128

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



The tenia and the denial of proof

By Charles-Edouard!

In the margin of a reckless hope for a vaccine:

DTG-25 mg (or even DTG-12 mg) is a much bigger loss than the 4/7 intermittence. Pharma doesn't want it? So what? We don't ask their opinion... Now, the doctors are something else. First of all, an infectious disease specialist is a low wage job: 35 Euros per consultation, that's 8 times less than a lawyer (350 Eu/hour). So if you do 1 consultation per year, instead of 2, well, it's a disaster, already that you don't earn much. PreP is 4 consultations/year, it's already better, and the guys are neither sick nor boring. So the problem is not the Pharma (overpaid) but the doctors, underpaid, but overestimated (since there has never been one to cure you...). That should make you modest!).

The Tenia and parasitic ideas

Ultra-sanitized, we know salmonella, legionella, tuberculosis and others only through the rare 'news'. Reading TREMPANO, one quickly understands that living in Senegal requires a top immune system. Not only is there a risk of catching these diseases, but also of dying from them! How stupid it is to believe that your risk is identical to that of people bombarded with pathogens!

So you probably don't know about tapeworms, those long tapeworms that cling to your intestine and feed on your food. You don't realize it right away. You can easily get rid of it with a deworming pill. It barely bothers you, and this tapeworm suffers the pangs of death, wiggles, lets go, and you find a long rubbery tube in the toilet bowl. Baptize it with the name of God, or of a pedophile Monsignor, before flushing it. By the way, baptizing your excrement is quite funny and salutary: it feels good.

Misconceptions are like tapeworms. They parasitize you, discreetly, and, once rid of them, you feel so much better that you want to shout it to the whole world. But there are places where people are religiously attached to them. Septism(the obsession to do 7/7) is a sacred parasite. If you don't revere it, don't expect to get your medical degree. Has anyone ever seen a poisoner's apprentice get his degree by checking the box 'cholesterol is innocent' or the box 'BCG is useless'? Those who had the right answer did not become doctors...

So, yes, I just compared sepsis to a condom for a small cock. Oh, but you are quite irreverent! Well, yes... A false idea, invalidated by experience, deserves no better than ridicule and contempt.

Septism, it doesn't exist...

All are parasitized, that's the normality. The variety, the deviant subspecies, has hardly appeared. The variation, the speciation, will take place only gradually. The time of the Tempists(those who adapt to the chronophysiology of HIV) has not yet come. The numerical threshold has not yet been reached. But it is coming...

4/7: we hope it will not go further

From a doctor, about the 4/7, I heard, once: 'we hope it will not go further'. There, I remained on the ass. In what way? Where does she get this from? Where does she get it from that we hope it will not go any further. Of course it does! Between Iccarre, ANRS-4D and Quatuor, you have about 1000 patients in 4/7, under the title of the trial, in success. And about 1000 other title of what Morlat allows it, since 1000 days, already! And that it begins to do well!

You can imagine that among the number, there will be some who will have skipped a few doses, inadvertently, while remaining undetectable. In ANRS-4D, there are three assholes who have been found out, but there are those who have been missed. They know it. Then there are others... who think.

So they'll ask their doctor (septistic, not yet fired): why don 't we go to 3/7. Oh, don't think about it, my good girl, 4/7 is already enough! Really??? And the failure rate at 3/7, how much is it? How much is it!?

We have never seen anyone fail Triumeq® 3/7, nor Triumeq® 2/7. Same with Eviplera® 3/7. Show us failures! Yes, show us! The demand for proof is on the other side. All these people who talk about it, they have nothing (real) to show. When I spoke above about condom for small cock, it is well of that: if you have finery, show them! Let's see what happens! If you have artillery for real, then shoot it! Or else, shut up!

Especially since how do you want Merck to increase sales of its MK-8591, the EFdA, the one whose half-life allows a weekly intake? They're going to say you take What's-His-Name® on Sunday and Truvada® every day? That's silly... The only way Merck can get back in the game is with MK-8591, and its only commercial advantage is that it's weekly. It's not with the little Doravirine that they're going to get back on track. Now we're going to laugh! Anyway... Apparently Merck has sensed the trap and intends to foil it with 2 tricks that we will understand by reading this article and this presentation of Pr Molina: we are going to have fun! Because we too know how to turn the situation to our advantage.

And then, the ostracism will change sides. Everyone will be worming their way in, bending over the toilet bowl, naming the beast after Prof. R***, Prof. M***, Prof. P***, and... Flush

In the news

- The tiger mosquito almost eliminated by a new method of control (source: Futura)
Before the middle of the 20th century, Darlington stated: 'It is not far from heredity to infection'. A vast subject! The spermatozoon brings nothing but its chromosomes. 'The spermatozoon is the bandit in its pure state, said Cioran. From there to see in the male only a parasite... Or in the virus, only a male.
Think of it this way: the virus as a spermatozoon, fertilizing the CD4, giving birth only to ... males, while practicing parthenogenesis at all costs.

- The cycle creates a selection pressure: it is not in the press... I am the one who wrote this... We will come back to this

- Islatravir : presentation of Pr Molina: 3 doses of MK-8591 (0.25 mg, 0.75 mg, or 2.25 mg) are equally effective: let's see what Merck will choose... Hi, Hi, Hi... Not necessarily the strongest... And even, we are talking about 0.2 or 2 mg ! See how, with my discussion on DTG-25 mg, I am probably far from the mark!

