Molnupiravir Mutations in the Wild | Hacker News Reader

Molnupiravir Mutations in the Wild

science.org

63 pointsetiam28 comments

From near the end:

"Actually, I think the same thing about Paxlovid treatment. In that case, the worry is the rise of mutated forms of the coronavirus that are also Paxlovid-resistant. That’s more or less inevitable, but we should not accelerate it by handing out the drug to populations where it won’t make much difference."

We have a real mismatch of incentives here. In order for Paxlovid to remain effective, it would need to not be used very often (so that a resistance to it doesn't constitute a big advantage for that variant). This is ok, if we only give it to elderly or otherwise high-risk populations. But how high-risk?

Many individuals want to consider themselves "high-risk" in order to get a prescription, but would be better off if everybody else besides themselves is not considered high-risk. It's a classic Prisoner's Dilemma.

Add to that the fact that the makers of Paxlovid (or Molnupiravir, for that matter) have an incentive to want it to be prescribed as much as possible, and we have both individuals and corporations pressuring the system to do exactly what it should not do, which is hand out the anti-viral to way more people than it should.

This cannot be fixed without changing the system (e.g. paying drug developers by a bounty system rather than with a patent).

I'm not sure that prisoners dilemma is the right framing of this problem.

First, there's value in decreasing the viral load of ALL patients regardless of risk, as viral load is likely proportionate to risk of onward transmission. If it decreases onward transmission, then the math would likely favor its use in all cases, since exponential spread gets costly fast.

Second, we continue to focus on hospitalizations and deaths with increasingly poor data and with no focus on disability. Treatment may decrease risk of long covid in non-"high risk" patients, which itself may be beneficial.

Third, while we should expect paxlovid-resistant variants to pop up, the fact that we prescribe it about 4x the rate of molnupiravir and don't see nearly that level mutation should be somewhat comforting. It seems equally plausible that a new "long branch" lineage would pop up with resistance irrespective of evolutionary pressure from paxlovid prescriptions. If that's the case, it'd be a shame to ration its use to only have it go bad anyway (this is basically what we saw happen with all of our monoclonal antibodies).

Fourth, this entire conversation should be less focused on who we deem worthy of one of our last remaining treatments, and more focused on how we're allowing a very quickly mutating virus to spread virtually unchecked and with basically no investment in any further treatment or prevention. None of us need to be prisoners here if we were continuing to invest in new treatments, better vaccines, improved air filtration and ventilation, and paid sick leave.

SARS-CoV-2 has already spread everywhere. The majority of people worldwide have been infected at least once. Exponential spread is no longer a thing. Transmission will continue forever at lower levels, just like other endemic human coronaviruses such as HCoV-OC43. At this point, giving Paxlovid to a few more COVID-19 patients is unlikely to significantly reduce the spread of SARS-CoV-2.

There may be good reasons to prescribe Paxlovid more widely. It's just that reducing transmission probably isn't one of those reasons.

If you re-read what you have written and try to detach your thinking from the various polemics of how bad lockdown is...

"Exponential spread is no longer a thing." -- Clearly wrong. Every time a +ve person breathes out on a bus, in a pub, at the office, exponential spread is occurring. The only difference is that many of those people had a recent immune event (a booster or recent infection) and suppress it immediately, or if it has been some time, they get a COVID infection and their T cell response kicks into action and suppresses it. People can have multiple infections per year. People with weakened immune systems will still get very sick.

Because it is still propagating with new variants there is still the potential for significant widespread waves of illness. It might be very important to be able to issue Paxlovid or something similar to everyone who is sick, or even give it a prophylaxis to e.g. cancer patients.

In the literal sense, exponential spread _of Covid-19_ is clearly no longer a good description in the US (or many other countries). It may describe the spread of new variants, but the impact on most people of getting the latest variant of covid-19 is about like the impact of getting the latest variant of influenza (which can kill you, but normally does not). The number of people with covid-19 is not going exponentially up, as it once was, it is now coming in waves that are probably never going to reach the peak of the initial Omicron.

Now, literally speaking, every new variant of covid-19, influenza, or any cold virus is obviously going to be exponential (and half of the time, exponential decay). But the population is no longer "immunologically naive", in western countries.

Tragedy of the commons seems a more appropriate analogy than prisoner's dilemma. This is "basically" (ignoring all the scientific differences) the same problem as antibiotic resistance, and the paradox where if everyone takes antibiotics, selection pressure leads to dominance of the bacteria most resistant to those antibiotics. And indeed, this situation is frequently framed as an example of "tragedy of the commons." [0]

[0] https://www.cambridge.org/core/journals/journal-of-law-medic...

I would agree that "tragedy of the commons" could work. But the basic feature of "prisoner's dilemma" that I was referring to is that we're all better off if we all avoid taking antivirals or antibiotics when we are not high-risk, but each individual is better off if they defect and everyone else does not.

  > if much higher rates of mutation were doing the virus a favor overall, then it would already be mutating at those rates.

This sounds reasonable, but is it actually true?

Edit: Long tail events are hard to reason about, and successful mutations are very definitely many sigmas out on the curve. And optimisation cost function is hard to think about: short-term survival has different parameters than long-term chance of becoming the dominant variant. “Punctuated” mutation rates might be the ideal nursery, versus a constant mutation rate?

I don’t think the claim in the article is true at all. A high mutation rate is definitely bad for the virus in the short term, which is why Molnupiravir has an effect on reducing disease in individuals. But, of course a high mutation rate also increased the likelihood that a more dangerous variant will be found.

Recent and related:

Covid drug drives viral mutations – and now some want to halt its use - https://news.ycombinator.com/item?id=34717514 - Feb 2023 (211 comments)

Also:

Indication of molnupiravir-associated mutations in SARS-CoV-2 sequencing - https://news.ycombinator.com/item?id=34554580 - Jan 2023 (16 comments)

The molnupiravir development story is a nice case example of what's gone wrong under the corporatization of American academics. The drug came out of reseach done at Emory University, funded by US federal agency NIAID, as their PR blurb reports:

> "The discovery of molnupiravir at Emory was supported in part by funding from the National Institute of Allergy and Infectious Diseases and the Defense Threat Reduction Agency. (Dec 23 2021, Emory press release)."

The university then did the usual thing in these cases, i.e. the researchers involved set up a small biotech company (Ridgeback Biotherapeutics) which was then acquired by Merck. This was made possible by US Bayh-Dole law from the 1980s, which allows universities like Emory to exclusively license taxpayer-finaced research to private entities, instead of allowing anyone to develop it.

The U.S. government then dumped an initial $1.2 billion into purchases, followed by another $1 billion more recently, a little over a year ago:

https://www.reuters.com/world/us/us-government-buy-14-mln-mo...

Despite 'promising clinical trial results' (which may or may not have been manipulated to give good outcomes), in reality the drug seems to be of relatively little benefit, only slightly decreasing length of illness and with no effect on death or hospitalization rates (Dec 2022 study in BMJ):

> "No benefit was seen in terms of hospital admissions or death rates. The group treated with molnupiravir had 105 cases of death or hospital admission (0.8%), and the control group had 98 cases of death or hospital admission (also 0.8%)."

> "The median average length of illness in patients who took molnupiravir was nine days, which compared with 15 days in the control group. After adjusting for other factors the study authors found that patients taking molnupiravir recovered 4.2 days more quickly than patients in the control group."

https://www.bmj.com/content/379/bmj.o3055

Incidentally, and anecdotally, I came down with a fairly solid case of Covid-19 a year ago, and the cheap over-the-counter medication, diphenhydramine (Benadryl being the most well-known brand) knocked down my symptoms very effectively. This seems to bear out in research, although of course the U.S. government isn't going to fork over $2 billion to acquire a supply, and this drug is long out of patent (with a good safety record, though I did end up taking one tablet every 3 hours or so, a bit more than recommended). YMMV - but this is not an ivermectin-type claim:

https://ufhealth.org/news/2021/two-common-compounds-show-eff...

The whole molnupiravir story reeks of academic corruption, government contracting kickbacks, pharmaceutical profit-seeking, abuse of the clinical trial process, etc. It also reveals why researchers have little incentive to examine out-of-patent drugs as treatments for emerging diseases.

If they're capable of ignoring benadryl, they're capable of creating fraudulent studies about ivermectin too.

The first fraudulent studies right off the bat were the HCQ study and the ACE inhibitor study from Surgisphere, with completely fabricated data. People can't make the jump to looking at the other HCQ (or other drug studies) because, well, Trump, but they also did this with ACE inhibitors, despite the other studies showing a positive effect.

You need to be asking yourself: why weren't antihistamines part of the standard of care for COVID, when they were part of the standard of care for all forms of viral pneumonia back in 2016? (Sorry, that's the most recent time period when I had what my doctor at the time thought was viral pneumonia.) Why the Year Zero stuff?

What is the Year Zero stuff?

[Tangent warning]

I recall some scare awhile back about a possible link between diphenhydramine and dementia / Alzheimer's. Googling turns up a study from 2008. Anyone know if that held water, or if there is ongoing research into that link?

I've generally avoided the drug since hearing about that, but I used it much in the first place.

This has references newer than 2008: https://www.alzdiscovery.org/uploads/cognitive_vitality_medi...

At the top, it talks about "long term use", so it may be okay under acute circumstances.

Anticholinergics are associated with an increase of risk of dementia, and diphenhydramine is a pretty strong one, considering its OTC nature. I still use it occasionally myself, but I agree that it's a good idea not to take on a regular basis.

Here's a paper from 2019 that covers this: https://jamanetwork.com/journals/jamainternalmedicine/fullar...

Related recent threads:

https://news.ycombinator.com/item?id=34717514 221 comments

https://news.ycombinator.com/item?id=34554580 16 comments

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

> 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.

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.

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.

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

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.

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

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.

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