182

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Islatravir: a remarkable persistence

By Charles-Edouard!

The dilemma of injectables:

In a somewhat rommed vision of the role of historical associations (e.g. Act Up), we see activists struggling with a criticism, sometimes relevant, of therapies. But, for years, none of that! Some declare:
Les ActupienNEs, an association where expertise is our weapon to fight against AIDS in the face of the authorities and the current under-information. (sic)
If you are not funded, you run out of money quickly, and if you are, you shut up! Injectables, as attractive as they are, are a real massacre: overdosing at its peak. And no one, no one to ask the slightest question... That's how it is...

Islatravir and persistence: Stage 3 of development

This ticket is crucial for the future! We must understand the implications... In our previous posts, here and there, we had followed the 'classic' development aiming to gain in efficiency and lose in toxicity. Well... It was funny, but well... An inefficient or toxic molecule would not find a buyer today. So, the gain of efficiency or the loss of toxicity, it's good but it's not likely to move in the houses. With step 3, we're approaching what is so specific to Islatravir, which means that we'll be able to do intermittent treatment more comfortably, but we'll also have to do it: no escape! So, it is important to follow up!

The toxicity of metabolites

The problem of intracellular metabolites: Degradation of nucleobases leads to loss of biological activity of nucleosides and sometimes free nucleobases are toxic. It is therefore desirable that the glycosylated bonds of nucleoside drugs are stable in vivo.

As expected, 4′SdN showed strong activity against all existing resistant HIV strains.

Next, metabolite toxicity was tested in mice. The 2-aminoadenine (EAdA) and guanine (EdG) forms were highly toxic. Degradation by adenosine deaminase is a serious problem in the development of antiviral nucleoside drugs. The researchers finally recognized that 4′SdN (candidate in the previous step) was not a good solution due to its toxicity (metabolites) .

However the 3′-OH group is essential to prevent the emergence of resistant HIV. Different variants have been created: EFdA, EFddA, EFd4A, ECldA... EFddA, EFd4A and Ed4T, d4T, which do not have a 3'-OH group, were effective against wild-type HIV but decreased in activity against resistant HIV. On the other hand, EFdA and ECldA, which have a 3'-OH group, showed excellent anti-HIV activity against wild-type and resistant HIV. In addition, these selectivity indices (the ratio of the toxic dose to the effective dose) were greater than 100,000. This result indicates that one can have both the presence of 3'-OH groups and low toxicity.

It should be kept in mind that in these inhibitors, the original form but especially the tri-phosphate form are active (cf Tenovofir, Abacavir, etc)

EFdA and its triphosphate form, EFdAtriP, are not a substrate of DNA polymerase (no toxicity there...). EFdA is therefore not toxic. The half-life of EFdAtriP in plasma was 17 hours in vitro, but more than 100 hours in vivo, which indicates that EFdAtriP is very stable and remains active in vivo: this indicates that RT also uses the phosphate form, EFdAtriP, as a substrate in vivo. This is the Kiss-Cool effect!

A new mechanism, therefore a new class

The EFdA is now well away from its ancestor, with its sulphurous reputation. We'll see later who this clunky ancestor is and quickly retracted by the marketing teams, who jumped on the observation that EFdA is a translocation-defective RT inhibitor that cannot move from its initial binding position to the next substrate-accepting position because the binding to RT through its 3′-OH and 4′-ethynyl groups is so strong. This is a defective RT inhibitor by translocation. Whew!

(Bah... If you figured that out, hats off!)

No intracellular degradation, in vivo

The trick is there! Once in the cell, Islatravir is metabolized very slowly, the metabolite, itself active, is also metabolyzed very slowly. In a word, it persists ad vitam, so to speak. And who is the good model of an ad vitam persistent inhibitor? Lead (and other heavy metals). If we are not careful, we can reasonably ask ourselves the question of 'lead poisoning' with Islatravir. There would then be a real problem of cumulative dose, which, in the long run, could bring back the toxicities of its infamous ancestor. For the moment, according to the designers, this would not be the case... But it's always the same story!

We will follow with attention how Merck's marketing services could try to hide this, by planting a forest of arguities around this jewel. It started with the idea of selling Islatravir at a dose of 0.75 mg. Now the project is at 20 mg. That suits us... As I said before, I don 't see how Merck will be able to sell this e-th ARV without promoting its only distinctive advantage: persistence!

Weekly intake and 1/15

In fact, the weekly (or even better) oral intake is the objective enemy of the treatment obligation... You may not have realized it, but those who are obsessed with the injection do...

Obligation of treatment / Judiciarization

I guess now everyone understands that the pass, supposedly yours, is in fact remotely disengageable... It's freedom conditioned to the goodwill of whoever runs the central servers. Brrr... We'll have to take refuge in the bush. It's pretty awful, when you think about it.