The French genius: QUATUOR is TOP!

Moment of glory for... Dr Roland Landman, who presents results from Quatuor. One can read with amusement the comment of Margolis, once a researcher who found nothing, now a ViiV employee (Director of HIV Drug Development at ViiV, the article doesn't say so...). The buzz is here:

QUARTET: IT WORKS!!! .

Well... I'm very happy, and so are you. There is nothing to say: it is Nickel from Nickel. Really, it's CHAMPAGNE!

I don't know what to say in this case: Bravo! Congratulations! Legion of honor! Leibo, you are the most beautiful...

Oh yes... A last word for the road: take a deworming and get rid of the secret doctors! Quickly!! It's urgent!!!



overmedication is an opportunity if you know how to take advantage of it!

127

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



DTG-25 mg episode 4

By Charles-Edouard!

Here's a Patrick who would have done better to understand intermittency than to play the fool.
This is what the omerta on the intermittence gives: the moral responsibility is in the opposite camp. Sensitive to false testimony, and with a mind obviously clouded by overmedication, this is one person who has been totally closed to our arguments. ARVs freeze the situation; in the absence of active replication, the lymphocytes return to a more usual equilibrium. When they thaw out, they return to their former equilibrium in a few months. Therapeutic vacancy in LOTTI or SALTO conditions is favorable. For those who have already passed through an AIDS stage, such as our Patrick, it is the announced disaster (some of them manage to control their disease for a fairly long period of time: the PTC).

The septists have the double punishment: the infamous responsibility of overmedication, and, boomerang effect, the aforementioned Patrick will finally understand that intermittence (ICCARRE/OMNIBVS) is the uninterrupted maintenance ofthe viremic suppression. Let's hear it...

DTG-25 mg: necessary dosage vs usual dosage

The two tables, made public by ViiV(see episode 3), are rich in information: there are no yellow, orange or red primary mutations under DTG, but there are red ones under RAL or EVG: under RAL or DTG, you almost inevitably need 2 other molecules to block the possible appearance of mutations that would make RAL or EVG inoperative. Under the old INIs, these red boxes require IRT, including in group 1 (naive or successful patients), or failing that, in maintenance, a BI in a well-synergistic couple. Moreover, EVG is ONLY available in IRT, and the admissible reason is this bright red table; without even mentioning the second table (successive mutations).

On the other hand, it is not surprising that MONO-DTG works! It is right there under your nose! And obviously, if you have been through RAL or EVG you are at risk: secondary mutations may have appeared surreptitiously, and you may be in the case of table 2, and there a third molecule (or a double dose of DTG) are useful or even necessary. No one will ever tell you that, Merck because RAL is on its last legs, Gilead because they hope to convert EVG to BTG (Biktarvy) and ViiV because Mono-DTG takes 25% of their profit. Not even the FDA, because their specification is flawed.

I made a small synthetic diagram, inspired by the poster of Seki (ViiV, CROI-2010). Here, it is very clear!

Phase 2 ??? What phase 2? Nothing to beat...

You, you thought blithely that the phase 2 trial is used to determine the minimum dose required for maximum effectivenessYou try several doses and you take the one that has the best result, at the lowest dosage. For Evafirenz, the trial is clear: 200 mg should have been chosen, and many suicides would have been avoided and many more patients would have had access to treatment. The Phase 2 trial serves a purpose, otherwise why do it? Well no... We do it and we don't care... The proof by Fujiwara(ViiV powerpoint, here):
Maximum tolerated dose is not minimum effective dose!... But the most shocking is the 'A priori...' which is defined as follows:
1. Starting from data prior to the experiment.
2. At first sight, before any experiment.
If you choose the dose BEFORE the experiment, you have made a decision, on paper, without any intention of taking the phase 2 trial into account.

The trial is mandatory, but it is not mandatory to take it into account!!!

So what do you do if you can't tolerate the maximum tolerated dose (like 10-15% of patients, at 3 years)?(see ANRS study)? Do you switch? And for what? And why? Whether you tolerate it more or less well, or even very well, why stuff yourself at 30 Euros per day?

So you have those who laugh at the effectiveness of DTG, some who regret the dropout rate, higher than in the advertisement. But, not one to go and look at the phase 2 trial. What is the point of trusting doctors who don't read the trials. Did they get their diploma in a Bonux package? And, when did they get this old-fashioned sesame?

Scam? But where is the scam?

Indeed, someone takes a zirconia and sells it to you as a diamond, there is deception; if a 300 mg pill has only 100 mg (or plaster), there is deception. But how does the manufacturer benefit from overdosing? Try to think about it...

Let's take an example closer than rosuvastatin:
For HIV, Lamivudine is in daily dosage at 300 mg/d. at a price of 69.42 ���� (Reimbursement rate: 100%) by Mylan for 60 tablets of 150 mg, scored (source)

For HBV, the same Lamivudine is in a dosage of 100 mg/d. Price : 88,43 € Reimbursement rate : 65% for 30 tablets(source)

For 69 Euros, reimbursed, you have 60 pills of 150 mg; for 88 Euros, you have only 30 pills (100 mg): it is twice as expensive (taking into account the reimbursement), for 3 times less!

The average Frenchman doesn't see the trick, but the average American, without social security coverage, quickly understands that buying Mylan 300 mg (in fact 150mg x 2), cutting it in 2 (or in 2/3) will save him $50 per month. $600 a year for the little lamivudine of my two....

