186

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



4/7 in Italy! It's coming, it's coming...

By Charles-Edouard!

Very pertinent question, asked here:
What could be more natural than to think about it! When you see success rates of almost 100% in 4/7 for others, and a prolonged efficiency for yourself, you would like to think that limiting yourself to 5/7 would have been a missed opportunity. As it is iterative and Darwinian, the next increment is 3/7, it is obvious. This is not validated by a large clinical trial... So what??? it has not been invalidated either. If you don't even look for it, you can't find it!

The experimental method is described in FASEB-1: make sure of the good susceptibility of HIS virus (something that must have been done before initiating 4/7, so normally it's good), make sure of the efficacy at 4/7, don't try it under Isentress, Genvoya, Kaletra (but who still takes that?) monitor at the beginning by CV 1 month, 2 months, 4 months, 6 months (at the beginning only), and that's all! BIOLOGICAL follow-up necessary. The medical follow-up? Well... For the comfort of the mind? Maybe ? And still ... In any case, the medical follow-up in 3/7, did exist (100% success rate, subtracting the risk combos), and, in practice, it disappeared with Leibowitch...

What does the ANRS tell you? It could not be clearer: " Get on with it"...

A new publication in 4/7

This publication comes from Italy. We had distributed our biblio to various clinicians. Including them... Did it help? I don't know. We can see that French works are abundantly cited (ICCARE, Leibowitch, Calin, ANRS-4D, Quatuor). Normal, there are not many others (Breather, in 5/7, at most...). The results are the same: 100% success, a few dropouts... It's like usual... Nothing new... And the nothing new is reassuring!

The very interesting discussion is in the body of the text. That's why I made a translation in french, in extenso. You have to read it. There is a vibrant tribute to ICCARRE, despite a small inaccuracy: Leibowitch et al. published in 2010 (FASEB-1 and 2015 FASEB-2), BREATHER was published in 2016, so Leibowitch is earlier, not the other way around...

The dosages... They are instructive!

They made 4 dosages per patient... It is instructive, because as in ANRS 4-D, there are cheaters, and it shows! There seems to be 1 or 2 who take more, but mostly a dozen, or a third, who take less. And it works just as well! It shows us the way: 4/7 is good to start... It's a start... And, after a while, you have to grow up

The threshold dose is a joke!

The threshold dose is determined by the failures when introducing the molecule in a new therapeutic scheme. Never in the long term, never... I challenge you to find a threshold dose at T plus 1 year that is equal to that seen in the short term. The good example is Nevirapine, with its dose-dependent failures at less than 6 months(thanks to poor tolerability in some), but no failure beyond 8 months. No failures: no threshold.

The authors discuss here the doses observed after 3 days of interruption (but perhaps more, the patients were just doing their own thing), and we are successful even at values well below the IC90. Note that the 'official' therapeutic dose is 3 times IC90 for Rilpivirine, while it is 15 times IC90 for the more effective Dolutegravir. Look for the mistake...

The Eclipse exists: we see it, so what does the threshold dose mean? Moreover, in the long term, we don't know how to determine it. In the stable phase, it's just a flan!

Can do better...

I like this kind of publication: it is an obvious progress in the percolation of ICCARRE at the international level. This publication is in addition to the others. This poses 2 problems:

- as long as one perceives that the Eclipse is only a few days long, for everyone(vision of the 2000s), it is quite logical to consider the results of others for a reflection on oneself. Now that we have Eclipses that are both longer and more dispersed, these tests on others, on non-identical viruses, no longer make any sense!

- The tests accumulate ad nauseam. Medical Darwinism obliges, it is only a question of time that we pass to 3/7... And what a waste of time! Obviously, if 4/7 is as 'good' as 7/7, it is no less 'bad'.

The 'enemy' of yesteryear was 7/7(will there still be people to practice it in a few years?). It has fallen. The new 'enemy' is the 4/7: it will necessarily fall one day...

In the news

- Satoshi Omura, Japanese Nobel Prize winner, presents I*T as a treatment against C*D: no doubt, a Nobel Prize is no match for 'fax checkers' without the slightest scientific background. It should be noted thatin vitro I*T is as effective on Omega as on the others...

