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CP-COV03 a broad based antiviral for Covid and many more (soon to receive emergency use authorization?)

Osaca

Senior Member
Messages
344
I decided to make this post now, because I recon someone was going to make it sooner or later in any case and it seems CP-COV03 could receive emergency use authorization in Korea within the next month after their Phase 2 trial has been a success http://www.hyundaibioscience.com/page/news.php?mode=view&no=55&page=4. If that should really be the case an a priori discussion could be interesting. Hyundai Biosciences has also applied for emergency use authorization with the FDA and the EMA as well as applied for the patent in 23 countries including Korea, the United States, Europe, China and Japan.

CP-COV03 also known as Xafty is an antiviral based on Niclosamide. Niclosamide has long been identified as a multifunctional drug, via drug repurposing screens (Anti-EBV, Anti-MERS, Anti-SARS-CoV etc.) https://pubs.acs.org/doi/10.1021/acsinfecdis.0c00052. The problem is Niclosamide has poor bioavailability and low concentration in target organs. What Hyundai Biosciences has developed is a new drug delivery system that delivers sufficient Niclosamide into the cell to overcome the low bioavailability problem, as such they have shown to achieve a 5-fold increase in bioavailability (see here for some more info: https://www.mdpi.com/2073-4360/13/7/1044). This in turn turns on the cell’s autophagy mechanism that the cell would normally use to eliminate the virus on its own, i.e in this process, cells identify the virus as a foreign substance and remove it themselves.

Herpes viruses hijack and control autophagy, a method which was supposed to be the body's strongest defence mechanism to clear the virus naturally by degradation. Having the ability to override this in an infected person's body by use of a drug-induced autophagy could be helpful in defeating herpes and other viruses that inhibit or hijack autophagy in the body https://www.nature.com/articles/srep09730.

For EBV we know that “Huang et al. demonstrated that niclosamide inhibits EBV lytic replication in lymphoma cells and epithelial cells and causes irreversible cell cycle arrest in lytic EBV-infected cells via disrupting mTOR activation, offering the potential to treat acute EBV-associated infectious diseases.”.

If it were to be successfully approved or with a successful Phase 3 trial, CP-COV03 is expected to be a game-changer drug in the war against viruses as it is inexpensive, easy to mass-produce and has a ‘viral removal’ mechanism that is in principle applicable to all viral infections.

The pharmacokinetic (PK) data of CP-COV03 from their clinical trial is noteworthy. As a result of analysis based on the blood collection results of 60 clinical participants, the highest blood concentration of the top 10 patients with the highest blood drug concentration of CP-COV03 was 660ng/mL on average. This is a value that far exceeds the drug concentration (IC100) that inhibits the proliferation of the Corona 19 virus by 100%. The IC50 (inhibits 50% viral replication) of Niclosamide is 0.28uM and IC100 is 1uM. The researchers claim that CP-COV03 can maintain IC100 for 12h. As an example: Paxlovid is modeled to maintain IC90 in 90% of the population. However as Siebe (https://twitter.com/PatientPersists) points out on Twitter things are a bit more complicated than that: Siebe_status.

Furthermore, Hyundai Biosciences has announced that it has been running a Long-Covid study with this drug for quite some time (https://www.archyde.com/hyundai-bio-cp-cov03-long-covid-researcher-clinical-trial-started/, https://www.newsdirectory3.com/hyun...inical-trial-begins-cp-cov03-very-long-covid/), but the results are still outstanding and no references or official information on this trial can be found. A Twitter user has said he is participating in the trial: lokeolliji.