When the price is crushed, i.e. not in proportion to the dose, then the retired, the poor, the parents of infected children, all will jump on the bargain; and it is as much loss of profit for the manufacturer...

A little thought before the next step

To get a head start on what's next, try to imagine for yourself what a base dosage of 10 mg would have meant for the healthcare system, for profits, and also for yourself, as part of maintenance.

Some people think that by doing 1/2, they are doing intermittence, the only proven way to dynamic remission: this is incorrect: they are only correcting the dose, wisely, as we will see.

Others say that if they do 3/7 or 2/7, they are lucky to be the 'happy few', the privileged ones... But where do you get that from? Do you know the failure rate for 3/7 maintenance under Triumeq ® ? Have you ever seen someone fail at 3/7 (or even 2/7)? In MONO-DTG, if we are not careful, there are failures, but not in those who minimize the risk (good compliance, no Achilles' heel and/or early initiation). So there, Happy, Yes... Few, No!...

When injectables arrive, at an exorbitant price, are you really going to inject the whole dose? every month? For life???

If you think that overdosing is a malpractice, look to your doctor, who, in the chain, is the last but one before you. The doctor has every right to advise you to take half a Tivicay®. It's his job, the useless privilege of not using it

Over-medication is an opportunity, as long as you realize it and take advantage of it

OMNIBVS

I'm in OMNIBVS all the way and, despite a unheard of adversityI've just won a decisive move. A great thing that changes the game, so morale is up!

Especially since the first batch of 1/15 is on its way! This is also really important and as soon as I'm done with DTG-25 mg, I'll give you my thoughts about the transition from 2/7 (Triumeq® or Eviplera®/Odyfsey®) to 1/7, then 1/15. Yours truly continues his successful descent, currently at 1/10, with the NFC (Nouvelle Formule de Charles-Edouard). The first one is for those who will have provided an email address, which can be done simply by leaving a message here(email addresses are not published, of course).

Judiciarization

- We had announced here that ViiV filed a complaint against Gilead for plagiarism (Bictegravir). We will soon resume the investigation. Indeed, new, imperceptible movements give us the keys to a secret YALTA, which redefines, in all discretion, the new power relations in the medical-pharmaceutical underworld. To be continued...

In the news

- Massive attack on Nevirapine. The disappearance of Videx® from the shelves has taken the orthodox iccarrians by surprise. They were almost the last users in France. Eventually, Videx® will have to be replaced... This explains the urgency to launch OMNIBVS without delay. I don't understand why they don't see what's coming, confident as they are in their temporary solution: they are wrong. By the way, this is exactly why I didn't want to get on that train, even though it was well underway, and why no clinician wants to take up the torch from that angle. It's a shame, but hey... We'll find a solution... I mean... We'll... Other than me, I don't see a lot of people...

I have more confidence in Nevirapine, which will always be marketed in India or China... But in France? Its days are counted if we are not careful. I will comment further, get ahead: Nevirapine Explainer May 2018 (US Congress), the DTL strategy.

Good Weekend, good stuffing and not too many meds ... Right?

126

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



DTG-25 mg episode 3

By Charles-Edouard!

In margin of the Lambert Affair (out of our subject, here), a letter of Dr S. PALIARD-FRANCO:

Oh, come on!!! Science and Faith are not in harmony. It is a misplaced trust to place it in those who privilege conviction over proof. Joyeux is a religious activist, almost homophobic... Here is a doctor, writing, in her capacity, to another, Minister of Health, who affirms, right in the eyes (as Dr. Cahuzac would say): by his will, he could have contracted a fatal infection. A deficiency in cellular immunity on demand!!! The proof of his will would be that his immunity, autonomous, insubordinate, works... And, in addition, one could even choose the infectious agent for oneself... One can commit suicide at the first pneumococcus passing by. It is the other side of the same joke that would like the force of conviction to heal, miraculously, a Lourdes in reverse, so to speak.

Many people place their trust in soul supplements (homeopathy, prayer, yoga, overdosing, overprescription...) that viruses, bacteria and macrophages have no use for. We must denounce it. No! criticizing an idea for being false is not a discrimination. Mocking an 'invert' (cf Joyeux), is! To affirm that the Faith of some does not cause harm to others is inaccurate. Misplaced conviction rots everything around it.

Let's go back to our sheep, with our minds cleared of this parasitic nonsense...

DTG-25 mg episode 3: DTG-50 mg, criminal chemical incarceration

This is also a scam of a somewhat original kind. As in prestidigitation, the trick is to divert attention from what is actually happening. The context dazzles us, collectively, and we get distracted, including by the question of Mono or Bi therapy, while the trick, the deception, is right there in front of us.

Their novel is an affabulation for the enlightened. They have committed their crime, before our astonished eyes, and have even signed it: the culprits have named themselves as if to better conceal their cheating.

We had already drawn up the picture:
- the original pharmaceutical sin: the slant and the S
- the escalation test is mandatory but they don't care
- EFV 600 mg an unfortunate precedent
- the trauma of multi-dose rosuvastatin
- DTG and the famous specifications

Our investigation continues...

The curse of efficiency lost but not quite

During pre-clinical development, they will realize something that will satisfy them while posing an unexpected problem. DTG is remarkably well designed... In the laboratory, after many attempts, one always ends up selecting mutants; one cannot think of biology without Evolution. The mutant loses fitness, of course, but gains resistance. It gains more or less resistance. If it gains a little, it remains susceptible to about the same dose; if it gains a lot, the molecule loses its effect, almost completely: the dose must be multiplied to overcome it; this multiplier coefficient, FC for Fold Change, is the indicator of this loss of effectiveness. It is quite well known: the mutation at position 184 confers a resistance to Lamivudine with a moderate FC (ca 3.5): it remains usable. Q148K gives a FC of 83 against RAL and 1700 against EVG: here one should not dream anymore, one would have to multiply the dose to stratospheric levels to overcome it.

Under DTG, and in patients naive to INIs, it is almost impossible to develop mutants with moderate or high FC. Seki explains here:
All single mutants [...] do not alter [DTG] activity by more than a factor of 5.
Fujiwara completes here, I quote:

On the other hand, if you already have a mutant, typically acquired under RAL or EVG, acquired by you (a failure for example), or by whoever gave it to you, this mutant can mutate again and have a moderately high FC, high but not prohibitive: FC between 10 and 20. That's a lot and not too much at the same time. It would have been better if this FC had been a bit lower, but 20 is playable! Hooray! We will be able to bring a solution to the patients of group 2, those who are up to their necks in shit. And at the cost of a higher dose. The FDA will give you anaccelerated MA, which will allow you to exploit the patent for another 2-3 years .

So for group 1, you're going to need a dose for HR < 5, and for group 2, you're going to need a dose for HR between 25 and 50.

A dose for group 1 and a dose for group 2: and these are not conspiracy theories: there is indeed a dose for group 1 patients and another for group 2 patients: this is written in the instructions in the box!

One dosage for some (the vast majority), and one dosage for a few others, perfectly identifiable.

The problem jumps out at you: the requirement is a ratio of 1 to 10, but the suggested dosage is in a ratio of 1 to 2. Can you see the trick? The CF is low for group 1 and ten times higher for group 2, with the icing on the cake that you can't switch from group 1 to group 2. 2 needs, 2 dosages, but the ratio of needs and the ratios of supply differ by a factor of 10!

And the whole aberration comes from there! If your cab chooses a slightly longer route, it passes... If it goes around the ring road 10 times, it's a real swindle. Well, it's the same! At 50 mg, you (from group 1) are swollen by a factor of 10!

The curse of lost-but-not-quite-effectiveness could have been a problem for ViiV, but they're going to pass the buck, and the curse is now on you. We'll see next time how ViiV will succeed in his trick, no one knows...

Towards the obligation of treatment / Judiciarization

David Hynd must attend daily appointments if his HIV levels exceed a certain threshold. Read here. This is the first time that British Columbia has use the courts to force someone to take a treatment against HIV. Let's bet it's not the last... What's up? We didn't tell you about it?

In the news

- DOVATO (DTG/3TC Combo) is announced! What??? The Gilead-o-latre media is not telling you about it ???? Of course, there will always be some idiots who will entertain doubts and lead the poor patient into a daily and deleterious TRI. And others to believe that it will be cheaper. 27,540/year Still!. It's too expensive for Lamivudine ($6600/year for a generic sold for $30/year to NGOs and $300 in India) and 50mg of DTG, which is far too overdosed! Our discussion on DTG-25 mg is very timely!

- especially since Mono-DTG just won a landslide victory: Non-inferiority of simplified dolutegravir monotherapy [...] randomized, controlled, multi-site, open-label, non-inferiority trial. The ViiV stipendiaries didn't tell you about that either! We did!!! and we will come back to it in detail! (read also: Predictors of virological failure in HIV-1-infected patients switching to dolutegravir maintenance monotherapy)

- Atripla® in 1/2 dose works as well as in daily dose: We already knew that! We have the confirmation here: Randomized clinical trial of the efficacy of every other day fixed-dose efavirenz/tenofovir/emtricitabine versus continuous therapy. When is regulatory listing expected? Morlat, are you there? Morlat, do you hear?

- Hurray!!! Finally a study that shows that the Eclipse is manipulable: We demonstrate a reduction of the reservoir by measuring what, only, we care about: the Eclipse. The new Gilead's 'shock and kill' clears deadly virus in monkeys. As usual, the natural Eclipse is, in median, 21 days.

The French genius

What is this cool music you are listening to right now? Oh, in its reference version by the lovely Scott Ross, it's a bit abrupt; KEMPFF makes it subtle, audible, invites us to to bird recallby J.Ph. Rameau, otherwise a bit old-fashioned. If you liked KEMPFF, you might like his Bach Sicilienne BWV1031

Feel free to comment, like, share and use

overmedication is an opportunity if you know how to use it!

125

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



DTG-25 mg episode 2

By Charles-Edouard!

You are spoiled for choice! In Paris, there is a plethora:
https://charles-edouard-ma-liberte.blogspot.com/p/medecins-allegeurs.html
You have to wonder where you can be so stupid as to say that Eviplera is not for this: 100% success in ANRS-4D, and very popular practice in Paris/Marais.

The trauma of multi-dose rosuvastatin

This post follows our first episode: DTG-25 mg ep.1

Here is a story that every pharmaceutical manager should know. To get 50% more effect, sometimes you have to double, triple, quadruple the dose. In chronic diseases, this will increase the cost of the treatment quite a bit. And when it's a metabolic manipulation without any proven clinical interest, it may be a problem for the FDA, the health insurance company and the insurance company. To prevent them from looking too closely, the industry has found a way to avoid this: charge the same price whatever the dose. It increases its market share, without any problem for the health insurance company or the patients...