In the news

- The doctor who made this video is very British... If you can live with it, it is a very clear explanation of the difference between the new Pfizer drug and IVT: New Pfizer drug and ivermectin

- A clarification from D. Raoult on confidentiality in HIV: it concerns us all and it becomes problematic. On this Video, at minute 7:30 We will come back to this, it is really important!

The French genius

This old tune is haunting, we all know it, it comes to us from past times and ballads us: Mon amant de la Saint Jean...

More subtle is this extraordinary film of Jean Cocteau: Le Testament d'Orphée or don't ask me why... You can find the complete version on DailyMotion. It is bizarre, at the limit of understanding, and also very French! very! The Chinese version makes no sense. You can listen again to the magnificent Danse des ombres heureuses (here, Rampal on youtube), extracted from Orpheus. This revolutionary work will trigger a new quarrel after the famous one called "des Bouffons" (which opposed Rameau and Rousseau). Here the partisans of the French operas, the "Gluckists" and those of the Italian opera, the "Piccinists" will clash.

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good weekend, good stuffing and not too many meds ... Huh?

181

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

DTG: a failure without induced resistance

By Charles-Edouard!

DTG: did my failure create resistance?

For those of you following along, I failed a lot of copies, a lot! Plus, it was maybe the only time I was behind on my resume schedule. I did it at 3 months, instead of 1 in the exploratory phase. That's how it is, sometimes I get stuck abroad, without access to the CV, or to the meds for that matter, hence the interest of the 1/X: you leave with a few weeks of treatment, but you stay for months (and months...), it's all good! Well, I did what I shouldn't do. Leibowitch said it again and again: you have to make your CVs(in the exploratory phase, of course).

Even if I was late, I did it... I was on DTG monotherapy, 150 mg in 1/7 (collated in a capsule, which is perhaps the problem). Well... The failure was only a half surprise. The height of the failure was a real surprise! I blew up my counter, and I think I even made the highest failure of all I read in Mono-DTG, that's saying something!

Damn, didn't I create some resistance?

Catching up with the DTG

Even Leibo didn't have much of an idea on the subject... However, I knew one thing, on the Integrase, my virus is clean! It's not complicated, it has never seen RAL (let alone EVG, I'm not that stupid). So, for me DTG would act like an Absolutegravir, a concept I developed, not tested, except that here it is the truth.

Understanding that viruses that have been exposed to old INIs (RAL, EVG) are likely to acquire new resistances under monoDTG is the Achilles heel of this strategy. On the contrary, when we look at the rare French publications on DTG resistance, we identify multi-resistant patients (INIs) included in the rescue trials. I have not seen any published resistance on originally clean viruses. In other words, de novo resistance on non-pre-exposed virus does not exist! And if you find any, please correct me.

This is very important because it is the cause of the extraordinary overdose of susceptible patients because the choice of the dose was guided by the dose needed for mutated viruses. In a word, thousands of patients are being overdosed with DTG (and soon injecting themselves) at a dose chosen to control the virus of the few who had messed up with the virus: you don't treat your virus, you treat someone else's.

For me, DTG was an Absolutegravir... So, if my vision of what is an Absolutegravir is right, this is the opportunity to try it! Leibo proposed a drowning. I decided to try resuppression with DTG, there would be time to do a drowning, if needed, later on. I have already explained the chosen scheme: I resuppressed with DTG, without making a resistance profile, assisted by usual and less usual companions: it worked like a charm. In 1 month it was fixed, as usual for DTG, so no damage... So DTG is still part of my world.

Has DTG remained an Absolutegravir?

If you failed Mono-DTG, you might be afraid that this wonderful property (Absolutegravir) is now a thing of the past... In Eclipsotherapy on Dodeca, we don't really care. But then again... If DTG is amputated, we might as well take it off Dodeca... The resistance profile, was not done, I resuppressed without worries, so basta!

Except that... The Lab got mixed up with the brushes! Yes, yes... It happens! They did a genotype in addition to the DNA quantification. Well... I don't have a lot of confidence in these explorations at the limits, but well... They did it, they did it

Well yes! No resistance mutations in the INI

That's it... that's what I thought! My virus stayed clean (at least what the lab says). I was a little suspicious, but it's reassuring to know that! You're doing great in Mono, and, you're still perfectly susceptible! DTG is great for those who know how to use it! And to use it alone! I was very careful not to associate it with 3TC, because the 184, you get it every time. But we're clean there too!

And elsewhere? I did 4/7, 2/7, 1/7, 1/15, 1/21, failed 1/27, Mono-DTG 25 mg 7/7, 12 mg 7/7, 150 mg 1/7 (failed) and nothing. Nothing from nothing... Not a single acquired mutation... Nowhere

In the exploratory phase, you have to make your CV!

Well... I didn't stay on Mono-DTG for long, so that must help a little. Since then I do my CVs religiously, in the descent phase. In stabilized phase, no... No injections, no more blood tests, the less I see the 'specialist', the better I feel... She is nice, very nice... She's nice, but you won't get better with her

Icing on the cake: the disappearance of the tank

This allowed me to discover(fortuitously, but not that much...) the disappearance of the tank: my big topic of the moment.

