Capitol Hill Blue Forums Science and Technology Health, Medicine & the healing Sciences Medications that might help against SARS-CoV-2

Columbia University study of hydroxychloroquine use in hospitalized patients found no benefit.
Two problems:

!) They only gave this antiviral to patients when they were full of virus enough to be hospitalized. Oh, they were nice enough to not count patients who died within 24 hours! This is WAY too late to use an antiviral. Not surprising at all that it didn't work. Doctors do the same stupid thing with Tamiflu.

2) No mention in the abstract of Zinc. One of the biggest benefits of HCQ is that it's a zinc ionophore, and zinc blocks viral replication. But I guess doctors think of zinc as a mineral, and therefor only important for deficiencies.

There's been studies with non-hospitalized patients in earlier phases of the infection that also did not benefit of HCQ.

What is the evidence that zinc helps? Any studies?

Read the actual paper: "Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360)."

So the sickest patients had worse outcomes, when you give them an antiviral drug that does not help very sick patients. Duh. We already knew that. That's exactly what the VA study told us. HCQ is not a miracle drug that can save people as a last resort.

They also were giving some patients remdesivir, azithromycin, or some other antiviral drug. It's pretty messy, but they say they fixed up all of that with some whiz-band stats.

>What is the evidence that zinc helps? Any studies?

Easy to Google. Lots of papers about hydroxychloroquine as a zinc ionophore. Lots of papers on zinc blocking corona virus replication in vitro. Some government health authorities recommending the combination. Some studies underway, ie:

HCQ and Zinc Trial

Actually, the whole "compassionat use" system is totally ineffective for antivirals. You have to ask the FDA for a drug for your dying patient, when the drug does not work for dying patients. I suspect that has happened a lot with remdesivir.

Do you have a link to the VA study? The quote you mentioned is apparently not from the VA study. It is from a Columbia-Presbyterian study.

Again, a point you seem to be persistently not taking into consideration; I heard (not sure of its accuracy as I haven't read the VA study) that even AFTER correcting the statistical treatment to account for the higher acuity of the patients who received HCQ, the disadvantage *persisted.* I'd like to read the study to, one, confirm that it was the case, and two, see the statistical treatment of the data, in order to form an opinion.

Several studies have arms that differ in one or more aspects but you *can* adjust the data for it.

Re: Zinc, we'll see, when the study concludes. Too bad it's open label. Hopefully the researchers will be unbiased, but after all the shenanigans pulled off by Professor Raoult of Marseille, I'd much prefer a double-blind study.

Again, in-vitro activity and in-vivo activity are two *vastly* different domains, and Medicine is shock-full of potential drugs that had in-vitro activity against infectious agents and didn't pay off in-vivo. I'll reserve judgment.

And again, there is no proof that HCQ helps less severe patients, either. That's another point you're persistently not taking into account.

What evidence do you have that HCQ would help for less severe patient? The theoretical activity in-vitro to inhibit replication? That's NOT proof of clinical usefulness.

*Regardless* of a drug's promising characteristics in-vitro, theoretically, or due to mechanism of action, it *can* fail miserably in a real-life in-vivo clinical situations, and again, the History of Medicine is shock-full of those. Actually this is way more the rule than the exception. Most in-vitro-active drugs fail to show a clinical benefit.

When RCTs come in with the prophylaxis element (one would hope that if it helps in earlier phases, it would help with prophylaxis) or with just mild cases being studied, in paired and randomized, double blind, controlled trials, THEN I will believe. Not before. Not a second before. Everything else is anecdotal.

I am not claiming early or prophylactic HCQ + zinc works. I am just pointing out why these studies don't prove it doesn't. Scepticism is good. Pretty essential for actual scientific method. We are really talking about hypothesis formation here. If you have the wrong hypothesis, your study proves nothing. Most of these "studies" are not even experiments. They are data mining. If the working thing never occurred in that data, you will not find it.

I've stated the hypothesis that some qualified medical professionals have advanced based on peer-reviewed journal papers. Clinical trials are underway to see if it works under those conditions. I have no dog in this fight, no stock in the company that makes it. But I see a lot of stupid mistakes being made over and over. If we get a good study that tests this hypothesis, and it doesn't work, then great. We will actually know something.

Yes, the evidence is in vitro. But some of that in vitro work was using cultured human cells, and this drug has been used in billions of human doses. So a lot of the reasons for in vitro --> in vivo failures have been eliminated.

I never implied that it's been proven that the drugs do NOT work. If I haven't made it clear here, I made it clear on Debate Politics in the long thread about HCQ being given to New Yorkers. I posted several times there to say that while efficacy hasn't been proven, lack thereof hasn't been proven, either.

