲 𝗛𝗲𝗻𝗿𝘆 𝗙𝗼𝗿𝗱 𝘁𝗿𝗶𝗮𝗹.
𝗧𝗵𝗲 𝗛𝗲𝗻𝗿𝘆 𝗙𝗼𝗿𝗱 𝘀𝘁𝘂𝗱𝘆– a retrospective observational study where they reviewed medical records of 2451 patients who received treatment for Covid-19. Remember that this isn’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.
𝙄𝙣 𝙩𝙝𝙚 𝙦𝙪𝙚𝙨𝙩 𝙩𝙤 𝙜𝙚𝙩 𝙙𝙖𝙩𝙖 𝙤𝙪𝙩, 𝙩𝙝𝙤𝙪𝙨𝙖𝙣𝙙𝙨 𝙤𝙛 𝙨𝙩𝙪𝙙𝙞𝙚𝙨 𝙬𝙚𝙧𝙚 𝙞𝙣𝙞𝙩𝙞𝙖𝙩𝙚𝙙 𝙞𝙣 𝙖 𝙫𝙚𝙧𝙮 𝙙𝙞𝙨𝙤𝙧𝙙𝙚𝙧𝙡𝙮 𝙛𝙖𝙨𝙝𝙞𝙤𝙣. 𝙈𝙤𝙨𝙩 𝙤𝙛 𝙩𝙝𝙚𝙨𝙚 𝙖𝙧𝙚 𝙥𝙤𝙤𝙧𝙡𝙮 𝙙𝙚𝙨𝙞𝙜𝙣𝙚𝙙 𝙖𝙣𝙙 𝙡𝙖𝙘𝙠 𝙨𝙘𝙞𝙚𝙣𝙩𝙞𝙛𝙞𝙘 𝙫𝙖𝙡𝙞𝙙𝙞𝙩𝙮 𝙙𝙪𝙚 𝙩𝙤 𝙚𝙞𝙩𝙝𝙚𝙧 𝙫𝙚𝙧𝙮 𝙨𝙢𝙖𝙡𝙡 𝙨𝙖𝙢𝙥𝙡𝙚 𝙨𝙞𝙯𝙚𝙨 𝙤𝙧 𝙥𝙤𝙤𝙧 𝙢𝙚𝙩𝙝𝙤𝙙𝙤𝙡𝙤𝙜𝙮. 𝙏𝙝𝙞𝙨 𝙞𝙨 𝙖 𝙝𝙪𝙜𝙚 𝙢𝙞𝙨𝙨 𝙞𝙣 𝙩𝙚𝙧𝙢𝙨 𝙤𝙛 𝙛𝙪𝙣𝙙𝙞𝙣𝙜, 𝙧𝙚𝙨𝙤𝙪𝙧𝙘𝙚𝙨 𝙖𝙣𝙙 𝙩𝙞𝙢𝙚.
𝗨𝗻𝗳𝗼𝗿𝘁𝘂𝗻𝗮𝘁𝗲𝗹𝘆 𝘁𝗵𝗲 𝗟𝗮𝗻𝗰𝗲𝘁 𝘀𝘁𝘂𝗱𝘆 𝗳𝗶𝗮𝘀𝗰𝗼 𝘄𝗮𝘀 𝘃𝗲𝗿𝘆 𝘂𝗻𝗳𝗼𝗿𝘁𝘂𝗻𝗮𝘁𝗲, 𝘂𝗻𝗲𝘁𝗵𝗶𝗰𝗮𝗹 𝗮𝗻𝗱 𝗶𝗻𝗲𝘅𝗰𝘂𝘀𝗮𝗯𝗹𝗲. 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.
𝙏𝙝𝙞𝙨 𝙞𝙨 𝙬𝙝𝙖𝙩 𝙧𝙚𝙖𝙡 𝙨𝙘𝙞𝙚𝙣𝙘𝙚 𝙡𝙤𝙤𝙠𝙨 𝙡𝙞𝙠𝙚. 𝙄 𝙧𝙚𝙨𝙥𝙚𝙘𝙩 𝙇𝙖𝙣𝙘𝙚𝙩 𝙖𝙨 𝙖 𝙟𝙤𝙪𝙧𝙣𝙖𝙡, 𝙄 𝙗𝙚𝙡𝙞𝙚𝙫𝙚 𝙤𝙩𝙝𝙚𝙧 𝙧𝙤𝙗𝙪𝙨𝙩 𝙖𝙣𝙙 𝙫𝙖𝙡𝙞𝙙 𝙙𝙖𝙩𝙖 𝙩𝙝𝙖𝙩 𝙨𝙝𝙤𝙬𝙨 𝙃𝘾𝙌 𝙞𝙨 𝙞𝙣𝙚𝙛𝙛𝙚𝙘𝙩𝙞𝙫𝙚, 𝙗𝙪𝙩 𝙄 𝙖𝙢 𝙩𝙝𝙚 𝙛𝙞𝙧𝙨𝙩 𝙩𝙤 𝙨𝙖𝙮 𝙩𝙝𝙖𝙩 𝙬𝙝𝙖𝙩 𝙝𝙖𝙥𝙥𝙚𝙣𝙚𝙙 𝙬𝙞𝙩𝙝 𝙩𝙝𝙞𝙨 𝙨𝙩𝙪𝙙𝙮 𝙛𝙧𝙤𝙢 𝙨𝙩𝙖𝙧𝙩 𝙩𝙤 𝙛𝙞𝙣𝙞𝙨𝙝 𝙬𝙖𝙨 𝙨𝙝𝙖𝙙𝙮, 𝙚𝙫𝙚𝙣 𝙩𝙝𝙤𝙪𝙜𝙝 𝙩𝙝𝙚 𝙧𝙚𝙨𝙪𝙡𝙩𝙨 𝙛𝙞𝙩 𝙢𝙮 𝙣𝙖𝙧𝙧𝙖𝙩𝙞𝙫𝙚. 𝙏𝙝𝙚 𝙧𝙚𝙨𝙪𝙡𝙩𝙨 𝙤𝙛 𝙖 𝙨𝙩𝙪𝙙𝙮 𝙢𝙚𝙖𝙣 𝙣𝙤𝙩𝙝𝙞𝙣𝙜 𝙞𝙛 𝙩𝙝𝙚 𝙢𝙚𝙩𝙝𝙤𝙙𝙤𝙡𝙤𝙜𝙮 𝙞𝙨 𝙥𝙧𝙤𝙗𝙡𝙚𝙢𝙖𝙩𝙞𝙘. 𝙏𝙝𝙞𝙨 𝙞𝙨 𝙘𝙧𝙞𝙩𝙞𝙘𝙖𝙡𝙡𝙮 𝙞𝙢𝙥𝙤𝙧𝙩𝙖𝙣𝙩.
𝗜 𝘄𝗮𝗻𝘁 𝘁𝗼 𝗲𝗻𝗱 𝘁𝗵𝗶𝘀 𝗯𝘆 𝘁𝗮𝗹𝗸𝗶𝗻𝗴 𝗯𝗿𝗶𝗲𝗳𝗹𝘆 𝗮𝗯𝗼𝘂𝘁 𝘁𝗵𝗲 𝗼𝗽-𝗲𝗱 𝗯𝘆 𝗛𝗮𝗿𝘃𝗲𝘆 𝗥𝗶𝘀𝗰𝗵 𝗶𝗻 𝗡𝗲𝘄𝘀𝘄𝗲𝗲𝗸. I won’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.
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.
Data shows Covid-19 studies disorderly:
Havery Risch article in Science Based Medicine: