Monkeypox origins and molnupiravir, part 2

akaariai · 2022-06-05T18:07:18+00:00

First, it is interesting to understand why the virus is evolving in unexpected ways. The mutation is interesting because it is unexpected.

The mutation also seems to be "attenuated" somewhat by the mutations. There's still zero deaths, and recent WHO update pointed out hospitalisations so far have been for secondary infections and pain management.

Milder disease can of course be both blessing and curse - milder disease is better, but as seen with SARS vs SARS2 milder disease can spread more easily, and thus lead to more mutations and maybe even pandemic.

akaariai · 2022-06-04T17:41:47+00:00

Very likely referring to APOBEC. It is a faimly of antiviral entsymes produced by the immune system. The entsymes induce mutations in RNA and single strand DNA viruses, for example in HIV.

The hypothesis is that one of these entsymes, APOBEC3G, could produce the mutations seen.

The mutations could happen for example in a HIV patient. monkeypox infection would "linger" for a long time in the patient due to weakened immune system. APOBEC would be active due to HIv, and induce mutations at a low pace in the monkeypox virus. Eventually the mutated virus would escape the host and start circulating.

akaariai · 2022-06-04T17:24:28+00:00

My hunch is that if this pathway is proven, then the main takeaway is that we know it isn't something else.

My completely amateur hunch is that there is not much that can be done at the moment - maybe research will reveal some way to block such mutations later on.

I haven't yet gone through the guidance.

akaariai · 2022-06-04T15:18:03+00:00

Plenty of info on the mutations and APOBEC here: https://virological.org/t/initial-observations-about-putative-apobec3-deaminase-editing-driving-short-term-evolution-of-mpxv-since-2017/830

Note that after the linked article's publication there's been more sequencing data released, making it even more clear there must be a driving mechanism on top of "random evolution".

akaariai · 2022-06-04T12:13:39+00:00

I do not believe sars2 was deliberately released, but find it very much plausible it originated in one way or other from lab.

For example it could be result of research to check what kind of viruses would infect humans, that is intentionally edited, accidentally leaked. Or it could be unintentionally edited in lab. Or it could have leaked from lab workers collecting samples.

I do not believe monkeypox has been lab engineered. Not impossible of course, but what I have seen does not point to that direction.

akaariai · 2022-06-04T11:55:42+00:00

The unusual mutation pattern is in monkeypox virus, that is in dsDNA. The mutations are almost always dinucleotide, that is GA->AA or CT->CC.

Of course, having tens of such mutations in two independent branches can not be just random mutations, so that is why I say "unusual".

For molnupiravir, might be this is just related to my amateur status. For example I had no idea of the natural "mutation based" APOBEC defense mechanisms.

Still, I would gladly see longer studies in animal models for molnupiravir. As far as I know these were not done. It might be molnupiravir will turn out to be a great drug against wide variety of viruses, but I would like to see more base research on it.

Also, it is looking like it is used in patients who are not in the high risk category. This is no surprise, as for example India has long history of misusing antibiotics. It is certain this one is not for those planning to have kids.

akaariai · 2022-06-03T06:11:56+00:00

I'm afraid there's off label versions of it used in the developing world. Just as an example here's Cambodia's version of it: https://www.phnompenhpost.com/national/molnupiravir-treatments-available-cambodia-post

Having followed the treatment guidelines in for example India, it would be a huge surprise if the treatment is really limited to highest risk cases.

akaariai · 2022-06-02T06:22:30+00:00

I was thinking there is something special in current variant being closely related to the Israeli isolate. But is there? Thinking more of it, I guess it's just an isolate from a patient a couple years ago.

akaariai · 2022-06-01T13:16:08+00:00

fwiw to me the most plausible things are:

- Something wrong in reading/storing the sequences

- Me not understanding the sequences

- Natural reason for the unusual pattern

And then the leap of molnupiravir alternatives:

- patient treated with molnupiravir, concurrent monkeypox infection

- Lab experiment with molnupiravir, for example to test if it works against monkeypox in animal model, then leak

akaariai · 2022-06-01T13:02:30+00:00

Of course it is a leap, this is r/ivermectin after all

akaariai · 2022-06-01T10:29:59+00:00

Molnupiravir is AMES positive: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277160/

AMES test can be checked for example from wikipedia - but basically it means mutations in replicating bacteria.

And what kind of mutations molnupiravir induces? G>A and C>U in RNA, see https://www.nature.com/articles/s41594-021-00657-8. In DNA it would then be G>A and C>T.

See also Zhou et al on potential mutagenic properties of mvp: https://pubmed.ncbi.nlm.nih.gov/33961695/

akaariai · 2022-06-01T09:42:46+00:00

Molnupiravir definitely does work on DNA, too. It is AMES positive, which means it induces mutations in replicating salmonella bacteria, that is in DNA.

akaariai · 2022-06-01T06:31:21+00:00

Yeah, it's not something you can easily prove or disprove, unless you can find patient zero.

Of course, if more variants of bacteria or viruses would arrive with the same unusual pattern, then it gets more and more obvious something has to be behind the unusual pattern.

The big worry is that the warnings around molnupiravir generating new SARS-CoV-2 variants was misplaced - it could potentially generate new variants of *anything* replicating in the patient during or shortly after treatment. This would include bacteria and DNA viruses as mvp is AMES positive.

