An old malaria medicine, hydroxychloroquine, has gone viral on the internet. But is it really an antiviral drug?

The medicine has been seen as a potential treatment for Covid-19, the disease caused by the novel coronavirus SARS-CoV-2, almost since outbreaks started. This week it made headlines, due in part to tweets from President Trump and in part because of a small French study of 42 patients that seemed to show that hydroxychloroquine, particularly when combined with the antibiotic azithromycin, helped decrease patients’ levels of coronavirus. Unfortunately, the rumors about the drug’s efficacy have also encouraged some to buy and even consume a similarly named fish tank cleaner; one person has died.

But 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.

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Jun Chen, one of the authors of the Shanghai study, called the French study’s results “interesting” but said they needed to be evaluated in another randomized study.

“Both our study and theirs had many limitations,” Chen wrote. “But personally, I would say that hydroxychloroquine was not a ‘magic’ drug, if there is any antiviral effect. And in fact, hydroxychloroquine has never been effective in any viral diseases, despite its in vitro antiviral activity.” “In vitro antiviral activity” means that the drug stops the virus from infecting cells in the dish.

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The first mention of the Shanghai study came from a paper in The Lancet Global Health, where the results were described as positive. One of the authors of the Lancet paper, Oriol Mitjà, wrote via email that changes on CT scans showed “that the drug has some efficacy” against Covid-19. In the Shanghai study, worsening of the disease that could be picked up on a CT scan happened in 33% of those on hydroxychloroquine (that’s 5 patients) versus 47% of those in the control group (7 patients).

Mitjà was even more optimistic about the French study, saying it has “new and stronger data.”

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But objections have been raised to the French study  paper, even as it’s bounced around the Internet. Fox host Sean Hannity even shared another doctor’s letter on his experience using the hydroxychloroquine/azithromycin combination on his television show on March 23.

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. The Shanghai study, which showed less impact from the treatments, adds to the questions about the French study, wrote Tim Morris, a statistician at the MRC clinical trials unit at University College, London.

“The [French] study gave very little useful information about whether hydroxychloroquine might help,” Morris wrote. “The Shanghai study is better (because they had a meaningful control group) but gives us very little information that hydroxychloroquine doesn’t help.” The data, he wrote, are “compatible with a wide range of possible effects,” which is statistician-speak for, “Nobody knows whether the drug helps or not.”

The Shanghai study, Morris wrote, is a step in the right direction toward some bigger, better trials that are kicking off. The first of these might give some answers in April — a short time when it comes to clinical trials, but potentially after the United States, and particularly New York City, will have seen a tsunami of Covid-19 cases.

Some doctors on the front lines will use these drug combinations, particularly with patients who are so sick they are on ventilators. As one doctor told me, the risks associated with these drugs, like heart rhythm disturbance or worsening psoriasis, don’t warrant not using them in patients who are in serious trouble. But there is also a need to conduct studies of them to find out if they are truly effective. New York Governor Andrew Cuomo signed an executive order saying that pharmacists should not dispense the drugs to treat Covid-19 unless they are part of a clinical trial. Studies for another drug, remdesivir from Gilead Sciences, are expected to read out in the coming weeks.

Zach Weinberg, one of the co-founders of Flatiron Health, a division of Roche, remembers the difficult transition of going from working in online advertising, where his first company was focused, to Flatiron, which is focused on cancer. In software, more data is better. In cancer, the wrong type of data can lead to conclusions that are not only incorrect but dangerous.

“Sometimes people confuse saying, ‘the study doesn’t tell you anything’ with saying the drug doesn’t work,” Weinberg said. “That’s a really important distinction. They’re not the same thing. I’m not saying the drug doesn’t work or does work. What I’m actually saying is nobody knows if the drug works or doesn’t work.”

His lesson: when dealing with a pandemic, listen to experts who are used to grappling with these problems.

“Society tends to put people who’ve been successful in one area on a pedestal, and draw the conclusion that means they’re expert at many things even though the expertise that they had in one area has nothing to do with the other,” Weinberg said.

  • This is a fair, balanced article about the positive and negative aspects of the drugs’ use so far. It even touches on the anecdotal stories (of which there are dozens now and they are very promising….at least in some patients who were NOT getting better on their own). We’ll know in a week or two much more since NY is beginning to try it on a wider group of people, but unfortunately politics is STILL getting in the way of people honestly looking at the situation. On another blog (hilariously titled For Better Science) the writer takes time out to mention that Trump sang the praises of the initial results, so therefore his “cult” would swarm anyone criticizing it. Seriously, how delusional do you have to be to write about science while smearing 40%-50% of the population as stupid because you don’t like who they voted for? We have got to stop this insane need to bash everyone that doesn’t agree with us at every opportunity….especially now when we’re trying to figure out how to stop the implosion of our economy because of our efforts to contain the spread of the virus.

    I’m hoping this works on at least a large percentage of the populace….not because of what politician I like, but because I don’t like watching my friends try to figure out how to feed their children or pay their bills without a job.