As long as it is reimbursed at 100%.

No chance, the medication is of a questionable and contested utility. It is only partially reimbursed or not at all... This is the case of statins, of which the most powerful(no one says useful) is rosuvastatin, a drug that inhibits blood sugar at a very high rate, but whose effect is not proportional to the dose. It inhibits more at 40 mg than at 5, but not eight times more... Whatever, they will market it at the same price. You can find the prices in the USA, for the different doses, on this comparative site. We can see that, more or less, the 40 mg is at the same price as the 5 mg.

So what did the smart guys do? They were prescribed 40 mg and cut the tablets in 4! And as the association of retirees echoed, all American retirees, forced by an iniquitous system, started to do it! That's as much loss of profit for AstraZeneca: they collected 5-7 billion dollars per year, but the price fouling must have cost them between 500 and 800 million per year! When you like it, you don't count, but when you count, you don't like it!

So, multi doses, yes, at a pinch, but the crushing of the price especially not! do you understand the logic?

You can offer multiple doses without cutting into your profits, what they really need to do is avoid price gouging. ViiV is going to work on this... The same dose/price strategy can be seen in the Bictegravir component (Gilead). To understand how extortion is the order of the day in this industry, just read this article: Decoding Big Pharma's Secret Drug Pricing Practices

DTG and the famous specifications

Reading the FDA document is highly recommended. Normally, the FDA is supposed to protect you. It must also authorize what deserves to be authorized, and not spend ages on it. It is therefore quite legitimate to propose to manufacturers a methodology that allows them to prepare their file in the best way for a faster approval. This is also in the interest of users.

Even if it defends itself for reasons of responsibility, it is, to our knowledge, the only document from an administrative authority that can serve as a guide to the industry. As a result, this document is established as the one and only specification (CoP). If your file is satisfactory according to the CoP, you are in an ideal position to obtain the Holy Sesame (American MA). This is normal, after all.

The French approach, which simply comments after the fact, is doomed to failure: the Transparency Commission will certainly slap you on the wrist, you will be awarded an ASMR that is sometimes very unfavourable, and it will only cost you during the economic negotiation, but your MA will nevertheless be granted. So, because of the lack of construction, the ANSM cannot protect you in any way: they are pissing in a fiddle. The FDA is something else...

The FDA document expresses the expectations, and these expectations reflect the state of the art: it inhibits any progress, including in terms of dose. Under the pretext of protecting you, it protects the FDA, the industrialist, at the cost of an inescapable overdose, because it is the FDA document that orders the overdose.

To be considered worthy of FDA approval, the new molecule/drug must bring an anti-retroviral benefit to 3 groups of patients: these groups are
- treatment-naive, susceptible patients
- multidrug-resistant patients in therapeutic impasse
- multi-resistant with possible options

very precisely:

Group 1: Fully susceptible to all approved drugs, treatments, or prior therapies with a well-documented treatment history demonstrating no virologic failure.

Group 2: Drug resistance to multiple drugs and multiple drug classes. Unable to construct a treatment regimen capable of suppressing HIV RNA to levels below the limits of quantification of the test.

Group 3: Drug resistance present and able to construct a regimen capable of suppressing HIV RNAs to levels below the limits of quantification of the test.

(In some ways groups 2 and 3 are somewhat confusing)

In addition, the FDA does not consider that a new ARV can be used alone. All this is very restrictive and DTG developers will have no choice but to comply...
To be convinced, let's take the example of an Absolutegravir, whose definition we recall: a molecule against which no resistance develops, whatever the dose. An Absolutegravir is used like an insulin... Too low a dose, the CV goes up without developing resistance. In other words, the barrier to new resistance is infinite in height.

This Absolutegravir is an ideal situation and allows us to imagine variants. Here is a definition for a type of Quasi-Absolutegravir.

Under this QAG, and even in case of under-dosing, it is impossible to develop a new AMR (mutation associated with resistance); the eventual rise of CV only reflects an insufficient dosage. On the other hand, it has a (small) defect: there is a mutation that makes it 100% ineffective. This mutation cannot be acquired under QAG but may have been acquired under earlier, weaker X-gravir.

Such a molecule would be of phenomenal interest for Group 1, but of no interest at all for Group 2: this hypothetical QAG does not meet the CoC of the FDA: it cannot be marketed!

What a shame! Because it would be damn useful ! But even if it did exist (and we can even reasonably assume that it does) it would, in the long run, mark the end of profits for the manufacturer, who will only offer it as a very last resort.

Let's take another QAG-2. With this QAG-2, and even in case of under-dosing, it is impossible to develop a new AMR (mutation associated with resistance); the possible rise in CV only reflects an insufficient dosage. On the other hand, it has a (small) defect: there is a mutation that makes it 50% ineffective. This mutation cannot be acquired under QAG-2 but may have been acquired under earlier, weaker X-gravir. Here, this QAG-2 will meet the FDA CoC: it meets the needs of group 1 but also of the other groups, even if only partially. It will pass the review with flying colors. Obviously, we have to propose a dosage that meets the needs of group 2&3. This is exactly what the development team is going to do: in a presentation (see here, the source is here), they explain perfectly this double objective:

The dose proposed to the FDA serves a dual purpose. Well... We understand... but what if this second objective (efficacy on resistant mutants) does not concern you at all? Why on earth would you take a dose of rescue therapy (second line) when you are not concerned by anything? Why repeat at auction(brazenly and stupidly): we are all different, if we forget that we belong either to one target group or to the other and that we can know it.

Frankly, you don't care about taking the right dose for a Genvoya® -resistant patient(and even then... it's not always right) when you don't have to!

Do you want to go into treatment with rescue Pentatherapy? No, that's ridiculous... So why take such a huge dose of DTG?

We'll see in a future post, how ViiV went about maximizing, at your expense, its financial efficiency, with impunity...

Judiciarization

Opioid crises in the United States: pharmaceutical officials prosecuted(Le monde)

In the news

- Plosmedecine protests against trials for the sole benefit of industry and to the detriment of a healthy scientific discussion: The Ethics of Switch/Simplify in Antiretroviral Trials: Non-Inferior or Just Inferior?

- Doravirin ® is ultimately not terrible: DRIVE-AHEAD Trial's results and the need of a right comparator drug.

The French genius

The Goldberg variations are a hymn to silence. The interpretations by Glenn Gould are unforgettable. Unsurpassable? Not sure... We were missing a genius interpretation, on the harpsichord. Did you dream of it? S. Ross didn't do it, Jean Rondeau did! And you will find it on YouTube

Feel free to comment, like, share and use

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

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



DTG-25 mg episode #1

By Charles-Edouard!

From an astute reader:

The discussion on DTG 25mg will be interesting, and, super important with the announced arrival of the injectables, where you will be able to take half a dose, without risk of forgetting...

DTG 25mg: it's time to open the debate!

Science is the approach that keeps us from getting it wrong. (inspired by Carl Sagan) Science is the honest search for knowledge about reality (PZ Myers)

It is the art of asking questions, good questions. Let's open the debate on an inspiring, edifying, exciting and life-saving subject. The doctor has the privilege of prescribing: choice of molecules, dose and rhythm. This privilege has been distorted by not using it. It has become unbearable and will become even more so: the combos are constructed at the sole whim of the industrial and financial Lego, the doses chosen in spite of common sense, and the rhythm, without even taking into account the chrono-physiology of the virus.

While the overmedication is obvious, since the arrival of Tivicay ®, nobody asks the question: but why the hell so many milligrams: 50! only that!!! There is no justification for such a choice. However, the drop-out rate, due to side effects, is 10 to 15% after 3 years, while on the other hand the antiviral power is unequalled, and purely virological failures are rare...

When one is so close to the ZeRo-failure, one can legitimately ask oneself the question: have we not put ourselves too far from the cliff...

We open the debate with this simple question: where do you get the idea that 50 mg are necessary? (in general, and for me, a patient, in particular)

One of our allies laughed at his colleagues who poison their patients with DTG triple therapy, while he does bi and mono. To which I replied that he was just as much at fault for never having asked himself the why and how of this 50 mg...

Here is how we will explain the question:
- the original pharmaceutical sin: the slant and the S
- the escalation test is mandatory but they don't care
- EFV 600 mg an unfortunate precedent
- the trauma of multi-dose rosuvastatin
- DTG and the famous specifications
- DTG exists in 4 doses
- DTG-25 mg has been evaluated and we don't tell you about it...

The abuse is so blatant to our readers that the feeling of a plot against us and our finances overwhelms them. Let's stick to the facts:

The original pharmaceutical sin: the slant and the S

The pharmaceutical grail: the S curve. Galen is credited with formalizing the following observation: the slave prepares opium for his master, who is insomniac. Too little, it has no effect, the right dose, he sleeps well, too much, it kills him. Over a certain range, the effect is in proportion. 2 times more and the effect is doubled. Hence the idea of an oblique line, with, at its foot, a gentle slope, and, towards its highest point, either a saturation (it is then a medicine) or an explosion (it is then a poison). It is basic and primitive, of course, but that is how it works, in general. From the name of Galen, we call the art of preparation: galenics...

The Grail for the pharmaceutical industry is to find this S-curve: once they have the curve, they are almost sure to succeed, especially in terms of regulatory approval: it is so canonical that their presentation to the authorities will go smoothly. Of course, after the first obstacle: toxicity.

In the Dolutegravir story, you may have missed an episode: ViiV (GSK) had, initially, a very different plan ... The basic idea was to put on the market a lambda INI, like Raltegravir or Elvitegravir. But it was too toxic. That's why ViiV is in trouble... Nothing but old molecules in the portfolio and nothing to renew.

Another company, unknown to ARVs, but known elsewhere(we'll come back to this), Shionogi, Osaka, Japan, has a 2nd generation INI, a good candidate. Shionogi: Kadors of inhibition! ViiV buys the rights for 10% of its shares (estimate: 2 billion dollars, anyway...) and royalties (unknown percentage, probably high). Who from Renault or Nissan has the power? In practice? Here, it's a bit the same... ViiV is rather the false nose of Shionogi. The introduction of Dolutegravir must be successful at all costs, the survival of ViiV depends on it.

The S-shaped efficacy curve means that beyond the linear zone, when the dose is doubled, the effect is not doubled. But, it costs twice as much... You have a little hunger: you eat a small banana, it does it... But well... Just... So you eat a second small banana, just to be safe. We all get trapped... Eating a small banana was a great plan. The second one is an extra soul, the angel's share. For a very marginal benefit, it cost you twice as much.

The cost increases linearly, in proportion; the desired effect saturates.

the escalation test is mandatory but they don't care

Once the phase I test (toxicity) is over, the regulations require a phase II test: dose escalation. In practice, the dose that will be retained is part of the tested doses. If there is no additional benefit to increasing the dose, there is no need to increase the dose.

The FDA, which was historically established to protect the patient, imposes this formalism. However, in view of the results, it is not the FDA that decides on the dose... The industry proposes, the FDA disposes. So the FDA does not formally impose the optimal dose.
The manufacturer can choose to market one or more doses. Faced with several possible dosages, the manufacturer(we specify the manufacturer) makes choices, choices that he will optimize in order to maximize his financial income. In principle, he will be cleared of these choices by the presence of two recourses: the FDA (or the ANSM) can refuse, and, in fine, the physician can adjust the dose. The FDA sets the rules of the game in advance: the document is here...

The industrial pharmacist only proposes... The responsibility of the dosage is medical, not pharmaceutical. In practice, the only last line of defense against poisoning by cumulative toxicity is the patient herself.... So the escalation test is only a formal exercise, whose conclusions the manufacturer can easily, under some excuse, ignore.

EFV 600 mg an unfortunate precedent

I must be about the only one to report this sad case: see here or this raging article: Dose optimization: a strategy to improve tolerance and reduce the price of antiretroviral drugs, by Hill, Ananworanich and... Calmy! (sic)

The phase 2 trial clearly indicated an advantage to the 200 mg dose. There was no objective reason to choose 600 mg. Apparently no one can say who chose 600 mg, under what circumstances, and on what authority. Every time you brought it up, you were sent back to your 22m. Until the ENCORE-1 trial, its validation by the WHO, and the marketing of the product, which nobody, nobody talks to you about! They are all walled up in a complicit silence... With DTG, it's the same thing again, but we know the actors and their role... How much is EFV overdosed? 2 times? 3 times? 6 times? Who knows... With DTG, we go to frightening multiples: 2 times, 5 times, 15 times, 25 times ... Amazing!

Well, let's continue next time...

In the news

- Levothyrox: the study that proves patients right: a simple re-analysis of the trials. We do the test, we let the manufacturer do the interpretation, and bam! the disaster. See our analysis of Isentress HD and its 1200 mg!

- HIV infection is no longer decreasing in France. Repeating the same mistakes leads to the same failures. Targeted screening has reached its limits... Adding another layer will only have a marginal effect.

- Colorectal cancer screening is so boring that it is being abandoned. We are sorry in advance about the 'sales' of the reimbursed condom. A good intention, ridiculed by the administration...

- We learn, thanks to an Actupian document, enlightening and staggering at the same time, that Gardasil, this unfortunate vaccine so expensive and so controversial is now free in CEGIDD. If you are at risk (e.g. young gay man), this is to be considered carefully. The benefit/risk ratio is crap for the general population (girls and/or boys, who cares), but for a person at proven risk, it's another matter.
For my part, being at high risk for Hepatitis B, I am vaccinated. Not to the point of demanding, loudly and clearly, the vaccination of infants! Forcing a medical intervention for the sole benefit of others is a crime against humanity (Nuremberg jurisprudence)

- One learns, by the way, a decision taken in secret: the BCG vaccine, whoseinefficiency will have been demonstrated only later, is no longer compulsory for the health workers. The scandal is so huge that we wanted to get out of it by the back door, touch by touch.
Today the BCG is buried! But they are not going to trumpet it from the rooftops. Some vaccines are useful, others not! You have to stop talking bullshit... Forcing people to take useless or even dangerous vaccines is putting gas on the fire and feeding the anti-vaxers.

overmedication is an opportunity if you know how to use it!

123

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



relief and intermittence

By Charles-Edouard!

A reader asks the inevitable question:
This is the question everyone will ask... Almost everyone... Others will go for 3/7. It is the purpose of the OMNIBUS project to answer it. Reminder: this blog is not a medical advice

relief vs. intermittence

Since our Staff at the Salpêtrière (Sept. 2018), it is agreed to call lightening, which uses fewer molecules and intermittence, short and ultra-short cycles. Reducing the concentration of EFV from 600 mg to 400 mg (or even 200 mg) has no other name than 'correction of methodological error' .... Obviously, there are people who will want to do both ... Especially since the 4/7 in commercial dual therapy is inevitable... Inevitable, because the only advantage of MK-8591, the EFdA marketed by Merck is its half-life of ... 168 h! To think that the 4/7 in BI will not be done is a nonsense... It is quite legitimate to ask oneself, as of now, the question.

For carefully selected patients, MONO-DTG works very well, and I can assure you that it is very pleasant, since the tablet is very small. I have had it work in half (7/7) and quarter (7/7) tablets! I assure you that when you take your quarter of a tablet in front of a witness, she is amazed... Mono-DTG has a remanence of 3-4 days, it is written in the Vidal, and tested in the ING XXX trial; So people who succeeded in their Mono-DTG in 7/7, went to 4/7, including my excellent friend jesuisdutreize. The weak point of this strategy is that there is an Achilles heel if the virus has been treated, at some point, by RAL or EVG. For those whose virus is old (pre-2007), just look at the prescription history. For the new ones, it is a bit different, because their virus could have been treated (badly) by the person who gave it to them. However, we do not know how to make a relevant genotype for this case, so there is a random risk, all the more so since Isentress ® (RAL) was used liberally, as in Holland or in the West of France...