- Before/After critical analysis of the pasteurian 'predictions', it's here, and it's scouring! (it's good too...)

- Very well documented article by Helene Bannoun: The origin of the Covid-19 virus

- Very interesting Evaluation of the methodological methodological practices implemented in Pfizer trials, by Christine COTTON

- Genetic Forcing, Self-Disseminating Vaccines, Chimeric Viruses... The sorcerers' apprentices of the genome by our excellent Bruno Canard, Étienne Decroly Jacques Van Helden (it's not free, but if you ask nicely...)

Pieces of Anthology

- The virus has not mutated," says Professor Karine Lacombe on RTL (at 4 min 50 sec): To be enjoyed in moderation!

- Typhus, a little history on Science.org:

The French genius

Today is Saint Darwin's day! It was Lamarck who discovered Evolution. Darwin, the Evolution under pressure from Selection. This is still relevant, even if many advances have been made since then. Our French genius is Montagnier, who died on February 8.
If he had not set up the Pasteurian Laboratory on Oncoviruses, there would not have been the very lucrative patent, there would probably not have been Barré Sinoussi or Schermann at the head of this world competition. There would have been a genius, but not French...

We don't care about the rest, the squabbles, the greatness and the smallness. Read again Darwin, Descartes or Newton, it's not all rosy either; they also said some bullshit with no equal; history will sort it out.

The fact remains that for us, Montagnier was the beacon of a whole generation! In fact, I am interested in 2 concepts that he exposed:

- DNA does not integrate randomly anywhere (so depending on where it is integrated, it will be more or less active)

- silencing(passive reservoir) is a reasonable therapeutic goal(as for tuberculosis)

We will come back to this, it is inevitable, since it is our salvation...

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Turn off the TV and don't be fooled by Pharisee venality

185

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



Isobolograms and the ineptitude of the single dose

By Charles-Edouard!

Isobologram: oral vs. injected dose

For those who practice ICCARRE-Premium (1/7 or better) the question of dose is subsidiary. With injectables, for the others, the question of the dose comes back, with an extreme acuteness: overdose guaranteed for 95% (or more) of the patients.

One of the arguments in favor of unnecessary (or even deleterious) overdosing is that many patients take their daily medication incorrectly. This is probably more pronounced in countries where supply is variable or even random (e.g. Maghreb). Okay, okay... Let's go for a 'regulatory' argument but what about the metronome patient? Does she have to dose every day, because Algerian women or others have problems to get supplies? Should she fill herself up daily with the pretext that the homeless desocialized, abandoned, are more and more numerous, and have real problems?

Another argument can be proposed: the variable bioavailability: it is, for example, notably problematic for Raltegravir for which Merck will have made the galenic 3 times!(At the end, they went as high as ... 1200 mg/d !!! And it was authorized! - To my knowledge, nobody takes it - ...): we inflate a little, because well... You never know... Especially since we don't want to know... With injectables, this argument is not valid anymore!

A single dose without taking synergies into account

Leibowitch kept coming back to the famous synergies, without any real further explanation. It's not that complicated. Take an antiviral A and an antiviral B, when you use both you can have an antagonistic effect (A + B is less than the expected sum of the effects), a purely additive effect (A + B gives the expected sum of the effects) or a synergistic effect (A + B does better than expected). Apart from any pharmacokinetic consideration...

Ritonavir improves intake by a known pharmacokinetic effect of slowing down hepatic metabolism: it is not a synergistic effect.

When La Scola (Raoult team) shows in vitro that HCQ + AT works better than the simple sum of the effects, it is synergy: there is no pharmacokinetic role (e.g. metabolism by the liver) in a test tube... On the other hand, there is no synergistic interest to put 2 NNRTI (ex. NVP, EFV, RPV) in a combo...

However, if we look carefully, the usual dose of a molecule is a unique value, which NEVER takes into account what we put with it.(there is at least one recent exception: do you see it?...).

What is an ISOBOLOGRAM?

Ah well... It's easy to understand!... It's like Isotherms or Isobars: we draw the curve of same efficiency by varying the dose of each component. The diagonal is the neutral curve: on it the effects of the products are added, simply. As for Dalton's law for gases: the total pressure of a gas mixture is equal to the sum of the partial pressures. One mixes, it adds, no more no less. If the curve is in the SYNERGETIC range, less A and less B are needed to obtain the added effect of A and B. On the contrary the curve can be in the ANTAGONIST (= ANTI-SYNERGETIC) area, in this case you need more A and B when mixing A and B to obtain the same combined effect.

