130

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



Supersonic Suppression

By Charles-Edouard!

Call unanswered, and for good reason...
Between the ICCARRE, ANRS-4D, Quatuor trials, and the fact that Morlat authorizes 4/7, you have between 1000 and 2000 'official' patients. The ICCARRians' testimony is here, and the others... nowhere... Not one to come and tell about his participation. Not one either to come and tell about a failure, especially as we have been able to highlight the lack of follow-up of the procedure.
The general instruction is to delete again by going back to 7/7, with the same combo. This is with the doctors who 'master' the procedure. There will always be a few who will change the combo, and patients sometimes find this to their advantage. The question of changing or not changing molecules is at the heart of this post.

Close-up CVs: it's essential

I had described here that I had failed the weekly single dose of DTG (150 mg, 1/7). Some readers have come forward and said: 'I can do it'. I believe them. But then again... For me, the use of DTG/3TC in 3/7 or 2/7 (inflated) had already given some warning and the attempt of Mono-DTG (150 mg, 1/7) was a bit of a last try...

Spectacular recovery: I was then displaying my highest CV. On my own, as much as all the other Mono-DTG failures combined! No discussion, but... Shouting resistance would be a bit too fast. With Absolutegravir, you have to expect a rise in CV when the dose is insufficient, a bit like an insulin that is not dosed enough: the objective is not reached, but without prejudice.

By the way, as much as I have a strong opinion on the uselessness of the proviral DNA measurement as a measure of the reservoir(I am therefore an A-Rouziouist), the existence, in my case, of a reservoir capable of restarting the infection is not in doubt. This is an opportunity to challenge some preconceived ideas: one cannot prejudge the height of the rebound(you can imagine that I did not expect this!), nor that one can 'feel' the rebound, as a kind of felt primo-infection(my primo, I remember it, thanks to him...): it is better not to rely too much on the reading of one's body or on luck. Analysis is more useful, as we will see here.

This was the one and only time I deviated from my rule of close CVs (unexpected detention abroad): CV at month-3 instead of month-2. Here again, the lesson is well learned. Afterwards, we do as we can... My new sequence, for example, is, reluctantly, month-1, month-2, month-3, month-6, but it is for professional reasons. So, here, CV at month-3, just after the change to Mono-DTG 150 mg, 1/7, will have been a mistake: might as well remember it!(it may not be Mono-DTG 1/7 that is at fault, we will come back to that). With the years, a certain fatigue to take blood samples every 2 months had been born, by dint of seeing <20 each time. But it is necessary in the initial phase of each change.

Drowning? Recovery? And with what ???

Well... Now you are faced with your $$$ copies (CD4, that's still ok...) and therefore with dilemmas in a drawer: to resume or not the treatment, with or without DTG. Personally, I have full confidence in the long fallow as a method of cleaning up mutants, and do not give any credence to the so-called over-risk of waiting for 350 CD4 as a threshold for resumption(cf SALTO trial, or HIV-CAUSAL cohort). Drowning was an option. Now... Fallowing (1 to 2 years, if you can), then suppression(without DTG, it was long, 18 months, in my case!), then the timid ICCARRian recovery, we took it for 5 years...

So I choose the recovery. But with what? No resistance test at hand. What to do with or without DTG ? Martinez and Lanzafame remove the failures at MONO-DTG and keep DTG. Bart Rijnders, Hocqueloux/Raffi, Katlama, change their approach... We will test if DTG has, for all intents and purposes, behaved like an Absolutegravir.

The virus is smart... So are we!

To the question Cheese or dessert, I often answer Cheese AND dessert! So we're going to develop 2 strategies and combine them.
Strategy 1: Triumeq
Strategy 2: NVP/TDF/F-3TC.

Like the concomitant intake of DTG and NVP leads to a total disappearance of DTGit is useless here. This becomes: combined strategy DTG/ABC/3TC and DTG/TDF/F-3TC, that is, in fact, 2 distinct strategies, combined: namely

Strategy 1: DTG BID 2x50 mg (strong but useless if you are not sensitive to DTG anymore)
Strategy 2: ABC/TDF/3TC (weak, not recommended, but useful in contrast, here).

We will be very attentive to the dynamics of recession. If the descent is slow, we will abandon DTG and quickly put NVP. We will then take note that DTG has become useless. We would regret it a little, but we know how to do the 1/15 without DTG. If DTG is of no use for dynamic remission (1/15 and more), no regrets. If the descent is rapid, we do not change hands, we keep DTG in our remission strategy, but not alone...

Admire the work...

Intake scheme	rhythm	duration	result
DTG/ABC/3TC in the morning DTG/TDF/F-3TC in the evening	7/7	1 month	<20
DTG/TDF/F-3TC	7/7	1 month	<20
DTG/TDF/F-3TC	5/7	1 month	<20
DTG/TDF/F-3TC	4/7	1 month	<20
DTG/TDF/F-3TC	3/7	1 month	<20
DTG/X/TDF/F-3TC	2/7	1 month	<20
NFC-1	1/7	6 months	<20
NFC-2	1/9 then 1/10	6 months	<20 (*)
And in project...		(*): last validated tag
NFC-3	1/12	6 months	start: Sept 2019
NFC-3	1/14	6 months

Supersonic descent offers new perspectives!

It is observed that the virus should have maintained a normal sensitivity to DTG. For a susceptible virus, DTG works equally well at 2 mg, 10 mg, 50 mg, in monotherapy of attack ( ING 111521 trial). It is a methodological error to confuse efficacy and speed(obviously, for a molecule with 1 LOG, e.g. AZT or 3TC, the absence of speed leads to inefficacy, but with DTG we are not in this context). So with 100 mg, on a susceptible virus we should have a very good speed of descent: this was the case. 2 x 50 mg, it's worth it at the initiation, during 1 month, but it's unbearable: depressive effect guaranteed! I endured, but the effect was perfectly visible, what a horror!

If DTG had lost all its efficiency, ABC/TDF/3-TC would have given us a flat kinetic. In the intermediate case, we would have jumped on the way down.

We will never know for sure! But DTG remains in our toolboxwhich is an excellent thing. We'll complete it, for sure, but it stays there. It is ABC that is on the hot seat, and will disappear, phew...

The attentive reader will have noticed that we went from MEGA-Copies to 1/7 in ... 6 months! If with DTG/ABC/3TC/DTG/TDF/F-3TC, 7/7, we did not succeed in the first month, then we could fallow (drown) and then NVP/TDF/F-3TC 7/7. Compared to a fallow (1-2 years)/Tradi-TRI (1 year)/ ICCARRE (4 years) strategy, we win!

Fallowing is the ultimate catch-up net: you have to make sure you have 12 to 24 months to go. Many patients start too early, but if they start when they could have reasonably postponed, it also means that they can afford to fallow. At the time they make the decision, which is too early in our tropics, they are not aware of it, but it comes naturally with time... The exploration of the Eclipse has several nets of catching up. Especially since the close-up CVs are easily accessible and DTG-double dose (or even triple dose) will shoot down any CV in no time. The mega dose to zap the asshole works, of course, what is stupidis to keep the same overdose once the undetectability is reached. This is silly.

And ... Hop!... Forward to the 1/15 (again)

Now, for my descent to 1/15, I'm going slower, since I made the descent to 1/7 in supersonic mode.

In the news

- You are indebted to him and he is dead: Kary Mullis invented PCR, won the Nobel Prize in Chemistry(just that... ). PCR has many applications, including one that concerns you: CV. There is a before and an after to PCR... Dr. Leibowitch, who has always been opposed to double-blind placebo trials, has finally been listened to since he demonstrated the possibility of obtaining an undetectable load(Stalingrad trial in 1995). Before the CV, we went in blind, using the 'guinea pig' patient. No CV, no intermittence...

Once a scientist, always a non-scientist... We make fun of his allegory on the luminescent raccoon, which he commented thus:

Hi, hi, hi...