The next step after the disappearance of the tank is... It is... for another time ;-)

In the news

- A vaccine injection that must be repeated every 6 months!?!? Hello Houston: There is a problem...

- Mr. Zureik answers the challenge (it would deserve the Canard Enchainé): As an answer we have seen better!

- Actually, it's quite simple, you read about what makes the soap merchants tick. It's often interesting! It makes them angry because it attacks their business! The Chinese with HCQ, the Indonesians with IVT, the downgraded with NVP, the Malagasy with their syrup, they must be laughing! A good real laugh is communicative, it is joy!
Pr Perronne probably had the wrong idea about the herbal tea... Molecules coming from Nature are always there and immune to prevarication.

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Science under finance is only ruin of the Man...

180

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Intermittence and flu vaccine

By Charles-Edouard!

The Thai health system offers the best quality/price ratio, it is well known. ARVs are not subsidized and are affordable for the average tourist. And the trip is fun! The problem is the cost of Biktarvy: 58 Eu./month (in France, it is at least 10 times that!), while NVP/TDF/F-3TC is 19 Eu. / month. There are many testimonies of use in 2/7... It leaves one dreaming! The (anti-)French social security system is a burden on the gross salary and favors relocations...

The flu shot? Not for me this year

Before, I had no objection... That was before I read, under the pen of the excellent Pr. Montagnier, that repeated vaccination does not bring anything, especially if one has already had a few natural influenzas. I am one of those people who listen to our best Nobel Prize winner. Do you have anything better to propose ? Well... So I listen... So, I made a bad quote: vaccine every 5-6 years, not more. On the other hand, I am very careful about the pneumococcus. Everyone around me is up to date.

2020: a useless vaccine!

I let myself be convinced by the usual TV shopping and I took the flu shot in 2020, so as not to be confused with the other lisp. As a result, I took the shot the only year the flu did not circulate

Vaccine and HIV: beware of CV rebound

Yes, yes... I know it's fashionable to participate in social networks by advising the vaccine to S+. All the more easy as for this blind medical advice, the selective censorship lets it happen... Of course...

You can look up the references on Pubmeb, there is a plethora of articles that note a (temporary) rise in CV just after the flu vaccination. The patient who is monitoring her CV during the ICCARRIAN descent phase can therefore consider doing her CV BEFORE getting vaccinated (eventually): there is no point in panicking. I even pushed the envelope a bit further by going to the hospital to have my blood sample taken (yuck...) and by handing my vaccine box to the doctor on duty, who made a face but did it, not for free, but for free!

It's not a big deal, but as soon as you mention the risk of blip, you get lynched!

Well... I did the vaccine and no CV, it's just as well, since we're going to go easy on the CVs, now that the 1/15 is well secured...

In France, flu vaccination is recommended for people over 6 months old belonging to a group at risk of complications (people over 65 years old, people with severe asthma or chronic lung diseases, people with severe immune deficiency). I have not seen a blind recommendation for S+ in general

The 2022 vaccine is kif-kif 2021??

According to Wikipedia, the effectiveness is usually assessed by calculations and simulations (whose results depend a lot on the chosen hypotheses ). Someone will have to explain to me the effectiveness of the 2021 vaccine, a period when Influenza has not circulated at all! In a context where people were cautious, it did not circulate: caution works! About the flu...

Weekly intake and 1/15

In fact, it's confirmed, my tank is gone (in the blood...) Before even asking the question of what made this possible, the question of what to do in 2022 arises.
I have never seen in the literature a trial showing the disappearance of the reservoir, i.e. with a before/after, including in the 'cure' trials (except perhaps, to be checked, the one in Brazil, recently). In other words, this is new... I'm exploring... Of course, this is great: here is what the biologist says

Obligation of treatment / Judiciarization

... The injectables are coming... That's it!

In the news

- Injectables are coming (finally!): the commercial match will soon be Vocabria(2 big shots every 2 months) vs Islatravir(in 1/7 'official' and more if affinity). The Tele- BichatAchat will have a great time!

- I am now on Telegram: see the link https://t.me/charles_edouard

- Another excellent article: Should we vaccinate against PCR detection or against Covid-19 disease? by Pierre Sonigo, Caroline Petit, Nathalie Jane Arhel

- No impact of HIV on the consequences of SARS-Cov2, according to this article, except, perhaps, when CD4 is low...

- Actions Traitements has a new information booklet: L'allègement thérapeutique dans le traitement du VIH. Go there if you want... My Practical Guideis online since... 2014!

The French genius

Samson François plays Debussy... This is not German music, nor even European! (I don't know what that means...) Suite Bergamasque : Clair de lune

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The real insider tip is to know which doctor to go to...