  • Obviously, the scientific community believes Plaquenil is promising, which is all that President Trump said. We know it is “promising,” because it has been moved to a Clinical Trial, as opposed to aspirin, which is not. So, it is a waste of everyone’s time to speak to that issue, unless you have no faith in the scientists. My question is, given the amount of positive testing and hospitalizations, why are we not having multi-tiered trials with people who have not tested positive, people who have tested positive, patients who are hospitalized, and patients who have been intubated? Further, those trials should be multi-tiered by dosage. The disease runs its course in days. Results should, therefore, be available in days. Where’s the data? As a researcher, the problem is almost always one of participant recruitment. I see no such problem here. Speaking of data, where is the data for those people who have rheumatoid arthritis? Many of them are taking Plaquenil. Do they show a different incidence than other high risk populations? I am continually amazed at the dearth of data readily available for collection and distribution.

    • One would think it should be already done however, the answer is money. To do a trial you need resources, people to collect the data, analyse the data, publish the data and as investigator time off your regular duties to focus on the trial, all points to money. I have very good idea for treating this virus however due to same limitations, not able to. This is just few steps in a trial, there is so much paper work involved it takes months to get through. Just try filling out NIH application for grant, seems like you need to get PhD in the application process itself.

    • Unfortunately, the new French study with 80 patients did not include the table with individual patient data. They did it for their previous study with 40 patients. Unfortunately, data hoarding hurts now. We urgently need a centralized place to collect all the past and incoming treatment data to accelerate finding a cure. A proof of concept of such a central spreadsheet can be found here:
      https://medium.com/@loladze_81206/manifesto-identifying-a-cure-for-the-covid-19-via-distributed-data-sourcing-and-analysis-9af6a0313198

    • No new in vivo (in human) data of any worth the last few days other than more anecdotal stories. There are several very large clinical trials that are being started in China and the US (NIH) and other countries however that will finally be sufficiently powered. I am a bit worried that they may use too low a dose of HCQ in some cases, and that they may not treat patients early enough in the disease where anti-villas would have an effect. So there are study design problems still in this respect, and that can lead to conflicting study results and mass confusion. But we may see a properly powered and designed study with results published in about two more months.

    • Irakli: Yes I read that article before I made my previous comment, and I still stand by that comment. That paper is not in any way a clinical trial, and it was not designed to be (and they say so in the article), because there is no control arm. They are just reporting data from treating 80 patients, and it gives no visibility as to effectiveness or not of the treatment because there is no way to know how many of them would have recovered without treatment along the same timeframe. So its a pretty useless article and you cannot draw any conclusions from it. Unfortunately Didier Raoult is now refusing to include any controls going forward, because he wants to focus instead on just treating every patient that comes into his clinic, and does not want to focus on research or data that would be useful in showing clinical effectiveness. He says so right in the article and cites a moral obligation to treat everyone now going forward. So we will not see any useful in vivo clinical research studies from him going forward. I know he is a respected immunologist, but he is starting to look like a bit of a whack job to other researchers.

  • I’m 64 .A white male.The only drug I’m on is Irbesartan,75 mg broken in half daily. Slightly high blood pressure.has been under control at the current level for 10 years or so. Last year,I caught what I thought to be flu.After a full week,I went to Dr.I was seeing ,felt very ill.Dr says I had COPD.Prescribed Amoxicillin.After a few days I had severe respiratory distress.Felt like I could barely get oxygen.Back to Dr. He said go home let it work.So I continued daily short walks,lots of water and rest.I very slowly made improvement.I finished all my meds increased walks.It t took at least a month to be much better.After 3 months I finally felt really good once again.I had never been that sick.Im thinking could I have had one of the coronavirus.I guess I will never know.I do not see that Dr any longer.I felt like he almost caused my death. Any thoughts? Thank You, David

    • I think you should have thanked that Dr who saved your life by not putting you in a hospital and getting you hospital acquired infection that could be lethal. If you are or were smoker, the story will be different. However, most of the viral infections can last about 2-3 weeks, however, the body takes much longer to get back to where it used to be. COVID19 was reported in Dec 2019, if you were sick prior to that, it will be unlikely.

    • As you said ‘ malaria drug’, not anti-viral drug. Virus does not have the same biology as a parasite(malaria).

  • I find it ridiculous that the China study posts their results as inconclusive about hydroxy when the therapy is hydroxy and z-pak taken together. The z-pak plays an important part in stopping the replication of the virus so I’m not sure why they are only testing the hydroxy alone.

    • It might be that the Chinese study was started before the preliminary French study results were posted, if so they would not have had a chance to be influenced by that study. I’d have to check the start date if that is available.

    • OK I checked the dates. The Chinese study was started February 6, 2020. The French study preliminary results were first published March 17. So the Chinese study had been designed and was well underway when they first would have seen the French study, hence they did not include an azithromycin treated arm.

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