- Offshoring at the root of the drug shortage in France. Offshoring ??? Ah Bon ??? Does it exist??? Until recently, ARVs were still produced in France. In Auvergne, precisely... And why on earth in Auvergne? Because it was the price to pay to the Chiraquie to obtain the authorizations without too much trouble. Since then, Brussels, Hollande and Macron have been there: nothing grows back!

The French genius

We had exposed, right here, (a little before everyone else...) that the Levothyrox scandal is due to a methodological error: Indeed, one should not compare Mean-to-Mean when the standard deviations are important! Especially not! This allowed us to point out the aberration that is Isentress® 1200 mg(1200 mg! where do they get the idea?) and which has its MA(yes, yes...). This same error occurs in another place in the theory of immediate return(we will come back to this). The re-analysis of the Levothyrox data confirmed the methological error. The authors very explicitly consider that the error was intentional. Le Monde wonders why Merck was overzealous in its evaluation of the new formula.

The multi-year prize goes to the HAS and the health 'authorities' who have been blamed for this sad Levothyrox affair! The mathematical breakdown is here : Why did it take more than 200 subjects to demonstrate the bioequivalence of a new formulation of levothyroxine with an old one?. Didier Concordet, Pierre-Louis Toutain & al. are ... veterinarians ... (from Toulouse). Ah???? Well??? The doctors, where were they? In the Bahamas ??? Well... We are not going to bite the hand that feeds us!

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

129

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 5

By Charles-Edouard!

Yes...It's been exactly 1000 days since 4/7 was authorized by the Morlat Report. Our practical guide dates from 2014: print it and put it under the nose of your doctors. At Homo Parisianus, 4/7 is becoming more and more common... For the 1/7, it comes slowly... Remain the province, the chicks, the disconnected of the Tout-Paris-Qui-Compte. One could have reproached Quatuor for a prejudicial waiting period: 3-4 years lost. Very formally, this is not the case: Morlat, who could have been blamed for this wait-and-see attitude, has in fact explicitly authorized 4/7, as early as 2017! Slow and proactive at the same time: Quatuor is here, in French: It's a flat-out success: we'll come back to it!

DTG-25 mg: Basic Dose (BD) and Rescue Dose

The FDA considers 3 groups: group 1: patients with no problems, group 2: multi-resistant patients, with no solution, group 3: multi-resistant patients, with options. Here, there is no need to dwell on group 3. Group 2, in the USA, is 5000 patients. Out of 1.1 million S+ patients, this is very few, even negligible. The manufacturer could very well want to concentrate its marketing choices on group 1: that would make sense. However, it would make sense...

Let's call DB (Basic Dose, in mg) the oral dose necessary to zap a wild virus (not mutated). This base dose will deliver a plasma dose roughly corresponding to the IC95 (or IC90), the 95% (or 90%, respectively) inhibitory concentration (for DTG: 64 nanograms/mL).

Let's look again at this table published by ViiV, but from the perspective of RAL (raltegravir, aka Isentress ®). There are several primary mutations in red, including one with an FM (Multiplier Factor, FC) of 85. For patients in group 1, i.e. 99.9% of the market, if you want to be sure of your chances, you have to cover the red zones, including the highest one, which invites you to choose a dose of 100 times the DB! It is no longer surprising to see Isentress HD dosed at ... 1200 mg;

For secondary mutations (table 2), it is clear that even at 100 DB, it is so red that it will not work: even at 12,000 mg... If we have resistances elsewhere, the deadlock is total.

Fast Track or... bankruptcy...

Offering a solution to group 2 is very hard, and at the cost of marginalization on the market. However... For ViiV, is an ABSOLUTE priority. Why is that? Because:
1 - it is possible, certainly the dose is high, but it is playable
2- it's urgent: ViiV is on the verge of bankruptcy: its drugs are old and will soon be genericized, ALL of them, which means a drop of 80 to 90% in turnover! Do you know many companies that are resisting to such a downturn?

Solving the problem of group 2 will save ViiV from a predicted industrial disaster: thanks to the (super) fast track, accelerated approval by the FDA. For ViiV, it is vital. On the other hand, we can observe that Gilead has been rather late to release the TAF. Big Pharma delays to perpetuate its profits, but sometimes accelerates to save its skin.