179

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Islatravir and safety

By Charles-Edouard!

As the HAS is struggling to rule, we sometimes read a lot of nonsense (anonymously, on the net):

Where on earth did this come from? The conditions for inclusion in ANRS-4D and QUATUOR are 1 year of certain virological success. The treatment starts with a horse dose (induction) followed, in case of success and stability, by a reduction. We do not start with a reduction of the dosage on the first day or the day before our own death! The undetectability must be reached and confirmed by a test at more than 6 months (cf rare cases, seen in the Gilead trial, for example, the load can be undetectable a first time, then rise again, it is Raffi who spoke about it, that is to say!), one leaves oneself a little margin, thus that leads to approximately 12 months after the first undetectability... It's simple: too early you lose the benefit of the induction, too late you lose years of unnecessary overmedication!

Islatravir, a development not very XXI century

In previous posts, we have seen how Dolutegravir marks a fundamental evolution in pharmaceutical chemistry and inhibitors in particular. We find this same modernity in the development of anti-SARS antivirals. The idea is simple and the most modern technology is beginning to make it possible. Inhibition is a key-lock system: the better a key fits the lock, the more efficient it is: it sticks as close as possible to the function and therefore prevents any other molecule from accessing the enzyme, i.e. the protein that catalyzes the reaction. No catalyst, no reaction. [As a reminder, in classical chemistry, an inhibitor is called a poison, of which the best-known example is... lead (as it screwed up the function of the catalytic pot, it was removed...)]

The modern method benefits from the latest advances in protein (including enzyme) imaging/mapping. It's long, it's complicated, but more or less we manage to make a 3D map, with a very high definition of the coastal profile, thus of the harbor which shelters the catalyst. It remains to design a Sardine that will block the port of Marseille. A lot of tools are needed, the map and docking software that calculates affinity, steric hindrance, etc.

There is a method and tools. So much so that it raises the question of 'discovery'. Indeed, the lock controls the key and there are not 2 perfect keys for the same lock! The one who presents an optimal key for the lock will obtain the patent, thus the exclusivity. However, he has only made the 'negative' of the card. The question then arises as to the fair remuneration of the person who has made... the card! Because the real discovery is the map, and the invention is its symbol(in the etymological sense of counterpart). And for a given map there is only one optimal pharmacore. This forbids any further invention! Dolutegravir marks a new generation of INI and also its end. The possible improvements, relative to this catalytic site, are marginal. It is therefore not surprising that Bictegravir(Gilead, actually Japan Tobacco, Tokyo) is the look-alike of Dolutegravir(GSK, actually Shionogi, Osaka): all this is drunk from the same glass of sake!

Well, Islatravir is just the opposite! It's a fin-de-siècle molecule, developed in the old way, and kept in a closet(yes, yes, this part is a bit painful to the heart, when you think about it), it's due to intuition, to experimentation, to expertise.

Islatravir: episode 2, safety

As we saw in a previous episode (read it absolutely), the starting point is a shitty ARV(we'll come back to that) which has been worked on to optimize the recognition. Great except that other enzymes recognize it too! It messes up the reverse transcriptase (what a bitch!) but also natural and useful polymerases. Shit!

Islatravir and... antibiotics

Many naturally isolated nucleoside antibiotics are available. Most of them have been modified with a physiological nucleoside, and although they have high antibacterial and antitumor activity, they were also very toxic and could not be used clinically (e.g. Tubercidin, Aristeromycin, Nucleocidin...). They were unusable... Therefore, in the 1960's and 1970's, nucleoside chemists chemically modified these antibiotics again on a single site in order to obtain nucleosides with a better biological activity.

However, once modified, the activity was lost in all cases. Dang!!! So, you're ticking your thing off at one point (or more), you eliminate the toxicity, but goodbye the efficacy��! Needless to say, by the turn of the 80's, no one was doing this anymore...

Thus, many researchers at that time left nucleoside chemistry, claiming that "nucleoside chemistry has no future" (especially in the United States, it became difficult to get research funding and the move was rapid). However, the Japanese researchers surmised that "loss of activity means loss of toxicity."

Loss of efficiency on the polymerase

The idea is the following. The problem is twofold: the selected molecule is efficient against Reverse Transcriptase(good) and Polymerase(not good). If we try to reduce the toxicity of the molecule/polymerase couple by the classical way (now abandoned) we will reduce the toxicity (towards Polymerase) and the efficiency (towards Polymerase), which is a good thing because it will reduce the toxicity due to the efficiency on Polymerase !

Therefore, if the toxicity of 4'SdN in which one of the physiological nucleosides is modified is high, it is considered that the toxicity can be reduced by modifying it further. This is because human nucleic acid polymerase recognizes our modified nucleoside (the candidate molecule) at one site (it attracts it as a docking port) and integrates it into the DNA or RNA, but it is expected that a nucleoside modified at two or more sites will not be recognized and will not attract it anymore!