The great news:
  • An alternative to Paxlovid that can be trialed in combination with other antiviral drugs due to its safety profile
  • We have data proving that Niclosamide is safe for long-term use. This should make it a lot easier to receive approval or trials, for instance for LongCovid
  • The mechanisms applies to many viruses and not only leads to a halt to viral replication, but could even remove the viral reservoirs
  • The company is running multiple trials and has applied for emergency use authorization all over the world
  • We don’t have to wait for Phase 3 results is Phase 2 results warrant EUA
The bad news:
  • The phase 2 clinical trial showed an extremely effective reduction of viral load for both the high dose, but also the low dose vs. HC, furthermore the high dose was more efficient. Why was the time of resolution of 12 acute Covid symptoms only yield a positive result for the low dose group? Does this mean the drug could still fail in phase 3? Some believe that side effects of magnesium were misinterpreted as Covid symptoms, but that seems rather speculative. (The main raw material of the drug is niclosamide, whilst dds technology was used to increase the absorption rate in the body. The material used as the carrier in this technology is composed of magnesium. There may be side effects such as abdominal pain and diarrhea due to high dose magnesium).
  • Could EBV or even Covid be hiding in places that aren’t reached by this mechanism, or can they somehow overcome this type of autophagy as well? Whilst autophagy is an antiviral function it has been shown that this is only one side of the coin as different autophagic pathways complicate the situation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744147/.
  • No data for the Long-Covid study has been published yet
  • The current majority of information available is in Korean. Whilst news reports are translatable, I do not know how things are looking in forums similar such as these that are happening in Korea. As such it's hard to get local opinions of the drug or even to speak to participants of the trial. Furthermore the standard mode of operation is different to what people in the West are used to and usual things for us like clinicaltrials.gov are often not used.

Professor Woo Heungjeong of Hallym University, who served as vice president of the Korean Society of Infectious Diseases, will be presenting the results of the COVID-19 phase 2 clinical trial at the upcoming conference of the American society of Microbiology in Texas (https://asm.org/Events/ASM-Microbe/). The presentation is titled “Clinical And Virological Efficacy Of A Potential Pan-antiviral Agent, Cp-cov03 In Covid-19 Infection” and the abstract of the presentation can be found here: https://www.abstractsonline.com/pp8/#!/10789/presentation/6711.

CNPharm/ Hyundai Biosciences aren't the only company that has been trying to repurpose niclosamide as a Covid-19 treatment.
Daewoong Pharmaceutical is also repurposing niclosamide as a Covid-19 treatment called DWRX2003. However, after inital success in Phase 1 studies the company was not able to recruit enough patients in their Phase 2 study https://www.koreabiomed.com/news/articleView.html?idxno=12385 and the information on clinicaltrials.gov isn't very informative https://clinicaltrials.gov/ct2/results?cond=&term=DWRX2003&cntry=&state=&city=&dist=. Did their drug fail?

images_medium_id0c00052_0003.gif
 
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Hip

Senior Member
Messages
17,824
The pharmacokinetic (PK) data of CP-COV03 from their clinical trial is noteworthy. As a result of analysis based on the blood collection results of 60 clinical participants, the highest blood concentration of the top 10 patients with the highest blood drug concentration of CP-COV03 was 660ng/mL on average. This is a value that far exceeds the drug concentration (IC100) that inhibits the proliferation of the Corona 19 virus by 100%. The IC50 (inhibits 50% viral replication) of Niclosamide is 0.28uM and IC100 is 1uM.

Thanks for posting these details.

I looked into the pharmacokinetics of CP-COV03 and niclosamide recently, and the issue with this drug is its very high plasma protein binding of greater than 99.8%.

This means that whatever blood concentration levels of niclosamide are found in the blood in pharmacokinetic studies, you have to divide that concentration by 1000 to get the free drug concentration, if we assume 99.9% protein binding.

It is only the free drug which has an active effect in the body.
 

Osaca

Senior Member
Messages
344
Thanks for posting these details.

I looked into the pharmacokinetics of CP-COV03 and niclosamide recently, and the issue with this drug is its very high plasma protein binding of greater than 99.8%.

This means that whatever blood concentration levels of niclosamide are found in the blood in pharmacokinetic studies, you have to divide that concentration by 1000 to get the free drug concentration, if we assume 99.9% protein binding.

It is only the free drug which has an active effect in the body.
Yip, thanks for pointing that out again. It's explained quite well in the link I shared in the post (Siebe_status) which also quotes the paper you sent.
 

Hip

Senior Member
Messages
17,824
Yip, thanks for pointing that out again. It's explained quite well in the link I shared in the post (Siebe_status) which also quotes the paper you sent.

I don't understand why in that link he says "99.8% of Niclosamide is bound to plasma proteins, reducing the available concentration by 50x". It should be 500 times, not 50 times.

Or if we assume 99.9% protein binding, it reduces the available (free) concentration by 1000 times.