A now famous example of SYNERGY is the addition of HCQ to Azithromycin, at usual doses, which is much more effective in neutralizing SARS-Cov2 than HCQ or AT alone: this is why the idea defended by G. Pialloux was stupid, i.e. to test HCQ alone! The guys are czar infectious diseases specialists, but SYNERGY ?? They don't get it... Yet it is a great classic for... Tuberculosis or malaria... Of course, this is done in vitro. In real life, you might have to test a bit, but at least it's a guide.

Efavirenz-Entricitabine (Atripla ™) isobologram:

In Atripla ™ we find the STANDART dose of Efavirenz (600 mg) plus the STANDART dose of Entricitabine plus the STANDART dose of Tenofovir. I give you a first Isobologram, where you can clearly understand the ineptitude of the thing!

We have no scruples to say that it is completely stupid! Since the ENCORE1 trial has proven that 400 mg is as good (or even better...) than 600 mg. We know that! Sponsored by Bill Gates... The Morlat report endorses this alternative... The 400 mg combination drug exists (Mylan). But... But... It is not marketed in France.

Look for the mistake! We'll see all this next time...

Weekly intake, 1/15 and treatment obligation

January 24th is my freedom day! Phew, it's over... The 1/15 means 24 doses a year, no more! It's an important day. Well...

Instead of pissing them off, we should give a medal to all those who have gone through 2 years of pandemic without getting sick even once!

Everyone will have understood what is coming next in terms of public health and that injectables, QR codes and other technological prowess will promote.

I keep well far away and the obligations suffered in France and elsewhere amaze me. And I find it very sad...

In the news

- I had quoted Pr. Fenton's intriguing post: The delay of 2 (or even 3) weeks between the injection and the validation of vaccination would not distort too much the efficiency if it wasn't for the ADE. Canadian statistics (Alberta): 50% of Covid cases occur within 2 weeks of the 'protective' injection. Not only are these people not counted as vaccinated, but they are counted as non-vaccinated, which they are not... Kiss Cool effect guaranteed on the efficacy ratio. We reduce the denominator, we increase the number and there you go! 95% efficiency on the counter... Except that the counter is a TV commercial...

- Along the same vein: DRESS (a French governement statistics body). Not knowing how to extract the vaccination status of all, it allocates the unknown cases between vaccinated and non-vaccinated according to a fanciful distribution key but favorable to the vaccine: vaccinated people are counted as non-vaccinated: and tada! We should say: not knowing, we don't count them, but here, we count them in the category that 'suits' our narrative best. Except that it is obvious and it looks ugly!

- Marco Nius makes an amazing simulation. On a small number of people, a marginal error in classification is enough to increase the relative risk from 1 to ... 5!

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Turn off the TV and don't be fooled by the Parisian venality

184

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



Mono-Cabotegravir: it makes sense!

By Charles-Edouard!

Read right here, in the discussion ...

Knock on wood... That is to say, hoping that it will hold up against all odds? At the beginning, in 6/7, I was a bit nervous. Knowing where The Monster is, at D+27 in my case, knowing if he has a reservoir lair), disappeared in my case, it helps to live confidently, without even touching wood. We can consider 2 approaches: Eclipsotherapy (measuring the Eclipse, then adjusting the tempo, or cautious advance, under frequent CV, at the beginning, starting with 2/8... This is how I discovered my new mode...

The Right Dose: a promise never kept

Overdosing does not happen by chance: it is imposed, among other things, by the emergency. ARVs, when combined, can do more than add up. By synergy, 1+1 = 3 or 4 or...10. Synergy will apply to A+B (e.g. HCQ+AT), but not to A+X. The Zotorities, (in fact, only the FDA counts) were considering an adapted dosage, reflecting the synergy. That's good, that's legitimate, but in a hurry... The pressure was on for a "let's see what happens next".