But let's look at the table of secondary mutations, for DTG this time, with 50 times the DB, that's enough! And moreover, in the clinic (SAILING trial), it will do it! For the FDA, for the DHHS (US guidelines), it's a great move! Whoever solves the problem of group 2 will not be objected to in the slightest. Translated into good French, the ASMR, delivered by the commission of transparency, will be rather nice! It is published here:


If you approach the MA with an ASMR of 5, you'll be passed over, with an ASMR of 4 you'll pass, but the economic committee will take its time. If you have an ASMR of 3 and a market price, it will go fairly quickly. This is in fact what happened, see the Efficiency Opinion (May 2014)

The naive patient... Indeed, quite naive!

So, you, patients of group 1, naively thought that the dose had been thought for you, and that by chance, by inflating a little, we solved the problem of group 2. Well, no... It is the opposite: we solve the problems of group 2, in priority, and by deflating a little, we will solve group 1(who can do more can do less), but regardless of the FM needed for group 1 (FM from 3 to 5).

INI	DTG	RAL	EVG
FM Max group 2	50	500	50000+
Dose for group 2	2 x 50 mg	unusable	unusable
FM Max group 1	3	90	500+
Dose for group 1	50 mg	1200 mg	with booster
Prior eligibility for group 1 (only)
7/7 Therapy	YES	YES	YES with booster
Bitherapy 7/7	YES	YES ?	NO
Monotherapie 7/7	YES	NO	NO
Eligible 4/7	YES	YES (?)	YES (?)
Eligible 3/7	YES	NO	NO
Eligible 2/7	YES	NO	NO
Eligible 1/7	YES (?)	NO	NO
Eligible half dose	YES	NO	NO

And this is how they will get a MA with a price of 600 Eu. for 25 DB (50 mg). In practice, this will make 1200 Eu. for the rescue treatment: the 50 mg at 600 Euros is the market price for the first line and, at 2 x 600, in the market price for the second. Nothing and nobody will find fault with this.

That is... 12 Euros per DB/month

You, patients of group 1, without the slightest risk to switch to group 2, you only need 5 DB (counting very large). But here's the thing, ViiV, they are not stupid: they are not going to propose a drug at 5 DB but at 25 DB... Of course, in vivo, one can obtain different results. And they are remarkably discordant: Mono-DTG which works very well here, in humans (and we'll watch what Morlat says about it), and, surprise, very badly in monkeys (Mesplède article). Whatever, what concerns us is us...

We'll see next time why and how ViiV is going to optimize its income a super max, at your expense. To get a head start, try to imagine the extraordinary loss of income for ViiV, if they had chosen 10 mg

In the news

- Stromae is better! A time forced to an artistic retreat after almost ending his life during a depressive episode triggered by a drug intolerance'I made a reaction to Lariam, an antimalarial, super super serious, he added in late 2017. I had a psychic decompensation. It's really not nice.' Really??? Does drug-induced depression exist? We don't even need Lariam, EFV, RPV, DTG are more than enough... Not to mention the interactions between drugs...

- Chlamydia: a vaccine is being developed. For an immunizing disease (you get over it, and then you don't get it anymore) such as measles or Ebola, it is well conceived. For non-immunizing diseases (HCV, HIV, Tuberculosis), it is already much less obvious! That the BCG is useless, they did not shout it from the rooftops! As for HIV, don't expect too much from the ANRS in this matter (given the mishmash of personal conflicts on the subject). On the other hand, finding an invariant, such as TAT OY, is already more encouraging: this is the BIOSANTECH approach. We will see...

The French genius

One can hold one's breath, but one comes out under high blood pressure! Film noir under a blazing sun, a dry hell under a torrent of sweat... No need for a big budget to make a cult film, a film that the Americans will remake. Well... Unless they remake QUATUOR, they'll let us have the exclusivity of the extraordinary economic gain, a real gold mine for us alone. That's just fine!

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

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?