MYTH: All the hydroxychloroquine hype

Oh man, I have a lot to say about hydroxychloroquine (HCQ). I thought this had died, but with a new viral video, I feel like we’re back at square one, so here we go. Putting this on the blog so that next month when someone hypes it up again, we can revisit.

So here’s the history of HCQ and COVID-19:

1) Bark from the cinchona tree was commonly used by the ancient Incas of South America to combat fevers, and in the 1600s, the bark's fever-reducing properties were brought back to Europe. In 1820, French chemists purified quinine from the bark and constructed a factory in Paris for its production. The new drug gained traction in the medical community and was used to treat malaria-related fevers (https://www.usatoday.com/story/news/factcheck/2020/07/21/fact-check-hydroxychloroquine-hasnt-helped-covid-19-studies-show/5407547002/)

2) The production came to a halt during WW2 and scientists around the world began to look for alternatives. Chloroquine and hydroxychloroquine were then synthesized and discovered to be even safer than quinine. While other more effective medications have been developed for malaria, we also learned that CQ and HCQ improved symptoms of lupus and rheumatoid arthritis. HCQ was approved for these diseases by the USDA in 1956.

**There are published cardiac effects for some patients with HCQ administration, it is not without side effects, though for lupus and RA, the benefits outweigh the risks.

3) In March 2020, papers out of China proposed the use of HCQ due to known effects that can reduce viral uptake and replication and reduce the cytokine storm seen in severe patients (https://www-ncbi.nlm.nih.gov/pmc/articles/PMC7184499/ , http://www.zjujournals.com/med/EN/abstract/abstract41137.shtml)

**Comment: These don’t have any actual data

**Comment 2: By now there have been studies showing efficacy against replication and uptake in petri dishes and culture dishes, however, we will focus on the data in human patients, since that’s what ultimately matters.

4) Released in late March, a highly publicized non-controlled observational study of 86 reported that 84 patients got better on HCQ and azithromycin within 6 days from a hospital in France (https://pubmed.ncbi.nlm.nih.gov/32289548/).

**Comment: It’s important to note that this data was interesting and worth studying further, scientists were very skeptical because there was no evidence that these patients fared better than controls, they may have all recovered even without the medication, and there’s a limitation to retrospective studies, we’re more likely to write papers on data that’s positive and shows an effect.

5) President Trump then began to massively play up the potential of this drug, calling it a game changer (https://www.statnews.com/2020/04/06/trump-hydroxychloroquine-fact-check/), and on March 28th, the FDA approves HCQ for emergency use in COVID-19 (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-30-2020).

**Comment: Due to the interesting results proposed out of China and preprints from France, the FDA felt that the potential benefit was high enough to allow doctors to treat their patients with HCQ for COVID, despite the limited amount of evidence available at the time. Emergency use is often approved for new diseases that haven’t been well studied or when preliminary results of medications used off label (for something it’s not already approved for) show dramatic improvements.

**Comment 2: That being said, scientists and statisticians were already very critical of the data coming out of both France and China (https://zenodo.org/record/3725560#.XyDiCx17kUv)

6) In May, a larger study from the same group looked back at patient records and found 1061 patients on HCQ and azithromycin (https://pubmed.ncbi.nlm.nih.gov/32387409/). Data showed that 973 of those patients fared well, with only 8 deaths, 46 transferred to the ICU or hospitalized for more than 10 days, and 5 still in the hospital at the time of publication.

**Comment: There’s still no control group.

7) In early June, we started to see data from controlled prospective studies (designed ahead of time) published and in preprints that dim any hopes of HCQ as a miracle drug. A few small controlled trials of HCQ+azithromycin showed no benefit over the control (https://pubmed.ncbi.nlm.nih.gov/32240719/) or were severely flawed, reporting HCQ improvements after removing the HCQ patients who were transferred to the ICU and died from their analysis (https://pubmed.ncbi.nlm.nih.gov/32205204/).

Three larger clinical trials out of Minnesota, the UK, and Spain, that showed no significant difference in treatments between control and HCQ in newly exposed patients and those with more severe disease (https://www.nejm.org/doi/full/10.1056/NEJMoa2016638, https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3615997 , https://www.recoverytrial.net/files/hcq-recovery-statement-050620-final-002.pdf ). A meta-analysis which has also complied data from many smaller studies to increase the probability of finding differences if there also showed weak or conflicting evidence for HCQ (https://www.acpjournals.org/doi/10.7326/M20-2496).