This means the niclosamide blood concentration of 660 ng/ml = 2 μM mentioned above becomes a free blood concentration of 0.002 μM. This is far below the IC50 of 0.28 μM.

So from what I can make out, niclosamide will not have any antiviral effect in vivo, as its free blood concentration will be too low.

The positive results from the clinical trials of CP-COV03 for COVID might come from some other non-antiviral mechanism niclosamide has.



We saw this before with ivermectin. Ivermectin is antiviral for SARS-CoV-2 in vitro, but in vivo its free concentration is something like 1000 times lower than its in vitro IC50. So there is no way ivermectin can be antiviral in vivo.

Yet some ivermectin studies showed benefits for COVID. It later turned out that the main benefit of ivermectin was protecting patients from Strongyloides coinfectionm, a coinfection that was caused by giving COVID patients immunosuppressive corticosteroids. This is why ivermectin seemed to work best for COVID patients in countries where Strongyloides is endemic.
 

Osaca

Senior Member
Messages
344
Yes, I agree with everything you said here, it should in indeed be a reduction of the unbound drug by >500x, at least if we consider the values in the Daewoong Pharmaceuticals study. However, this calculation assumes that we interpreted the Korean news statements correctly and that they were correct in the first place, which I'm not sure of.

It is hard to get verified information on CP-COV03 as the information doesn't run through the channels we're used to and the only information is translated news. What exactly does the statment "임상 참여자 60명의 채혈결과를 토대로 분석한 결과 CP-COV03의 혈중약물농도가 높은 상위 10명의 최고 혈중농도가 평균 660ng/mL로 조사된 것. 이는, 코로나19 바이러스 증식을 100% 억제하는 약물농도(IC100)를 훨씬 웃도는 수치다" which is also taken from the news and not official results mean? Is it supposed to mean unbound levels of Niclosamide which would extremely be significant but possibly unlikely (since this would be roughly 0.15g unbound Niclosamide in an average human which doesn't make sense at all if we consider the Daewoong Pharmaceuticals study), is it indeed the total levels of Niclosamide on which you base your calculations or is it something else? Without having reliable information I can't tell.

However, there’s one significant difference with Ivermectin I believe. Ivermectin was never shown to significantly reduce viral load in patients, something CP-COV03 quite clearly did.
 

Hip

Senior Member
Messages
17,824
What exactly does the statment "임상 참여자 60명의 채혈결과를 토대로 분석한 결과 CP-COV03의 혈중약물농도가 높은 상위 10명의 최고 혈중농도가 평균 660ng/mL로 조사된 것. 이는, 코로나19 바이러스 증식을 100% 억제하는 약물농도(IC100)를 훨씬 웃도는 수치다" which is also taken from the news and not official results mean?

Nearly always, these pharmacokinetic studies which test drug blood levels report the total concentration (unbound plus bound drug) in the blood. I've looked at dozens of these studies, in my efforts to try to find some enterovirus antiviral compounds.


When I was looking into CP-COV03, I found a rat pharmacokinetic study on niclosamide, which reported peak plasma levels of 354 ng/ml = 1.1 μM. So that is a comparable figure to the 2 μM discussed above.

CP-COV03 is more bioavailable than niclosamide, so rats given CP-COV03 would have a higher blood concentration. Nevertheless, once you divide this 1.1 μM figure by 1000 to account for protein binding, you unfortunately get a very low free concentration of niclosamide.


If CP-COV03 were to create high niclosamide concentrations in the blood, then it would also work for coxsackievirus B4, as one in vitro study showed for CVB4 the niclosamide IC50 is 3.88 μM (though niclosamide does not work well for CVB3, with an IC50 of much higher than 50 μM).




However, there’s one significant difference with Ivermectin I believe. Ivermectin was never shown to significantly reduce viral load in patients, something CP-COV03 quite clearly did.

I did not know that CP-COV03 reduces viral loads. Though reducing COVID viral load could be the result of some immune stimulating property of niclosamide.

Some compounds are not directly antiviral, but they can still fight viruses through boosting immunity.

If that is the case, then CP-COV03 could be a viable COVID treatment.
 

Osaca

Senior Member
Messages
344
I did not know that CP-COV03 reduces viral loads. Though reducing COVID viral load could be the result of some immune stimulating property of niclosamide.