So, before considering a MONO-DTG in 4/7, one must be sure that one is on the right side of the handle... The passage by 7/7 is thus rather a good idea. It is necessary to be perfectly compliant during this first phase. Then you can work on intermittence, under close biological monitoring, as always. MONO-DTG in 4/7 is great. Today, in Paris, Prof. Katlama is the reference for Mono-DTG.

OMNIBUS-Bicycle

Once we understand the process that leads to MONO-DTG 4/7, we understand better that the process that leads to Bi-DTG 4/7 requires a good real honest validation of DTG/x, in 7/7, for a while. From this point of view, the process is the same, whatever the x in DTG/x: either 3TC, or RPV, or ATV (boosted or not), or nothing. The cause is this Achilles Heel, identified by Katlama and confirmed by subsequent explorations.

Then there is the choice of the second molecule (or not). The undeniable advantage of Mono-DTG is that in case of failure (apart from the Achilles Heel), there is no resistance to DTG. Let's say, in any case, that DTG can continue to be used. Martinez, Lanzafame, and personally, myself, believe that it is enough to reinforce, without making a cross on DTG: that's pretty cool!

3TC: In case of failure under DTG/3TC 4/7, the weak link is not DTG but 3TC, in other words the M184 mutation: this one is a pain... It is easily eliminated by fallowing (1 year off treatment) but you will be bored for the rest of your life and you can say goodbye to dual therapies, to 'classic' intermittence, etc... The objective of DTG/3TC in 4/7 is good if it works, and then what do you do?

RPV: better not to be susceptible to drug-induced depression... DTG on one side, VPN on the other, there are many who can't stand it. As always, if you can handle it, it does, and it's Juluca®, in one pill. If there were no alternative, it would be attractive.

ATV: This is the stuff we're talking about. The highest strength barrier is DTG and ATV is right behind it, so it's concrete. I'm very happy with it, no liver problems, and it's a good way to get to 3/7. Leibowitch and Katlama agree, for once... and consider it for 2/7. That's really cool. Katlama says with booster, Leibo says without...

As long as I have to choose between MONO-DTG 4/7 and DTG/ATV 2/7, for me it's all clear: DTG/ATV 2/7... And there's nothing to stop you from starting MONO-DTG --> MONO-DTG 4/7 --> DTG/ATV 2/7, with Katlama for example.

OMNIBUS-3D

You can also consider, and this is the easiest way, to advance to 3/7 with your Triumeq®, it is eligible for the OMNIBUS-3D trial and so are you, since you are successful in 4/7. OMNIBUS-2D is not yet finalized, but Triumeq® is definitely in! Triumeq® 2/7

My personal experience includes 4/7, 1/7, 1/15 (modified Leibo method), Mono-DTG, in 4/7, in 1/7 (failure), Bi DTG with 3TC or with ATV. The only thing where we have the satisfaction of moving forward is 4/7, 3/7, 2/7, 1/7, etc

Strategy	Toxicity Unit per week	commentary
Bullshit IRR (7/7)	21	if you have shares in Labs...
Bi: DTG + 3TC, 7/7	14	validated (Lamidol)
Any classical IRT 4/7	12	soon outdated?
Bi: DTG + 3TC, 4/7	8	Omnibus-Bicycle, not started
Quadri-Leibo (2/7)	8	rigorously demonstrated, but Videx® unavailable
Mono-DTG 7/7	7	caution (Achilles heel and compliance)
Mono-DTG 4/7	4	caution (Achilles heel and compliance)
Quadri-Leibo (1/7)	4	rigorously proven, but Videx® unavailable
Charles-Edouard formula!	3	new 1/7 (1/15) under exploration

Who to consult

In this case, it's not the doctor that matters, it's the close CVs: if the doctor gives you the prescription, it's free, otherwise it's 70 Euros per CV: not the end of the world... This is the big advantage of Triumeq ® 3/7 or 2/7! You don't have to worry about it! The caution is to make sure that the CVs are close together

That's how I keep the same doctor: he is not at the forefront, that's for sure! In the worst case, no doctor would be suitable for me... Leibo is out of the picture, since he has announced to leave the case(considering his age, it's understandable and inevitable). Katlama, hurry up, retirement is coming soon, but once the plan is made, it's made.

I have published a list of caring doctors, you choose...

Obviously, the alter egos of de Truchis, like Landman or PM Girard, will not be an interesting second opinion for you, it's kif-kif, besides, they are bound by the ANRS trials...

For an enlightened strategic definition Katlama(or maybe Valérie MARTINEZ) at the Salpé, and you also start to take issue with Jean Derouineau, who had the good and nice idea to ask to be part of the list and who does a little bit of everything, in town medicine.

News from Omnibus

It's finally happening! The consultation period around the protocol is coming to an end and it is finalized: we still have to convince some clinicians, and this is well on the way. Well... It's going on... As for the financing, I'm making progress too... Well... Needless to say that the winds are against me, but well... I've just succeeded in an absolutely smoking coup, in a related field, and, moreover, I've been told that the financing is on the right track. And it's a nice funding! I'm going to have the approval letter framed, I'm so happy!

In the news