It's understandable. The promise is legitimate... The labs are doing their jobs, each one on its side, proposing the maximum dose, without even trying to position themselves on an optimum of efficiency, cf RAL, EFV, and so on, the Zotorités have done theirs: authorize, and behind... Behind... The medical profession is absent! Patients you have been betrayed! Betrayed by whom? The medical profession which has failed to keep its promise and its self-proclaimed deontology of not doing (too much) harm!

They did not do the job! Period! Some of them have tried a little, the Fauci, Leibowtich, Katalama, A. Calmi, with more or less intelligence and more or less perseverance. The associations have seen their members change, the initial pugnacity is lost: nobody cares and the victim is you! Doubly... Firstly because the overdose is never a plus in terms of health, and also because the billion Euros thrown out of the window, it is as many relocations, unemployment and social suffering!

Overdosing: EFV, NVP, RAL and the ultimate... DTG

In a famous article, A. Calmi gives some historical examples. Alaxandra, why stop in such a good way? Why offer the dosage only to patients who do not tolerate it well, as if toxicity was limited to intolerability.

The most devastating drug is Efavirenz. First, because its tolerability is so poor. Secondly, because the shameless dose of 600 mg has finally been replaced by 400 mg (see WHO). Ah yes... Replaced in the USA and in countries that depend on American aid... Yes, today we have better combos in Kinshasa than in Paris. It's to die of overdose! Finally, because the phase 2 trial did indicate 200 mg as the dose to be retained. Even worse, this trial, which is supposed to protect against overdose, was done at 200, 400 and 600 mg. 200 mg was the lowest dose tested. So to know the dose to be retained, it would have been necessary to (re)test lower. A theoretically favorable value is ... 60 mg (in combination with TDF/F-3TC), but it has not been tested!

RAL is a real galenic disaster: the manufacturer is on its third galenization! In the UK, the reference treatment is RAL 1200 mg + ABC 600 mg + 3TC 300 mg, PER DAY! It's crazy! And people are taking it! Without question ???

NVP is a lot of nonsense! Even in Bichat (Peytavin ?) we realized it! That's how obvious it is! The bioavailability of the prolonged form (XR, in 1 tablet) is such that the dose in fine is 4 times less than the ANRS threshold dose, and it works. This dose is reached with a single standard 200 mg tablet. The ANRS threshold dose has not been corrected for this. So we have publications with NVP 200 mg + 3TC 300 mg, without concern. Note that patients who take 400 mg embedded in a plastic foam only receive 200 mg, so they do not realize it but their dose has been reduced de facto. The fact remains that this drug is too expensive and moreover it is not beautiful to see!

The worst of the worst is DTG: 15 times the IC90! Only that!

DTG is overdosed: CTG is the proof

The FDA distinguishes 3 types of patients: the newcomers(the naive, so aptly named), the experienced(yes, yes, they do participate in full-scale experiments) in success, the experienced in failure: If we propose a pharmaceutical formulation to these patients in despair, it is the MA assured, without discussion. This is normal. For the latter, it is 100 mg/d. Well... let's not quibble, that's the dose used for rescue, in a perilous situation. At the usual rate of ... 1200 Eu/month, it is classic, shocking but classic. The others? Well, it's less. But not less turnover, right? I'm a big Pharma who just saved your ass, so be nice. 600 Eu/month is the usual rate. And by simple rule of three, for 600 Eu/month, you will get 50 mg. Is it useless? But we don't care: we have to save ViiV from bankruptcy (all their drugs are in the public domain).

So we give 50 mg to people who don't need it. Who doesn't need it? People who have a susceptible virus? Who is susceptible to a susceptible virus? People who are genotyped seriously (or even phenotyped) and people who are successful. So, in these people, yes! we can lower the dose, even to the reasonably acceptable dose in the phase 2 trial, i.e. 10 mg of DTG. But we, the chemists stuffed with $$, have something better! We will give you the same corkscrewbut change the handle. We change the name, the thing, we redo the studies, we drown the fish poison and... We change the dose(of the same corkscrew)... And... The target population.

We fire the Trojan horse, the failed patients, the few who have allowed us to stuff the whole planet, and us (in $$) at the same time. Read the HAS, here: right on target:
In these patients, 50 mg DTG is 15 times (15 times!!!) the IC90. With CTG, at 30 mg, it will be 2 times less corkscrew (technically we say pharmacore), that is 7 times the IC90 . And it is indeed the ideal IC90, since we have selected the susceptible patients. So even 30 mg seems huge!

