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Comment by karmicthreat | Hacker News Reader

Not exactly related but why doesn't Nirmatrelvir/Paxlovid not have this issue? Or is it just at a smaller scale?

Molnupiravir is special in that it works by making viral replication more error-prone, with so many mutations that the virus cannot reproduce at all. If a virus manages to replicate anyway, it may do so with more mutations than normal, and this could theoretically increase the chance of a new variant arising.

Paxlovid's mechanism doesn't involve inducing mutations, so it doesn't have this concern. It's a protease inhibitor, blocking the virus's ability to break down proteins. Viruses can still develop resistance to this class of drugs, but only using their natural mutation rate.

That sounds like a catastrophically bad idea.

Doesn't seem that bad to me, the virus doesn't need Molnupiravir to mutate. It can do very well by itself, in the billion people and animals it infected. The fact we are seeing convergent evolution shows that it is naturally very good at this.

By increasing the mutation rate way beyond the sweet spot (that what's Molnupiravir does) the virus may get some desirable mutations, but won't be able to hold on to them. And if, thanks to the drug, the patient is cured, it is bad news for the virus, those who are not infected can't produce new variants.

But like antibiotics, I think this is an "all or nothing" drug. Either give maximum dose to do as much damage as possible, or don't give anything at all. Too small a dose may promote building resistance instead.

It was 2020 when the drug was undergoing development.. literally throw everything at the wall and try to stave off the mass death from uncontrolled spread. Fortunately other therapeutics worked as well, the vaccines were developed quickly and had very high efficacy, and subsequent strains of Covid mostly became more mild (this wasn't a guarantee, regardless of how insistent people may be).

The drug works, it reduces hospitalization and mortality in people who take it, but we don't actually need it for the most part so these studies are just further confirmation of that.

The study linked in another comment finds that it doesn't reduce hospitalization or mortality: https://www.bmj.com/content/379/bmj.o3055

And while I understand the "see what sticks" mentality, drastically increasing the mutation rate of the virus responsible for a global pandemic... seems to me like it's on the order of "maybe we start dropping nukes, that'll slow the spread".

It doesn't in vaccinated people - but it did in unvaccinated people. There was no guarantee that we'd develop a vaccine in any reasonable amount of time, and reducing deaths and the overburdening of our limited health care resources was the #1 goal in 2020.

TFA is about why it is not obviously a catastrophically bad idea.

After the recent Project Veritas videos on Directed Evolution, it seems like that’s the actual goal

It's a bit ambiguous to me in that Merck originally argued that molnupiravir would be less susceptible to resistance for Reason A, then now that the bad news is coming out, we have a plausible sounding explanation Reason B that it does have a weakness to resistance. The fact that the stated reasons can just flip on a dime like that bothers me intellectually.

But on another level the whole issue is less relevant than the fact that the West has already been recommending Paxlovid over molnupiravir anyways, not because of resistance concerns but because Paxlovid works better and has less side effects, etc.

> The two drugs of course have very different mechanisms. Paxlovid inhibits the viral main protease and thus slows replication of the virus, while molnupiravir induces so many mutations when the virus does try to replicate that even if the process finishes that resulting viral particles are not able to function.

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