Hydroxychloroquine may not be the "magic bullet" it's cracked up to be

We've seen a lot of politically divisive controversy about hydroxychloroquine (HCQ) and its purported effectiveness against the COVID-19 virus.  The arguments in its favor have been based on very small trials, and are hotly disputed.  I must admit, on the face of news reports alone, it looks very promising . . . but when one digs deeper, there are all sorts of potential and actual complications.

Derek Lowe writes the widely-respected and -referenced chemistry blog "In The Pipeline".  We've encountered him in these pages before.  He's written a very thorough and useful analysis of what we know about HCQ, and the potential dangers it represents.  It's a bit technical in parts, but very informative.  Here are a few excerpts.

There are a couple of other things that need to be noted. One is that hydroxychloroquine itself actually lowers the activity of the innate immune system; that’s why people take it for lupus and for rheumatoid arthritis. Many people are saying that perhaps it will work best if taken early in the course of infection, but this effect ... should be kept in mind. Another potentially important point is raised in this preprint – which, it has to be said, is not human data but mouse toxicology. But with that in mind, the authors report what looks like a bad interaction in that species between HCQ and metformin. And by “bad”, I mean about 30% mortality. If this translates at all to humans, it could be bad news, because (as mentioned above) diabetics look like a high-risk group and many patients may well have been taking metformin when they present at the hospital. We need more information on this. An investigational drug combination that showed this effect in mice would not move forward in the normal course of things.

. . .

It’s no wonder that this work has set off so many arguments: statistically, it’s like a funhouse mirror. Here, though, is where some of the folks pinging me on Twitter and sending me emails tend to get more worked up, especially to that point about anecdotal data. I can see where they’re coming from: if you haven’t done this stuff, you can look at a report of people responding to such a treatment and figure that the answer is here – right here, and anyone who doesn’t see it must have some ulterior motives in ignoring what’s in front of their face. But that’s not how it works.

It’s weird and startling, though, if you haven’t had the opportunity to go back through clinical research (and even patient treatment) and seen how many things looked like they worked and really didn’t. It happens again and again. Alzheimer’s drugs, obesity drugs, cardiovascular drugs, osteoporosis drugs: over and over there have been what looked like positive results that evaporated on closer inspection. After you’ve experienced this a few times, you take the lesson to heart that the only way to be sure about these things is to run sufficiently powered controlled trials. No short cuts, no gut feelings – just data.

. . .

My job as a researcher has not to been to raise people’s hopes without data in hand, my job has been to try to produce such data so as to raise hopes with some reason to do so. When I see something to be hopeful about, I’ll say so, and when I think people are getting ahead of what we know, I’ll say that, too. Go back to the first things I wrote about the hydroxychloroquine/azithromycin work: I called it “potentially very interesting” and called for more data to see if it was real. That’s where I still am. Raising hopes just for the sake of raising hopes is not where I am, though, and in fact I find that whole idea to be cruel. We’re going to defeat this virus, this epidemic, by being as hard-nosed as we can be about collecting real data on real-world outcomes as quickly as efficiently as we can, not by talking vaguely about miracle cures and isn’t it something and wouldn’t it be great. You’ll need to go somewhere else for that. Try Dr. Oz, he’s good at that crap. I’ll stick to what I’m good at here.

There's more at the link.

I take Mr. Lowe's point about metformin very seriously.  A very large proportion of the middle-aged and older population in this country (and, I understand, in Europe) are prescribed metformin.  It's pretty much the standard treatment for pre-diabetic patients, and even those who are full-fledged diabetic if their condition is not severe enough to require insulin injections.  If HCQ interacts so poorly with it, it's no wonder that some physicians are seriously questioning the (very limited) investigations so far into its use against COVID-19.  From what Mr. Lowe reports, that could potentially worsen the condition - or even lead to the death - of up to a third of your patients.  Not an optimal outcome . . .

Part of the problem of public perception of the HCQ question is that too many of us expect - even demand - an instant cure from medical science.  We've grown too used to the thought that modern medicine can do anything.  It can't, of course.  As a pastor, I've spent too many hours at the bedsides and with the families of terminally ill patients to be in any doubt about that.  However, since the advent of antibiotics and other so-called "wonder drugs", public expectation has grown out of line with reality.  The coronavirus pandemic is likely to reset that optimistic fallacy.  (I remember my father describing how penicillin was regarded with almost holy awe during World War II, as it was the first medication that could bring severely injured men back from the brink of death by treating their wound infections, etc.  He said some of his fellow servicemen even demanded penicillin to treat ingrown toenails or dandruff, so convinced were they that it was a miracle medication that could cure anything.)

To really master COVID-19 is probably going to require a vaccine, and at least one completely new anti-viral treatment or medication.  None of them are yet available.  All we can do right now is try anything and everything, in as controlled and safe a way as possible, and hope for the best.  As the ancient medical principle teaches, "First, do no harm".  HCQ might do no harm, and even a lot of good, to some patients:  but it might harm many others.  It's a dilemma for which there's no immediate answer or solution.

Peter