Recently, a friend who works in the ER wrote to ask me about hydroxychloroquine.
Yes, I know. I was shocked, too. But my friend was sincere. Although most reputable news outlets have publicized that hydroxychloroquine doesn’t work against Covid-19, my friend read an article from Harvey Risch in Newsweek that seemed really compelling.
Risch has impeccable credentials – he’s an M.D. Ph.D. and a professor of epidemiology at Yale’s School of Public Health. And a lot of what he wrote for his July 23rd article is quite sensible:
Why has hydroxychloroquine been disregarded?
First, as all know, the medication has become highly politicized. For many, it is viewed as a marker of political identity, on both sides of the political spectrum. Nobody needs me to remind them that this is not how medicine should proceed.
Medical data isn’t perfect, and confirmation bias is very real. So there’s a chance that medical doctors really could hoodwink themselves into discounting a helpful medication, the same way that so many medical doctors get suckered into overprescribing drugs after pharmaceutical companies bribe them with gifts. Yup, medical doctors are human, too.
I know that I’m so dismayed by our current president that I’m inclined to distrust hydroxychloroquine just because he says the drug is great.
So it was a shock for me to read Risch’s article. He wrote that there was data showing that hydroxychloroquine, when used in a combination therapy early during a high-risk person’s Covid-19 infection, could dramatically reduce the risk of serious complications. If more people took hydroxychloroquine, he wrote, fewer would die.
Risch acknowledges that hydroxychloroquine is dangerous – it might kill 1 out of each 10,000 people who take it – but Covid-19 is obviously dangerous, too – it kills 3 out of each 1,000 people who contract it:
In the future, I believe this misbegotten episode regarding hydroxychloroquine will be studied by sociologists of medicine as a classic example of how extra-scientific factors overrode clear-cut medical evidence.
But for now, reality demands a clear, scientific eye of the evidence and where it points. For the sake of high-risk patients, for the same of our parents and grandparents, for the sake of the unemployed, for our economy and for our polity, especially those disproportionately affected, we must start treating immediately.
Those are strong words. And, really, the Newsweek article felt persuasive to me. And so I looked up Risch’s research in the American Journal of Epidemiology, hoping to see the actual data in support of his claims.
I’m lucky, that way. I’m a scientist, so I don’t have to trust the words of a supposed expert. I’m an expert. I get to look at the data.
The data are much less compelling than Risch’s words.
Risch discusses the results of an uncontrolled study by Vladimir Zelenko, a medical doctor in Monroe, New York: “For example, among Connecticut cases 60 years of age or older, at present the mortality is 20%. Thus it would be ballpark to estimate that some 20% of the 1466 treated high-risk patients in the Zelenko cohort would have died without outpatient hydroxychloroquine plus antibiotic.”
This is an egregiously inaccurate statement. The high death rate cited – 20 – is for older patients who test positive for Covid-19 and have such severe symptoms that they need to be hospitalized.
As described in the short statement released by Zelenko, he treated 405 people who visited his office complaining of mild cough, fever, headache, sore throat, or diarrhea. His patients were not given a Covid-19 test. Presumably, many were never infected with Covid-19.
It is not a surprise to see that a 60-year-old patient who takes hydroxychloroquine after developing a sore throat from seasonal allergies is less likely to die than a 60-year-old patient who is diagnosed with Covid-19 in the hospital.
Of Zelenko’s 405 patients, at least two 2 died. This is lower than the expected 1% mortality rate of high-risk patients who contract Covid-19. But this set of 405 patients included low-risk patients experiencing shortness of breath and high-risk patients experiencing mild headache, many of whom never had Covid-19.
Zelenko’s report is two pages long and written in extremely lucid prose. Risch either totally misread it, which is galling, or intentionally mis-described it, which is worse.
So, why was Zelenko giving people hydroxychloroquine in the first place?
Well, I’d heard that an in vitro study – which means “inside a test tube or petri dish, not a person” – showed that hydroxychloroquine reduced Covid-19 viral replication. But I hadn’t read the original paper. So I looked it up.
It should have taken me less than a minute to find this paper. Unfortunately, people have been pretty sloppy with their references. I get it. Covid-19 is scary, and it’s urgent, so people are publishing faster than usual.
I assumed that I could pull up almost any paper on hydroxychloroquine and Covid-19 and quickly find the citation for the original study. Indeed, most purport to be citing it. But in this, the citation that ought to have pointed to that study instead sent me to a paper on the differentiation of lung stem cells, and in this, the relevant citation incorrectly points to a paper on the drug lopinavir.
Ugh. I mean, these bungled citations aren’t that big a deal for me, personally – just means I had to give up on piggybacking and instead search Pubmed. But it undermines trust when you can’t get the little things right.
Anyway, the earliest reference that I found was from Liu et al., their study “Hydroxychloroquine, a less toxic derivative of chloroquine, is effective at inhibiting SARS-CoV-2 infection in vitro.” And, yes, I’ll admit – I thought about putting in the wrong link just to mess with you. But, if I did that, would you still trust me about the rest of this?
Liu et al. used Vero cells – a cell line derived from a kidney cancer in African green monkeys – and for Figure 1, they measured both how much hydroxychloroquine it takes to kill cells (about 200 micromolar is a cytotoxic dose) and how much hydroxychloroquine it takes to inhibit viral infection (about a 10 micromolar dose).
Okay. To me, that’s already sounding a little spooky. The bigger the difference between an effective dose and a lethal dose, the safer you are.
That’s why a bunch of hippies died after The Teachings of Don Juan was published. That book touted jimsomweed as a psychedelic. Indeed, the plant contains a high concentration of scopolamine, which can give people nightmarish visions of flying. It’s a powerful hallucinogen. But the effective dose is quite close to the lethal dose – when curious kids try to get high off it, they’re flirting with death.