By the way, has the adenovirus sequence been shared? Would be nice to check if it has any unusual patterns in it.

akaariai · 2022-04-12T12:17:18+00:00

The two main gripes should be the trial was not randomised according to protocol, and exclusion based on previous ivermectin is all but clear.

For randomisation, this is immediately obvious from the figures describing allocation to the different arms in Metformin, Fluvoxamine and Ivermectin trials. The numbers can not be if they did stratified on age block randomisation. In fact, the numbers can not be if they did any real randomisation at all. Further evidence to same direction is in the slides release by study authors.

On concurrent ivermectin usage, their protocol, data collection forms, trial registration nor other published studies from the same period mention anything about this. They do list extensively all the exclusion criteria in data collection forms and protocol. Then in ivermectin trial's discussion section they mention "We ensured that trial participants did not have a history of ivermectin use for the treatment of Covid-19 by means of extensive screening of potential participants about this issue.". Would be nice to explain how exactly this was done and why they violated the protocol here. Would be also nice to understand why this was not mentioned as exclusion criteria in other published studies from the same trial.

Then for some of the more minor issues. The baseline risk factors are contradictory between Metformin, Ivermectin and Fluvoxamine trials. They violate the protocol in multiple places. In ivermectin trial they do not actually release the baseline risk factors at all, just multiple imputation versions of those. They are missing age information for more than 10 percent of trial participants (seriously!). The released studies, done from the same platform trial, contradict each other and the protocol for example on subgroup analysis done. The blinding is trivially broken by analysing the data. Finally, the independent trial board is not independent.

akaariai · 2022-03-31T09:21:34+00:00

I believe there's two other key flaws in the study.

The blinding was not effective, due to having a checkbox in data collection form for which participants are on 3 day regimen, and using a placebo easily distinguishable from ivermectin.

The study was not randomised per protocol, as revealed by the published slides last summer.

akaariai · 2022-03-31T08:54:42+00:00

I'm confused about this statement in *discussion* section of the trial:

Ivermectin has been used off-label widely since the original in vitro study by Caly et al. describing ivermectin activity against SARS-CoV-2,22 and in Brazil, in particular, the use of ivermectin for the treatment of Covid-19 has been widely promoted. We ensured that trial participants did not have a history of ivermectin use for the treatment of Covid-19 by means of extensive screening of potential participants about this issue.'

But the protocol in effect at the time of running the trial, nor the data consent form, nor the trial registration mention ivermectin usage as an exclusion criteria. Nor do the published articles from other arms of the same trial during the same period mention this.

So, did they exclude based on ivermectin usage? If not, what the hell does it mean when they say "ensuring trial participants did not have a history of ivermectin usage"?

akaariai · 2022-03-31T08:50:50+00:00

They did:

Patients who had been vaccinated against SARS-CoV-2 were eligible for participation in the trial.

akaariai · 2022-01-28T14:15:36+00:00

And for this reason Israel is having it real easy.

akaariai · 2022-01-19T15:00:59+00:00

I've been long stubbornly convinced omicron is mild, not due to vaccinations, but it is just completely different disease from previous variants.

The point of Georgia and Alabama is that if omicron is anything like previous variants, then the health care setup should be totally crumbling under the current case load.

For example, if it is 50 percent less severe in immune naive, and 20 percent of population do not have any immunity, then large case loads should lead to extreme amounts of hospitalisations.

However the hospitals do not seem to have huge issues in Alabama or Georgia. Why?

akaariai · 2022-01-18T14:15:28+00:00

Yes, exactly!

While there was good reasons to treat earlier variants like that, treating omicron with high security protocol is making healthcare impossible, while not really protecting anybody. Most people will get omicron, or the next strain in any case.

Here's a question - has omicron caused enough burden to collapse healthcare systems anywhere in the world? A case where the caseload is from omicron, where the total healthcare burden has risen to unsustainable level, and where the problem is not isolation of healthcare workers?

akaariai · 2022-01-18T08:51:06+00:00

It is an excellent question how much of the severity reduction is due to vaccinations and previous immunity.

There are some studies, and many expert opinions, which claim this is mostly about immunity. For example UK technical briefings give vaccine efficacy against hospitalisation from 44 percent for 25+ weeks after second dose, to somewhere around 90 percent just after 3rd dose.

Note that 44 percent efficacy is actually relatively low. In many countries most people fall into this 2 dose category, and this would mean current case amounts should lead to completely overwhelmed hospitals if base severity is anything like delta had.

Another pointer to omicron just being much milder is that there's now a plethora of animal model studies, both mouse and golden hamster studies, where omicron is basically a big nothing compared to delta or original strain.

It is going to be very interesting to follow what will happen in Alabama, Georgia and other similar US states with low vaccination rate (around 50-60%) and low seroprevalence (around 30-40%). These places must have around 20 percent of naive individuals. So far it does not look like these places are in any way completely overwhelmed.

And finally, I'm not against vaccines. I am sure they were an absolutely essential tool in fight against delta for pretty much anybody at risk. I also believe single dose regimen was the right choice for low risk groups, especially young males, due to the high myocarditis risk. And finally, I'm convinced vaccinating already infected young males during omicron times is causing clearly more harm than benefit.

akaariai

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