Yes, smaller pilot studies, in-vitro activities, are, in terms of hierarchy of evidence, at best hypothesis generation studies (something I said over and over on DP, too). And they are good and important; otherwise we wouldn't have found many medicines that do work. But that's their only role: hypothesis generation. Then the hypothesis needs to be put to the test.

The existing studies, it is not that they have the wrong hypothesis. They are asking legitimate questions: does HCQ work for advanced cases of COVID-19? So far, the data on this is discouraging although like you said definitive proof isn't in yet; there's been case-control series, retrospective studies, small non-randomized studies, and even a couple of small randomized controlled trials (from China, one that suggested it works, one that suggested it doesn't). Large randomized controlled double-blind trials are underway (including for prophylaxis) but haven't concluded yet. Given that in the case of double-blind RCTs, only at the end one opens the envelopes to see who got the active drug and who got placebo, the conclusions are not in, yet.

My guess, from reading a number of studies, some better than others, some very flawed, some relatively decent, is that HCQ will not pay off. But it's just a guess. Proof will come when it comes.

Even cultured human cells can't match the real life situation of a live organism infected with an aggressive virus (for example, cultured human cells don't produce cytokine storms; are not subject to disseminated intravascular coagulation, are not subject to the full dimension of the host's immune response with its advantages and disadvantages). Also, the virus can't be sequestered in some organs and multiply too fast before the drug can stop them. Often the concentration of in-vitro inhibition can't be achieved in-vivo with regular, non-toxic doses.

A drug can show beautiful inhibition of replication in cultured cells... and then once the virus infects a live organism, it may rapidly overwhelm that organism in a way that makes the drug useless.

Again, in-vitro and in-vivo are not just different... they are VASTLY different. Again, in-vivo activity is neat to generate hypothesis, but proves NOTHING in terms of clinical efficacy and safety.

Billions of human doses: not for COVID-19. Safety is disease-specific, a point I made over and over but you come back to the idea that people with lupus, malaria, and RA have taken billions of those doses. Sure, neat. However, those people didn't have COVID-19 which didn't even exist when they were taking those billions of doses. Different ball game.

OK, is HCQ a huge poison that makes most patients taking it drop dead? No. The billions of doses used to treat malaria, lupus, and RA have already demonstrated that. But is it safe in humans for use in cases of COVID-19? We don't know yet, but the first few pieces of info we have are not encouraging.

I don't have a dog in this fight either. I hope HCQ works, I hope zinc works, I hope remdesivir works, I hope something else does.

But it hasn't been proven that any of these do work; it hasn't been proven that they don't, and it hasn't been proven if they may or may not help different degrees of patient severity; it hasn't been proven if they are good prophylactic drugs for SARS-CoV-2.

Look, about the in-vitro versus in-vivo: we don't need to go far. Remdesivir showed in-vitro activity against viruses of the Filoviridae family (Ebola). That generated the hypothesis that it might work against Ebola, in vivo. Well, so much for that. It was an utter failure in the real-life treatment of patients infected with Ebola. It's being repurposed now for COVID-19. We'll see.

Forty-five hundred dollars, for a ten dollar drug, if reports are any indicator.

POLITICO

And Gilead has an extensive history of developing very effective drugs, but at a sky-high premium.

Again, like in another link posted by you earlier, these are people from outside the company, speculating about the price the company is supposed to charge. That is, they are guessing. Let's wait and see what the numbers actually are, OK?

There are two factors that might bring the numbers significantly down:

1) Remdesivir for COVID-19 research was co-sponsored by the NIH. So, Gilead does owe a debt of gratitude to the government. So, the final price will have to include a negotiation in which hopefully (although with the Trump administration one never knows) the governmental side of the equation will pressure Gilead to be reasonable.

2) In previous pricing wars, Gilead didn't enjoy the HUGE world-wide exposure they are getting from this. The whole world is watching. Why do you think they donated 140,000 doses of remdesivir? Because it's great PR. They want to be seen as the saviors of humankind. If they make and sell remdesivir much closer to cost, they will earn a lot of goodwill with governments all over the world, and this may become a good capital for their future endeavors.

So, for now, I wouldn't pay much attention to pundits. We'll see how much remdesivir will cost to actual patients. It might be a lot less than these pundits are anticipating.

Again, to be clear: I have nothing for or against Gilead Sciences and own no Gilead stocks. I'm just expressing my humble opinion. I hope I'm right, but maybe I am not. We'll see.

Seems kosher to me. Free to the poor, an $8 scrip if you're insured, $45 over the counter. Everybody will be happy and Gilead CEO gets Medal OF Freedom from President Biden.

I love happy endings!

Yes! I love the President Biden part!