That's it! Islatravir's ancestor has just lost his toxic virginity!

... Without losing its efficiency towards the reverse transcriptase. An efficient aegis, whose first descendants are non-toxic... And it is not finished! Researchers are going to work on the metabolism (the life span), because it is the objective: to make a cheaper ARV!

Well... We'll see this next time

The French genius: Sonigo and Raoult, always...

You have to read the best! The best modern and accessible microbiologist is Raoult, unless you have someone else to suggest, if you wish. Even if he is not involved in the problem of the moment, we must read and reread Sonigo. He predicted, on the basis of general considerations, that the virus would become less dangerous as it would inevitably mutate. Let's go for the general rule, and we'll see if the massive Spikisation comes or not to disturb the context. We will see... Remains that Raoult, he comes with marbles, genomes: the virus/variant cannot not mutate and its effect d��croit at the grè of successive mutations. There you have it... The usual future of a variant is to disappear, within about 2 months of its emergence. A whole new understanding of RNA virus epidemics is emerging to the public eye.

For the record, THE video of Raoult which dedicates this erosion is here. Erosion considered by Sonigo and quoted in my post here. Because it is necessary to read and re-read Sonigo! And we applaud the prescience in this issue of JDS, remarkable! The interview dates from ... 1996! it reads:

One will also read with interest the interview with Leibowitch, and in particular this
Why is this important? because it is the culmination of a series of posts to come on the responsibility of all (including patients) in overdosing. To be continued...

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Turn off the TV and don't be fooled by Pharisaical veracity

178

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Lorgeril and his filly: a little science in a hysterical world

By Charles-Edouard!

Lorgeril and his filly: an already old observation

In the trial that paved the way for the marketing authorization of Genvoya(Gilead, again and again...) there is an annomaly, which, very appropriately, is resolved (by itself?) in the last stretch. I'm curious about this, but at the time I would never have questioned the solid science of double-blind trials. However, it was strange...

Is it possible to cheat a clinical trial? Normally not, but what about it? Once you open Pandora's box you find so many and more. The first one that made some noise was the Jupiter trial. The controversy continues (see BMJ article). And the valiant de Lorgeril, who put forward the cheating, will have been consigned to conspiracy, despite an impressive career (remember, the Lyon Study and the Mediterranean diet is him, among others). The denunciation of the Jupiter essay is here

So he has often discussed a bias in trials that seems to be on its way to being found in THE vaccination-that-is-not-a-vaccination...

Lorgeril and horse racing

His demonstration was brilliantly illustrated in a TV program that I did not find again. Too bad... It's still easy to visualize...

At the Grand Prix du Président de la République (yes, it would not be for sale, but it has a price...), the competitors are at the start. The favorite, Astra de Zeneca, makes a great start. She dominates! At the halfway point, her lead is clear: she wins, she wins! And it is the fall of her followers. The owner calls out to the judges: what's the point in continuing the massacre: for the sake of everyone, we might as well stop here and declare Astrée de Zeneca the winner, hands down. The public is all for the filly, favorite of the media.

The time to consult the Wise Men, which is, as we know, only a formality, Delta du Bengale comes from the end of the race and makes an unprecedented comeback. The outsider is relentlessly climbing back up and it is urgent to declare Astrée de Zeneca the winner.

It goes very fast and Delta du Bengale is neck and neck... Here she overtakes Astrée de Zeneca, beaten at the finish, to the great displeasure of Sir Zeizer, the owner

One must beware of a temporary superiority

The effect of statins is deceptive. They seem to be beneficial for a while, then the cardiovascular risk takes over. This is normal... In the end, everyone dies!

Obviously, the industrialist-sponsor of the trial has every interest in winning the decision at the most favorable moment! And to erase the traces of his misdeed. Out of compassion, the trial will be stopped in view of the obvious benefit (provisional, it is true) and we will even treat the control group in emergency. Oh the unfortunate ones who otherwise would have been victims of their abnegation: no more control group, no more remontada!!! And the trick is done!

Relative decline in the performance of genetic therapies

The hypothetical theater is being built in front of us: let the show begin! Israel, once shown as an unmistakable example, is turning into a fiasco... It's not yet sure, but it's taking the shape of a big increase of positive PCRs, for some or the others. Of course the pro-vaxx people look the other way. Yet Pfizer had negotiated with the Israeli government to have (and publish) the data, which they hoped would be unassailable.

Will Laurent Alexandre eat his hat?

A promise is a promise...

Obligation of treatment / Judiciarization

I had opened a section "Obligation of treatment / Judiciarization" concerning HIV... I kind of gave up because it's so hopeless! But well... Here we go straight to it!