Some compounds are not directly antiviral, but they can still fight viruses through boosting immunity.

If that is the case, then CP-COV03 could be a viable COVID treatment.
It reducing viral load is basically the whole reason why I made this post, as we otherwise wouldn't have any meaningful data. This is the data I refer to in my post: https://files.abstractsonline.com/CTRL/C0/5/8DC/EEC/AD6/42B/D94/364/4CF/5A1/FE3/72/g6849_1.jpg with a "remarkable 14-fold reduction in viral load compared to placebo within 16 hours after first dosing". It reduces viral load better than Paxlovid. Even if it wasn't directly antiviral, which is a possibilty (there's also the hyppthesis that Niclosamude works by blocking the endocytosis of SARS-CoV-2.), this would still be significant.

Without this data I wouldn't see a reason why CP-COV03 would have any use or why it would warrant an EUA.

Regarding the pharmacokinetic values. We don't have the values from the studies, but only from news reports, so I wouldn't count on them too much. The pharmacokinetic values are not from studies.

Is the rat study really comparable at 2mg/kg vs the ~1g used in humans?
 

Hip

Senior Member
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17,824
Without this data I wouldn't see a reason why CP-COV03 would have any use or why it would warrant an EUA.

Well we will have to keep an eye on the clinical trials. I wonder if they plan any trial for long COVID patients? EDIT: I just saw in your post that they are running a LC trial.

Hyundai Bioscience are making bold claims for their drug CP-COV03, stating on their website that it:
is effective against almost all viral diseases.

But I wonder what they base that on?

At the bottom of this page of their site, Hyundai Bioscience provide a table showing all the viruses niclosamide has been demonstrate effective against in various studies.

From the ME/CFS perspective, coxsackievirus and Epstein-Barr virus listed in that table are interesting.

The coxsackievirus study they mention is this one from 2012:

Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects

This is the study I linked to above, which provides a 3.88 µM IC50 concentration for coxsackievirus B4. But as we know, niclosamide cannot reach anywhere near that concentration in vivo. So why Hyundai Bioscience would mention coxsackievirus on their website is not clear.


And the Epstein-Barr virus study is this one from 2017:

Niclosamide inhibits lytic replication of Epstein-Barr virus by disrupting mTOR activation

If we look at the full paper on Sci Hub, we get the IC50 values for EBV:
The 50% inhibitory concentration (IC50) values of intracellular viral genomic DNA replication and extracellular virion yield were 0.13 μM and 0.092 μM, respectively, and 0.5 μM exhibited >95% inhibition of both viral DNA replication and virion production.

Again these concentrations of niclosamide cannot be reached in vivo.



Is the rat study really comparable at 2mg/kg vs the ~1g used in humans?

By my calculation, the rat dosing is the equivalent of a human oral dose of 65 mg.

The rat study used 5 mg/kg for the oral dose which reached 354 ng/ml = 1.1 μM in the blood.

To convert rat mg/kg doses to human mg/kg doses, you normally divide the rat dose by 6.2 (see page 7 here). So that division gives a human equivalent dose of 0.81mg/kg. So for an 80 kg human, that's an oral dose of 65 mg.
 

Osaca

Senior Member
Messages
344
Then indeed the rat study is not comparable. I would expect the Niclosamide of the Phase 2 trial to be somewhere between 4-12 times of that dose even with the extra weight of the whole Tween 60-coated NIC–MMT hybrid setup, or whatever they ended up using.

Regarding the effectivity on all viral diseases I agree that it's quite a bold claim and seems more like marketing than anything else, but I also don't think we can make any statements about reachable concentrations in vivo since we have no proper data (or do we really think they would apply for EUA all over the world with data that doesn't account for the amount of free drug available?).

The problem is that we can't keep an eye on their cinical trials, as these don't go through the channels we're used to. I suppose we would need someone from Korea to enlighten us on more details and how the EUA process is going.
 

Hip

Senior Member
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17,824
I also don't think we can make any statements about reachable concentrations in vivo since we have no proper data (or do we really think they would apply for EUA all over the world with data that doesn't account for the amount of free drug available?).

It could be that niclosamide has benefits for COVID by non-antiviral mechanisms, such as boosting the immune response against the virus, as I mentioned above. So the CP-COV03 drug could still be viable for COVID, but its mechanism may not be a directly antiviral one.