Mono-DTG works on susceptible viruses and serious patients

There is a wonderful Swiss trial with 100% success (try to do better!). Lanzafame published its results on patients, without too restrictive screening, it also works if you follow the protocol well. Once people have proven that the virus is not twisted and that they know how to follow the protocol, one wonders why on earth they should stay at 50 mg!

I did Mono-DTG 1/2 pill (6 months) then Mono-DTG 1/4 pill (6 months), in 7/7, with no worries, no failure, no resistance acquired, nothing, Nada. To me, I should not be offered VOCABRIA... With my experience of Mono-DTG 12,5 mg (7/7), I will always go for MONO-CTG 7/7, just for fun.

Mono-CTG injection: it looks good...

Good compliance is key to success with Mono. And what better way to measure and guarantee compliance than with injections? It is not easy to hide or minimize non-adherence with injections... So, then... Well, that's for another time! Subscribe now!

The orphan virus is making babies

- Will mass vaccination, with a mono-centric strategy, prove to be a big mistake? I doubt that history will ever judge it. The West has been living for 2000 years in a macabre, obsolete hysteria... And the inventory of this millennial error is still pending. Is vaccination reversible? In general, no... For a real vaccine, it is not... But here? Antibodies have a limited lifespan, it is a chance to seize! Also if your virus acquires resistance, you have the choice (if you are allowed to...) between overdosing and drowning. You have to make a choice and beware of resistance breeders. While we can, drowning is my strategy of last resort. Sonigo has been explaining for a long time that from evolution to evolution, the virus should become more contagious AND less virulent. P. Sonigo gave an excellent interview. Geert Vanden Bossche explains here, in French, that the succession of waves indeed favors contagiousness, but that there is no apodictic necessity for less virulence. I had said, at the beginning, that a selective strategy of Covidization of the youngest would be possible. Now on the table: omicronization of the injected...

The false witnesses and their obliged accomplices

Francis Palombi will have admitted having deceived the journalists of BFM, at the time of a shooting at the hospital of Neuilly Ambroise Pare. Caught red-handed, he declares: Bad comedian certainly. Sincere at least. I assume my convictions. Did BFM let itself be trapped? Or has seized the opportunity to stage the convictions of... BFM. The debate on intermittence will have been polluted by false testimonies AND those who allowed them. This is important: the responsibility of the false witnesses exists, but the responsibility of the media who carry an intention, even a conviction, is even greater.

In the news

- I had pointed out Fenton's post, here is the interview he gave (and which disappeared quickly...). Beyond this controversy, his blog addresses a very interesting issue: the assessment of risk by the Bayesian method

- two articles of great importance for us: A possible sterilizing treatment for HIV-1 infection without stem cell transplantation and Distinct mechanisms of long-term virological control in two HIV-infected individuals

- Links disappear with time... My new MegaArchive keeps this blog in-extenso as well as all the resources, including video: nothing will be lost anymore...

- Happy Holidays !!!

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Turn off the TV and don't be fooled by the Parisian venality

183

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

A giant step towards recovery and that's me!

By Charles-Edouard!

My tank has disappeared... or... did I make my tank disappear?

As long as you give a prize (INSERM) or a lot of $$, it would be nice to do it for a real real ization. And, to give to those who do. Not to the spectators! The spectators watch, amazed, admire and... Applaud!

Without further ado I reveal where I stand, and we discuss it afterwards. My tank is measured every year: 2015, 2016, ... 2018. Low but present, unequivocal. 2019 and 2020: three attempts where the lab said they were unable to do the measurement. 2021: the laboratory confirms the undetectability: it is without appeal: something happened!

And this something is huge: the disappearance of the tankit's gone under the radar! Now, if you find even one doctor capable of showing such a masterful Before-After, just let me know: I have never seen one: it is the GRAAL of the grail: no one has ever managed to do it, except by genetically modifying the individual and perhaps in the Biosantech trial (to be verified...). You know how to do this, you are part of the Kador, the STARS. And if you don't know how, well, you are not a STAR.