The 1/15 / My tank

Well... Almost 2 years in 1/15 and an undetectable CV... I'm looking for my "missing tank" ... Well, not quite disappeared but it is confirmed that it went under the radar. That's good, it's confirmed! How much is it? We don't know more for the moment! I hear that people argue that as long as it hasn't disappeared entirely, there would be no benefit in reducing it to mini-mini... Really??? How many people do you know who measure their tank every year, make new arrangements and see it drop below the radar in less than 12 months? Leibo would have been thrilled as hell: It is nevertheless the strategy that he went to expose to Pasteur...

The French genius: Luc Montagnier

Me, I gladly listen to Montagnier... 4 pillars support Eclipsotherapy and 2 are perfectly predicted by Montagnier!(I will do a paper on this... )
A very good view of things in this Letter from Montagnier

1/ Coronaviruses in general are not dangerous.
2/ The SARS-COV2 Coronavirus has a natural origin which has been modified in a laboratory from which it came out. It is a pathogenic chimera.
3/ Both DNA and RNA viruses are made up of nitrogenous bases that belong to nucleotides.
4/ Variants are all the more frequent as vaccines become more widespread.
5/ The messenger RNA vaccines aim at producing a toxic antigen: the Spike protein.
6/ The fate of the virus
7/ Vaccinating during an epidemic period is a nonsense, increasing the undesirable effects: epidemiologists know it.
8/ Nature is stronger than scientists: collective immunity is a delusion.
9/ The health pass imposes quasi-mandatory vaccination to too many people, to avoid the responsibility of the government or the manufacturers.


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Turn off the TV/Twitter and don't be fooled by Pharisaical venerealism

177

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

The request made to Marie

la HASByCharles-Edouard!

Haute Autorité de Santé: it drags, it drags...

It has been almost a year since the HAS was asked to include in its work program the formalization in its 'recommendations' of what is already in the 'Morlat' recommendations.

Well... 1 year already and no way to know if it has been included in the 'work' program. At this speed, it is not sure that the HAS still exists when it will be released!

The formalism to which one must adhere to make such a request is in itself a first barrier. But that doesn't matter... On the form the HAS has received the document in due form. But it's been 1 year since we had any news...

The technical argument: General statement to explain the request

This is how the text starts:

Privileged access to subscribers

The rest of the document is reserved for subscribers who will receive it with their monthly newsletter. Don't forget to subscribe!

Quote of the month...

From the famous Dr. Zelenko :

And you thought it was age and some comorbities!

Well no... If you are Chinese, Korean or even Indian (yes, yes...) your 'chances' of passing are not comparable with, well, let's take the most sinister example: Londoners(or even the inhabitants of the 93, that's not sad either!). As for the doctor, we've understood that for a long time!

The real insider tip is to know which doctor to go to...

176

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Genesis of Islatravir: 1- Race for Efficiency

By Charles-Edouard!

Islatravir and Soy Sauce

To understand Islatravir and what I'm going to talk about today, you have to be sure you've read this first post, because Islatravir is a novel that starts a thousand miles away from 1/15...

At the beginning was a group of Japanese university researchers who were looking for ways to add value to food products, by breaking molecules to make 'valuable' molecules at lower cost... In a word, cutting a big molecule, existing and cheap, rather than synthesizing, ex-nihilo. Vast program where the Ministry married them with a local Kronenbourg, a brewer of beer (agrobusiness, we say...).

The idea is to cut 'natural' molecules into elementary bricks. This allows to manufacture animated acids for which the market (pharmacy, biology,...) is emerging. The beer brewer doesn't care about this, but a manufacturer of Soy sauce, the one that decorates your Sushis (yes, yes...) has a division of specialized products. Yamasa (Soy Sauce) takes the place of Asahi (Beer) in this academic project. Surprising, isn't it? Neither Merck nor the usual parrots will tell you this. Because Merck will defend itself from the shameless price it will get for its research efforts, which were insignificant, as we shall see...

Islatravir and Efficacy Gain

The project is the manufacturing by (enzymatic?) cutting of molecules in bricks, with very high added value, at lower cost... At the turn of the century, the most expensive molecules, facing huge challenges of industrialization, are the ARVs, which the (third) world needs so much. So here are our brilliant university chemists(paid by the penny) who undertake to make a derivative ARV, which costs less! Thus saving the world from a certain AIDS death.

A major track is the increase of efficiency. Indeed, if we use less drugs for the same effect, it costs less per patient. Leibowitch develops a method(largely ignored by the medical-pharmaceutical mafia) which divides the cost by 10. The Japanese chemists will reduce the cost by ... One thousand!(and we will combine the two, hi, hi, hi... ). Efavirenz is 600 mg, Islatravir is 0,75 mg, which makes a ratio of 1 to 1000, by a ladleful!

So here are our chemists who start with an expensive molecule and try to improve it. Well... The scheme is hyperclassic, we start from a molecule with a known but moderate efficiency and we try to adapt the molecule to its target. A vast program!

Step 1: better resistance profile but high toxicity...