Some of the time drug companies don't even know how their drugs work, but in clinical trials they demonstrate a positive effect, and that is good enough to get a marketing license.

Having seen all the incorrect statements made by some researchers and doctors regarding ivermectin as an antiviral for COVID, when achievable free blood concentrations of ivermectin are about 1000 times lower than its in vitro antiviral EC50, I am now a little wary of statements claiming that any compound is antiviral in vivo for COVID.

But certainly we should be open minded about CP-COV03, and its possible benefits for long COVID. So I think it is good that you started this thread.



Then indeed the rat study is not comparable. I would expect the Niclosamide of the Phase 2 trial to be somewhere between 4-12 times of that dose even with the extra weight of the whole Tween 60-coated NIC–MMT hybrid setup, or whatever they ended up using.

The rat study results are within an order of magnitude of the human results, which is a reasonable tallying, given that different animal species can metabolise differently.

In humans, 1 gram gives a blood level of 2 μM.
In rats, the human equivalent of 65 mg gives 1.1 μM, so around 100 mg might give 2 μM.



Another approach to looking at the maximum blood levels of niclosamide achievable is examining the CC50, the cytotoxic concentration which kills 50% of the cells in your cell line. Obviously the concentrations you use in vivo need to be well below the CC50. The CC50 will vary with cell line type.

One paper says:
Evaluation of 50% cytotoxic concentration (CC50) on niclosamide-treated BHK-21 cells by using LDH assay showed that the value was less than 10 μM

Another paper says:
The 50% inhibition concentration (IC50) of niclosamide against HEV replication was 0.96 μM, and the 50% cytotoxicity (CC50) value in Huh7 cells was 16.17 μM


So in practice, you cannot really use niclosamide blood concentrations higher than about say 1 μM, which would be a reasonable safety margin below the CC50.


In antiviral in vitro studies, they often calculate the ratio of the CC50 / IC50, which is called the therapeutic index, or the selectivity index.

If the ratio is low, like say less than 5, then the antiviral compound is of no use, because the CC50 is to close to the IC50. But if the ratio is higher, like say 20 or more, then the compound may be useful.
 
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Osaca

Senior Member
Messages
344
I'm agreeing with what you're saying, but the pharmaceutical companies quite clearly know about the achievable free blood concentrations that Niclosamide has. After all we're basing our calculations on those of the study by Daewoong Pharmaceutical. The same company I mentioned in my post which is trying to develop Niclosamide as an antiviral in the first place.

Whether they know how their antiviral works, or if it really works is a whole different question. We should definitely be wary of bold claims of pharmaceutical sompanies that like scientific backing. Luckily, I think we should find out soon enough about CP-COV03, but I'm definitely not that naive that I would put big hopes into it. After all even the Phase 2 study had some unusual results. On the other hand it's one of the only Covid antivirals showing promise.
 

hapl808

Senior Member
Messages
2,052
I think in general pharmaceutical companies only have theories on how a drug works. If they actually knew the mechanism, then we wouldn't need double blind placebo controlled trials.

Medicine is much less precise than we imagine. Even blood concentrations just represent our understanding, so I'd be cautious taking those as the holy grail. And as you've said, who knows what other mechanism(s) might be involved.

We don't understand viruses - if Covid proved one thing, it was surely that. Many dogmatic things ID doctors and virologists have said over years turned out to be false. Unfortunately, if we don't really understand viruses, we understand antivirals even less well.

We've thrown tens of billions at one single virus (HIV) and I'd posit that's the only one we even vaguely understand or can treat. Sadly, we still spend more on HIV every single year than we've spent on Long Covid in the last three years, and I don't expect that to change. Although I hope I'm wrong on that. (Obviously hoping we spend more on Long Covid, EBV, and other viruses - not spend less on HIV.)
 

Osaca

Senior Member
Messages
344
Oh yes, medicine is certainly not an exact science and the pharmaceutical industry is closer to being an alchemy than a science.

Whilst, we might not understand viruses very well, this is shadowed by how little we understand the human body.
 

Rvanson

Senior Member
Messages
312
Location
USA
Oh yes, medicine is certainly not an exact science and the pharmaceutical industry is closer to being an alchemy than a science.