Everyone’s body is a little different from everyone else’s. Maybe a dose that’s safe for you would kill me. The odds of disaster are worse when the effective dose and lethal dose are similar.
So, Liu et al. saw cytotoxicity kick in at around 100 micromolar hydroxychloroquine, getting pretty high by 200 micromolar. And for their visual assay of viral infection, they bathed their Vero cells in 50 micromolar hydroxychloroquine.
To block viral entry, they were coming pretty close to just killing these cells with the drug.
And the problem is even worse inside a human body. You take a drug and it gets into your bloodstream. It’ll reach some concentration there. This is the concentration that matters most for toxicity.
But the drug will only be effective against Covid-19 when it reaches your lungs. When Marzolini et al. used mass spectrometry to measure how much of hydroxychloroquine was actually getting from a patient’s blood to their lungs, they found that it wasn’t at a high enough concentration to reproduce any effects seen in vitro.
Indeed, a randomized clinical study showed that hydroxychloroquine fails as a post-exposure prophylaxis. The drug was given to people who were worried about exposure because they’d spent time with someone who tested positive for Covid-19. The drug didn’t help – these people contracted the infection at the same rate as people who were given a placebo.
A randomized clinical study also showed that hydroxychloroquine fails as a cure. People who visited a hospital and tested positive for Covid-19 but had mild symptoms were given the drug. Their disease was just as likely to progress as people who received a placebo.
Hydroxychloroquine doesn’t work, and it’s toxic.
I was left wondering: why would Risch write these things? Why would he write that article for Newsweek? He’s clearly intelligent, and, from the tone of his writing, I feel confident that he wants to help people.
He might even believe wholeheartedly in the conclusion he’s presenting.
That’s generally true among scientists. Confirmation bias is insidious.
That paper from the team at Harvard? They did some modeling and argued that, if Covid-19 is seasonal, we will save most lives by periodically shutting down. But their model left out the waning immunity that would cause Covid-19 to be seasonal! Whoops. That’s why they reached the wrong conclusion.
Or the recent New York Times editorial from Iwasaki and Medzhitov, both professors of immunobiology at Yale, reassuring readers that they won’t get Covid-19 twice. Well, that’s not correct.
Some antigens confer immunity that lasts about as long as our lives. Most don’t. Influenza immunity lasts months, not years. The paper that Iwasaki and Medzhitov cited in their article, a study in which people were intentionally infected with a less dangerous coronavirus, found that immunity to that virus lasted months, not years.
Covid-19 immunity will not last forever. The relevant question isn’t whether you can be infected again, it’s how soon you can be re-infected. With the data we have so far, it’s reasonable to expect that the answer will be measured in months, not years.
There’s some good news – the second time you contract Covid-19, it’ll probably be less severe than the first. In addition to antibodies, your immune system has “T cell memory” to help you fight off subsequent infections. But, as is also described in the paper cited by Iwasaki and Medzhitov, even people who felt fine were shedding virus again the second time they were infected.
During the second infection, the research subjects were shedding viral particles for a shorter period of time. But, especially with Covid-19 – a virus that can be transmitted simply by talking – a person who sheds virus for a short time while feeling fine is probably more likely to transmit the disease than somebody who sheds virus for a whole week while feeling like garbage.
The person who feels like garbage will stay home. The person who feels fine won’t.
Still, though, I was left wondering – what underlying beliefs would sway Risch enough that he’d make these blunders?
Eventually, I decided to lump his motivation in with mine. Maybe that’s fair, maybe it’s not. Really, I have no idea what he was thinking, so this is just my best guess.
But I imagine that many of these people – Risch, Iwasaki, Medzhitov, John Ioannidis, David Katz, all of whom are very smart, and all of whom mean well – understand that the strategies we’re using against Covid-19 are both ineffectual and are causing harm.
No shutdown will eliminate Covid-19 – the best we can do is to delay it. And we can delay it only as long as we maintain the shutdown. Maybe that seems fine if you’re an older, wealthy person brimming with optimism about vaccine development, like Anthony Fauci who thinks we’ll have a working vaccine early next year, but it’s unconscionable if you think a working vaccine might be five or more years away.
I don’t think we should try to pause children’s development for five years.
Still, there’s no mathematical or logical way to prove what we should do. School closures definitely slow the spread of Covid-19. How do you balance the good of delaying an elderly person’s infection by three months (which is equivalent to a drug that extends a patient’s life by three months) with the harms we’re causing?
I know what I’d do, but other people have different priorities than me. And that’s okay!
I’d like to think, though, that I’m not trying to hoodwink anybody about the science in order to deceptively get them to do the thing I think is right.
Like, yes, I think schools should be open. I think we owe it to children. Right now, children are suffering, but this is our fault, the fault of grown-ups.
We have known for over a decade that we ought to make coronavirus vaccines – we didn’t devote enough resources to it, and now we don’t have one. We’ve known for decades that eating animals – both those sold in meat markets like in Wuhan and the ones raised in “concentrated animal feeding operations” throughout the U.S. – will create more zoogenic diseases, and we kept doing it. We know that a guaranteed basic income would’ve given people the resources they needed to self-isolate during an epidemic – we don’t have one. We know that guaranteed access to health care would keep our death rate down.
Climate change will make pandemics more frequent, in addition to making our world unliveable for future generations. And we haven’t taken action to stop it.
None of these failings are children’s fault. We, older people, have failed. We fucked up. And now we’re asking children to make sacrifices to dampen the impact of our mistake (although, again, it won’t work – it’ll just delay the eventual repercussions).
I think today’s children deserve a fair shot at a good life, and I think that school is an essential part of that.
But don’t let anybody try to convince you that it’s safe to re-open schools because hydroxychloroquine will stop Covid-19.