NRTIs are 2', 3'-dideoxynunucleoside (ddN) derivatives whose efficacy is due to the fact that nucleosides are RT chain terminators (CT). However, all these drugs have a low barrier to resistance. Since the structural difference between dN and ddN is whether or not they have 3'-OH, they surmised that the presence or absence of 3'-OH changes the resistance profile. A 4'-substituted 2-desoxynucleoside (4'SdN) substituent at the 4'-position was designed to achieve this goal (Fig. below).

In their hypothesis, the new compound can be recognized by Reverse Transcriptase (of HIV), and mess with it... That would be cool! The problem is that it is also recognized by the human DNA polymerase, which would be highly toxic.

Step 2: solve the toxicity problem...

Well yes... We might be able to treat better, of course, but increasing toxicity is not great, especially in the context of the 2000s. We will see next time how they solved this problem

Obligation of treatment / Judiciarization

The idea of making screening compulsory, regular, for all, from 15 to 75 years old, for transmissible diseases (HIV, HCV, Syphillis, etc) seems to me to be quite acceptable: screening is without danger, by itself it allows to reduce the epidemic, it does not imply a compulsory treatment. Voluntary screening with community pressure on risk groups has had its day: it is useful but we have reached a plateau. While we have spent crazy amounts of money(yours) for a virus that probably escaped from a research center(not from our country), we could finally put in place a total strategy of multiple screening. Of course, the associations, who gain from the 'targeting' and the martyrdom of the afficinados of natural contraceptive penetration, are against it. What the hell!

They are against you as patients and participate in the expansion of the epidemic, under the guise of fighting against it. They are the objective ally of BigPharma, which would not be at all happy with the extinction of the epidemic. Have we ever seen these associations of frightened seronegs come to your rescue for the intermittence? Never... Total radio silence.

Protocol medicine is becoming totalitarian medicine... It is inevitable!

In the news

- The front line in the global war on Benevolent Medicine is currently in the state of Goa, India. Maudrux, bothered by the Council to the Orders, is following up on it, here. This state has taken it upon itself to deal with the Indian resurgence of the epidemic by distributing Ivermectin widely. The crisis is being contained, which no one is talking about. After Chiapas, all of Mexico is getting in on the act. Opposite Goa, Tamir Nadul (180 million inhabitants) is a comparison for having followed the negative advice of the WHO and thus backed off. Two regions, in the same area, epidemic at the same time, 2 opposite strategies, this makes a credible judge of peace. Concerned' but not destitute doctors have taken the case against the State of Goa to the Supreme Court, citing the negative warning of the WHO. The Government of Goa, defends its initiative, with arguments in support. The Supreme Court lets it go ahead: see here...(one will remember the role of an Indian Supreme Court in the resolution of the Gordian knot where the ARV industry had taken the HIV world hostage)

- Remarkable interview with Prof. Montagnier: we will come back to it, one day, because his argument on the thermodynamic stability of DNA deserves our attention. The argument has its part in my strategy of reducing the reservoir.

- The IHU (Pr Raoult) publishes its series of 10,000 patients treated in day hospitals: no deaths in patients under 60 years of age, if HCQ/AT. If we exclude very old patients with low life expectancy (heavy comorbidities), they have only 3 deaths out of 10,000, if HCQ/AT. This is the largest single-center series in the world! Greetings to the Pharisees!

The French genius... seen from America...

Did you know that? The late Anthony Perkins (Hitchcock's Psycho), sadly deceased from AIDS, had tried his hand at French song. There is no more after in Saint-Germain... It's nice, and touching. You Tube offers it to you. Let's enjoy it !

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The real insider tip is to know which doctor to go to...

175

This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.



Bithérapies en Cycle Court

By Charles-Edouard!

Dovato in x/7: first favorable results!

The DUETTO trial (ANRS) is announced... Well... Why not: Relief AND Intermittence combined. CoronaFolie obliges, it drags on... To the point of arriving after the battle, a bit like Recovery. Too late, it's too late... Well, we know since August 2008, in the NCT00708110 trial (Phase IIa Dose-ranging Study of GSK1349572 in HIV-1 Infected Adults), that the action of DTG lasts 3-4 days at least after the last dose. So trying DTG/3TC in 4/7 makes sense. By the way, it's JeSuisDuTreize (Mono-DTG in 4/7) who hooked me up.

So, here is our ANRS, although not very valiant, which extends the success of Quatuor(not her idea...) towards a consensual thing, which allows at least to clear the ground where the stipendiated Pharmacolâtres had with impunity amalgamated Lightening and Intermittence.

Dr. Lanzafame submits a letter to the Editor of the International Journal of Antimicrobial Agents, by M to Phillipe Colson (IHU, again!) , which is published in March 2021. The original is here. I propose a translation here: Short-cycle therapy (5 days on/2 days off) with a Lamivudine + Dolutegravir regimen in a cohort of virologically suppressed HIV-infected patients

Dovato in 5 of 7: no failure in a cohort of 27 patients

As usual, nobody talks about it, but it is interesting (and that is why the omerta is total...), and here, it is not only the result that counts. One will be sensitive to the way of presenting... Well... 27 patients, various profiles, go from Dovato 7/7 to Dovato 5/7. Nobody goes above 50, so it's all good!