**Comment: It should be noted that there was a very concerning paper reporting increased death rates with HCQ at this time, however, there were concerns raised about the data and the authors refused to fully provide the data to the journal for independent analysis. So this paper was retracted and will not be further discussed (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31324-6/fulltext).

8) June 15th, the FDA revoked emergency use for HCQ and CQ outside of clinical trials because the benefits (small) stopped outweighing the risks (severe cardiac issues) (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and).

9) On June 20th, the FDA removed the HCQ arm of their clinical trial, citing no benefit in their data (https://www.nih.gov/news-events/news-releases/nih-halts-clinical-trial-hydroxychloroquine).

10) More recent data that still supports no improvement with HCQ (https://www.medrxiv.org/content/10.1101/2020.07.20.20157651v1).

**Comment: There are still more ongoing clinical trials that will continue to study and monitor the effects of HCQ: https://clinicaltrials.gov/

So new to the story, yesterday, July 27th, there was a viral video posted on Breibart and youtube and social media (red flags: none of these platforms are known for their scientific accuracy in absence of the same information also found on trustworthy sites). The video included a doctor telling a story about the 300 patients she’s cured with HCQ (red flags: anecdotes are not evidence, especially when there are known adverse effects, there’s an absence of scientific consensus, and the pediatrician, Stella Immanuel, and group, America’s Frontline Doctors, are relatively unknown). Now everyone is interested in HCQ again, but there is not new data to suggest any benefits. Also, we need to chat about how she ends the press conference with "any study that doesn't show a benefit is a fake study." THAT IS NOT SCIENCE! You follow the data, you do not get to cherry pick through data to find things that fit your beliefs. Point blank.

Also want to discuss the two articles "cited" by Dr. Immanuel. She first mentions a 2005 "NIH study" that says it works, however, this study looked at CQ against SARS-COV1, a different disease, COVID wasn’t around in 2005. The data from SARS-COV-1 studies absolutely informed scientists and researchers to try any medication effective against that virus first. However, that data just suggests what drugs to test, it does not provide evidence that CQ is effective against SARS-COV-1. Second, this study is entirely done in cells, it cannot be assumed to replicate or work in humans (80% of clinical trials fail after being effective in cells and mice). Third, virology isn’t the official publication of the NIH, and fourth, this study was done at the CDC.. not NIH. https://pubmed-ncbi-nlm-nih-gov.proxy.library.vanderbilt.edu/16115318/

The second study mentioned was an "NIH study" of hiccups that says it works. This research is a case study of one patient in which you tell their story because it's interesting and should be further studies. Anecdotes are not evidence, the hiccups might’ve gone away without HCQ, and just because the hiccups went away after treatment, that doesn't prove they're linked to COVID. Also, when someone tells you that a study “proves” something, run far far away. Finally, this study was also not conducted at the NIH, this was reported from doctors in a county hospital ER. https://pubmed.ncbi.nlm.nih.gov/32345563/

Update: I will also add the Henry Ford Health System study as this is a big one people are referencing. This was a retrospective observational study in which researchers found medical records for those on HCQ, azithromycin, HCQ+azithro, or none of the above. While this provides a better control than no control group at all, there is still very little control over the treatments patients are receiving, especially for a brand new virus that we were rapidly learning about back in March and April. For example, ~80% of the HCQ and HCQ+azithro patients were on steroids, whereas on ~30% of the azithro or control patients were on steroids. There was also a significant difference with anti-IL-6 medications, which suggests that we cannot know if improved recovery was due to HCQ, steroids, or something else. And the most important piece of information here is that steroids have shown clinical benefit in controlled trials, making the causality here even less clear. https://www.ijidonline.com/article/S1201-9712(20)30534-8/fulltext