Whilst, we might not understand viruses very well, this is shadowed by how little we understand the human body.
Indeed so. However, we do know of a medication that can help with ME. Apligen.

In all these years it had to be administered through infusions only, at very great cost and distance?
There is no pharmaceutical company that could devise a way for an injectional or pill form, while people with HIV can now consume a product that reduces HIV to an inactive form, as long as they take it?

No, it's not a cure for HIV at all, and we taxpayers still have to pay for it. A communicable disease that
need not have spread as it has for 40 years?
 

Osaca

Senior Member
Messages
344
Have you seen the anecdotal results the antiviral sofosbuvir long COVID? A few LC patients have obtained remission from this drug in a matter of weeks, and other LC patients are now gearing up to trying it.
Of course, but where the evidence for CP-COV03 might be lacking, it simply doesn't exist at all for Sofosbuvir https://www.thelancet.com/journals/lanam/article/PIIS2667-193X(23)00040-6/fulltext (some studies look a bit better, but it never comes close to Pax). I'm still a bit sceptical as I also saw alot of LC patient "achieve remission" from Ivermectin. Let's see if more anectdotal evidence pops in, I would hope so. I would certainly love to see a trial with a cocktail of antivirals, as that's the only way for other diseases as well.
 

Hip

Senior Member
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17,824
Of course, but where the evidence for CP-COV03 might be lacking, it simply doesn't exist at all for Sofosbuvir https://www.thelancet.com/journals/lanam/article/PIIS2667-193X(23)00040-6/fulltext (some studies look a bit better, but it never comes close to Pax). I'm still a bit sceptical as I also saw alot of LC patient "achieve remission" from Ivermectin. Let's see if more anectdotal evidence pops in, I would hope so. I would certainly love to see a trial with a cocktail of antivirals, as that's the only way for other diseases as well.

I agree, and so far, the long COVID patients who have recovered using sofosbuvir do not appear to have PEM, which makes you wonder whether they really have the ME/CFS form of LC, or some other form.

Many LC patients only have POTS, and others may have some ongoing heart and lung issues from tissue damage sustained during the acute infection, but not ME/CFS. And many LC patients have post-viral fatigue, which appears identical to ME/CFS, but which clears up on its own after some time.
 

Osaca

Senior Member
Messages
344
Oh yes. Post-viral fatigue is definitely confused with PEM far too often. I had extreme post-viral fatigue after my first Covid infection which then also reactived EBV 2 months later and caused a severe mononucleosis illness. Had I not later learned what PEM is I would have misinterpreted that for PEM probably, because the differences are not clearly communicated. But the differences are significant and life-changing.

Metaphorically I would say:

Post-viral fatigue is like running up a hill where you keep on slipping down and falling back, but eventually with enough time you make it up the hill (Exercise makes you worse and exacerbates symptoms, but you eventually, which can take a year or even much longer, get better and fitter. You don't get permanently worse.).

PEM is like trying to run up the same hill but your path is blocked by a unclimbable wall. If you run against this wall, you are pushed to the start of the hill and the wall is moved further down the hill or even to the bottom of the hill, leaving you stuck forever.
 

Hip

Senior Member
Messages
17,824
As I understand it, post-viral fatigue as an illness is identical to ME/CFS in symptoms, and may actually be the first stage of ME/CFS that you get after a viral infection.

In many people, their PVF slowly clears up after about 6 to 12 months (though it can last 24 months before clearing up). However in others, the PVF becomes permanent, and that's when they realise they have ME/CFS.

So I tend to think of ME/CFS as PVF which never cleared up.

If we could figure out why some PVF patients heal themselves after 6 to 24 months, it might throw light on the nature of ME/CFS.
 

Osaca

Senior Member
Messages
344
As I understand it, post-viral fatigue as an illness is identical to ME/CFS in symptoms, and may actually be the first stage of ME/CFS that you get after a viral infection.
That could be the case, but at least in my experience PEM and post-viral fatigue are very different and I think the majority of post-viral fatigue is somewhat a natural occurence rather than being a sort of pre-stage ME/CFS.

I would also not rule out that we're not even talking about the same thing as the names aren't clearly defined and things like PVFS exist, but aren't used anymore. And even I have to be honest that I haven't heard of post-viral fatigue as an independent illness.