We are talking about DNA(measurement of the reservoir according to the ANRS method) and not RNA(whose undetectability is maintained by the ICCARRE+ method)

Under the radar! it is under the radar...

When the numbers are low, the validity of the results is questionable... Yes, yes, yes... And we'll do it again in 2022(if this stupidity of sanitary pass has ended, if not, we'll do it later, or elsewhere... ). I'm not worried or in a hurry... from 2015 to 2018, the lab was able to come out with results, but not in 2019 (twice...) we suspected something! Again in 2020... These are background noise problems: the signal is drowned in a small hubbub. So for 2021, I used a little trick (that I got from Ananworanwich) to try to get the signal back to the best I could dream of. Who knows... But at least the machine spit out something! It spit out ZéRo, and that's not nothing!

When does it go under the radar?

Good question... First, when it was above the radar, it was for real. How do we know? because several months before the last 'positive' reading, I had a (very) high RNA reading (at that level of CV, it's not a blip!). This virological failure, frankly, will have been recovered with brilliance, and above all, a few months after the incident, the reservoir was as usual, in conformity with the classical observation that a short period under active viremia does not affect the reservoir level.

So moving the tank, one way or the other, is no small feat! You make a controlled slip and it doesn't change your burden. The alla Pharisee argument that intermittency (or even failure) would make the tank go up (boo!...) is at odds with what we know. There is no need to worry unnecessarily...

I think that the passage under the radar dates from 2019, and that 2021 is only a confirmation. Besides, after 3 unsuccessful readings, we could have already ruled. And all these impossible or null measures, are in a series that starts in 2019 and interrupts an earlier series of remarkable consistency!

No more reservoir? What's the point? What to do next?

As long as you have a tank left, there are a lot of questions that don't arise! Nobody asks them... And when you don't have a tank anymore, everything comes up: you are in terra incognita! So, we'll see about that next time

Obligation of treatment / Judiciarization

When a virus comes from nowhere and appears 800 m from the only laboratory in the world working on these living viruses, we say that a pangolin has been killed by a bat. When a variant appears without any known recent emergence (despite 2 million genotypes!) we immediately find the source: an S+ patient with uncontrolled HIV... Oh well... The use of some mutagenic molecule? No ? Really? No? Well... If you say so. Of course, there were some who immediately decried the situation and wished it would end: hear, hear !

In the news

- Raoult said he reviewed a forthcoming article on a very large prophylaxis study at HCQ... Hi... Hi... He knows the result... Do you? Not yet... He seems quite confident about the future, don't you think?

- In the meantime, a large prophylaxis study with VMI confirms, not surprisingly, that it has a role to play!

- Merck announces that it has stopped its Islatravir study in 1/7, under a pretext as futile as it is unverifiable. Let's keep an eye on Merck's next announcements on Islatravir. I bet that they did not hang up their apron and that the others finally gave in in the negotiations... Merck's initial objective was always injectable. The oral form in 1/7 was only for as long as there was no injectable solution... And if the injectable that we feel is coming does not work, there will always be time to come back to 1/7, but in IRT, this time, as it would have been reasonable to do from the start... We'll see... The saga continues, and we will come back to it.

- bad luck: Pasteur (Lille) interrupts its clinical trial... For lack of patients! In the middle of the e-ieme wave! You have to do it!!! it's here. By dint of being soaped the board, it wears out!(Even Pasteur... Apart from laying down algorithmic elucubrations that leave one quite perplexed...)

- Pr S. Gayet is an infectiologist who seems to deal with nosocomial diseases in hospitals (of which Covid is a part...). Behind his phlegm and his Alsatian accent, he says exactly the same thing as Raoult. It is less brilliant, less striking, but it is kif and it is here.

- A stellar article by Norman Fenton, who notes a wave of deaths, NOT Covid, among NON-vaccinated people, coinciding with the (NON)vaccination campaign, whereas this campaign is, for them, a NON-event! The (non covid) deaths of the freshly vaccinated (side effect: death...) have been attributed... to the cohort of the ... NON-vaccinated. So, of course, when you correct the bias, it looks bad. It's a bit hard to read and it's here.

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I'm walking against the current, because I don't know how to walk against my heart...

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...