Last, let's just mention the non-HCQ related things: 1) The Tea Party Patriots Foundation funded this and Congressman Rob Norman spoke, so yes it's political. 2) It's fear mongering AF: were not living in a spiderweb of fears, physicians aren't being silenced, there's not a coordinated attack on HCQ. 3) We do not know if children can spread the virus: lack of data is not lack of evidence. 4) Lockdowns do cause other mental health and violence related issues, which is why we want to quickly get this under control- the best way to do so, WEAR A MASK and STOP SPREADING MISINFORMATION. 5) Do they really think Fauci and his colleagues aren't hearing from physicians in a clinic? Do they really think physicians with their patients in these clinical trials are removed from patient care? 6) Comparing Sweden randomly to other countries without delving into the public health measures or their death rate is not helpful. Let's make a blog post about Sweden. 7) Scientists from all over the globe in all aspects of patient care and research are communicating more and sharing data faster than we ever have in history. 8) Publishing your thoughts on Twitter is not evidence. 9) If the schools have been shut down and COVID has been spreading, you cannot conclude that school closures have been causing COVID to spread. OMG.

...

So, let’s address a few reasons why people are grasping so hard to this therapy that is not been shown to be effective against COVID-19 (and what you can do yourself when you find yourself being sucked into new viral videos and conspiracy theories). If you do want to address this topic with others, consider opening a dialogue and listening for the reasons why others are so drawn to the HCQ misinformation.

1) We’re all overwhelmed by the constant news and influx of information on this topic that we’re also desperate for. There are still a lot of unknowns it’s having dramatic influence on our lives- our jobs, our incomes, our childcare, and our sanity. We’re all tired of this pandemic and we want our lives to resume as usual and a proven therapy would make that easy. However, wanting something to be true has never made it true, so a belief in HCQ will only make you feel good for a short period of time. Try a walk outside or a run through the woods or some chocolate instead.

2) We don’t even know where to turn for “the truth” if we tried. There’s just so much information out there, ranging from accurate, to partly true, to completely false: how do you figure out what’s real? Checkout my blog post on how to do your own research for more info: https://www.heathercaslinphd.com/post/do-your-own-research-how-to-determine-the-credibility-of-a-source-and-find-accurate-information

3) Even considering just the legitimate information, we’re tired of seeing “here’s some preliminary evidence, and some preliminary hypotheses, but we don’t know”. There are people who even believe that the legitimate science has dramatically changed many times, but honestly that’s really simplified and not very accurate. This is the scientific process at work- the process that happens over years and decades for every other drug on the market. If the constant slew of preliminary and early data is stressful to see, limit your time reading news articles that cover just one scientific paper, limit your time reading and watching local news for scientific information, and listen for qualifiers and descriptive terms like preliminary, association, and suggests.

4) There are already a lot of anti-science conspiracy beliefs about big pharma, and a cheap “cure” that’s being hidden from the public just feeds into that belief. To counter this, try to spread accurate information about clinical trials that do show promise and call your representatives to enact legislations that removes profits from healthcare and pharmaceuticals. There are amazing scientists working in pharmaceutical development and your real criticisms should be directed towards capitalism.

5) And then there are people who will really just back anything our president says for the good and the bad, those who are adamantly against scientific principles like evolution and homosexuality and climate change who celebrate anytime science appears wrong, and many people who’ve been ignored or legitimately hurt by science and medicine in the past. Any type of middle ground here will be much harder to find, and this is more of a marathon than a sprint, but if you work in the healthcare or research fields, consider working incrementally throughout your career to bridge the gaps. Introduce communities to real scientists, work to have adequate representation in science and medicine, and work to make your practice and your research equitable.

So in conclusion, wear a mask, physical distance, wash your hands, and help limit the spread of COVID-19. We only have one treatment that’s shown any improvement for patients (Remdesivir), and it only shortens length of symptoms by a few days (https://www.nejm.org/doi/full/10.1056/NEJMoa2007764). We are also still months away from vaccine approval, considering all goes well with the current phase 3 trials, and even more months away from widespread distribution. And for the best COVID-related information, moving forward, I suggest https://covidtracking.com/ and https://www.theatlantic.com/. Or checkout these scientists, physicians, and science writers on Twitter (@nataliexdean, @JuliaLMarcus, @angie_rasmussen, @EpiEllie, @CT_Bergstrom, @DrHelenOuyang, @choo_ek, @VirusesImmunity, @yayitsrob, @edyong209) and these amazing ladies on Instagram (@jessicamalatyrivera, @kinggutterbaby, @science.sam).