A tribute to Leibowitch and the Eclipse

This is encouraging... Can do better...

Why not 6/7 ? or 6,5/7, while we are at it ??? That works too! A fortiori! Staying miles behind the front line does not allow to flush out the enemy. What will these pussilanimities be worth the day when Merck will excite, at the cost of propagandist contributions, the cage to the crazy parrots? A short shot is better than a crooked shot(Katlama, Raffi and so on), but it is still too short!

7/7 End of game, thanks to Islatravir and ... Merck

I anticipated a simple marketing problem: how can Merck regain market share with Islatravir without taking advantage of its extended pharmacodynamics (more than 10 days)? First approach: divide the dose by 10... That way you have to take it every day, and it's the JackPot. Except that now with Biktarvy practiced for a long time in 4/7, or even 2/7 or better, there is not much room for a 7/7... And ViiV which proposes an injectable...

Merck is also considering an injectable, with Doravirine. Bad luck: it doesn't work! Well... It probably does work, but the worshippers of the Pharmacokinetic Goddess lose their minds and give up the game.

Anyway, Merck (cf MK-8507) has understood what makes Islatravir strong: a 'trick' invented... almost 20 years ago! and, unwillingly, we say, launches a bi-therapy in weekly doses. You read that right! Phew!!! Saved!

At least they think so... The Phase II clinical trial is here. We'll see if it's a success: it's about time! Because Merck is accumulating failure after failure(Dutrebis and Issentress HD, which nobody is taking... ). Did you see how fast they developed a new ARV with extended duration of effect? Funny ... No ??

What will Gilead do? What are we going to do? We'll see that another time...

Weekly intake and 1/15

The mystery of the missing tank is slowly becoming clearer... Is it its disappearance that allows the 1/15 or is it the 1/15 that caused its disappearance. Well... On this one we are rather on the right side of the handle. Better to be cured without really knowing why than to think about doing nothing (Rouxioux, Hoqueloux, etc.)

Obligation of treatment / Judiciarization

It may have gone unnoticed, but YouTube has explicitly listed, and named (please!), H*Q and I*T as cause for banning. They didn't mind Foley's decapitation, but Kory's, Perronne's, etc. explanations were not. Ah well, no! Let's go to the trash! Long live cancel culture! Well... The history of the Disappeared Reservoir will also pass perhaps under the yoke of censors, who made literary studies, precisely because Sciences put them off... Conjuration of the fools...

In the news

- Garches will be a difficult label to wear... Davido, trained at a good school, therefore, safeguards his professional future. He comments, positively, on an essay that leaves however perplexing: In serious pneumonia, in hospitals, an antibacterial profilaxis is given. Isn't this futile? A double-blind trial with a non-inferiority threshold. Well... The (small) group without prophylaxis does statistically no worse than the (small) group with. So it's all good! Except that in the group without, he has a death by... bacterial sepsis. But well... It doesn't bother anyone...

- The "Journal of Experimental Pathology" publishes the study of Claude Escarguel, on the interest of azithromycin in the prevention of long Covid! But well... Nobody is interested, especially not the ANSM, whose transparency commission seems to be invisible(read Maudrux here)... Well... We are not done with I*T since it is an inhibitor of entry into the reservoir... Funny, isn't it ?

We still haven't found the pangolin... Raoult, in 2 times 3 movements, he found you an intermediary for the M.1 (green monkey of Senegal) for the M.4 (mink of Mayenne, whose genome was withdrawn from the public attention). The Chinese, they are desperately looking for the Missing Pangolin. They are looking for, they are looking for... Just like the enlightened man of Nazareth, he probably never existed except in a hysterical delirium...

The State of Goa (India) is doing a deworming campaign by providing I*T kits to the population for therapeutic and/or preventive use, all at the same time, hoping to curb the epidemic surge that India is undergoing. The WHO has rightly denounced the uselessness of the gesture. We will see! As a result, no more pharmaceutical I*T is available, including in India... One can still find veterinary I*T, but it is difficult to find a factual difference (other than the presentation, as it is generally a paste), such as a difference in purity, in molecule, etc. Nada

The French genius taken over by a Russian

Ravel's bolero accompanied the Russian Pluchenko in his sporting and artistic feat: the quadruple-triple-double jump in skating. He is the first (the first Quad is by Browning, it seems). You can find this video on YouTube, which has not aged. It is sublime. It took more than 15 years for a small Asian jig (Uno) to make the first Quadruple Flip. Since then, there is not a single champion who does not combine several Quad.

Between the first and the second, there is a lapse of time, then everything accelerates to the point of banality.

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Turn off the TV and don't be fooled by Pharisaical veracity