132

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



Help yourself: ARVs will help you

By Charles-Edouard!

The blog is assailed by SPAM, so: on a recent article, the messages are published immediately. On an old article, they are moderated...

Intermittency is unstoppable

When you're at 4/7, it's normal for 3/7 to tickle you. Each time, you are there and it works. And as it works, you are there; so why not go further? It's Darwinian and recursive: at each increment you, and your virus, are in a new environment. There is, strictly speaking, no intention. Some people stop, at the judgement, the pre-judgement shall we say, at X/7. But this is only temporary and it is only a matter of time before they resume their journey, each time more astonished by their extraordinary success: they believe it to be exceptional: it is not! Find me even one failure with Triumeq® in 2/7 or Eviplera® in 3/7!

The intention, or the goal, shall we say, is most often the fear of side effects. Once at 1/7, we can say, for sure, objective achieved! However, there is nothing objective about this: reducing an overdose by a factor of 15-25 (e.g. DTG) by a factor of 7 is not an objective success.

Toxicity is not my initial motivation

My entry into intermittence had nothing to do with toxicity, which, like many, I had not identified as such, and which had already done its work of undermining, with consequences and after-effects that would be discovered and that the simple change to 6/7 would reveal. I am familiar with this state of mind of the patient who does not see the insidious toxicity, denies it, I have shared it...

My personal interest does not come from there, so it is not confined to that. One school of thought envisages a reduction, or even disappearance, of the reservoir. We see from time to time a manipulation exploring latency reversal cocktails or the role of DTG. Latency inversion was my hobby. I did it. In France, I must be the only one! Because, if there is a clique of peroers, there has never been the slightest manipulation. They are reasoners in rocking chairs.

Ananworanich, close-up CVs and FASEB-1

I don't give the same credit to the latency reversal anymore, but I did do what Ananworanich did(first-in-class clinician), with one notable difference: where she has about 30 volunteers, 15 in each arm, I only have one on hand.

We try the cocktail, in double blind, and then we stop the treatment to see if there is a difference in time to rebound. For the moment, NADA... The time to rebound is identical in both arms (intervention and control): 2-3 weeks. The difficulty is not there... We have no clinical support for our legitimate explorations (American veterans do, so it is legitimate and ethical).

That's when I discovered that you can do CV without a prescription! It costs, but, it's possible. Except that... Here's what's not possible: interrupting the treatment and going to the lab to have a CV done on Monday and Wednesday, every week, until it comes back. At that time, the lab's FRAU had warned me: CVs outside of the prescription = OK, but cevetic relentlessness = NEIN. And at the time, the labs that offered this service were not numerous. Today, one could establish a wandering strategy and proceed exactly like Ananworanich...

Except that, here too, the Ananworanich method is not the best: you have to let the virus rise again, then you have to delete it again, which can take a long time and subjects you to the risk of seeing your doctor-secretary change your combo at the same time. Today, with DTG, retreatment is simple and without the threat of resistance. Today I will not hesitate, in fact I did not hesitate to resuppress with DTG as we have seen.

There I discovered FASEB-1, and the possibility to explore the Eclipse, gradually, by small steps. It's much longer, but the pharmaceutical savings(less toxicity) is already a good thing! Even if you fail to go into remission (you wouldn't be alone), you'd have as many boxes of medication left in the cupboard, and that's not bad. Maybe we'll come back to this one day...

My goal is remission!

I've put a little water in my wine and I'll be satisfied with a remission with small feetAt 1/30, I'll stop, it's not a big deal. At 1/30, I'll stop, I promise.

The current philosophy in this matter is anti-scientific: if you stop, the virus will always return and it's not true, we know that now: the Eclipse is and it is 2-3 weeks. In addition, there is a significant proportion of patients in whom replication does not resume until after a month, or even not at all. The alternative, orthogonal, is to say that if you take 7/7, you are sure to remain suppressed, which is also inaccurate: there are exceptions (we may come back to this).

Between these 2 orthogonal propositions, in exact opposition to each other and equally false, there is an unexplored field of possibilities: what happens when you go through a slow withdrawal? That nobody has done, except me: we make X/Y (X can be 1, 2 or 3, we will come back to that) and we extend Y: 7, 10, 12, 14,... 21...

The more we advance, the more we have tools (molecules, CV, tank measurement...) and concordant proofs on the Eclipse. But surprisingly, clinicians are not interested in this: when I talk about it, it's a flop, which proves that Silicianism is deeply rooted in the minds of people who are not known for their sagacity. The world without Peytavin, without Rouzioux and without Siliciano is nevertheless a world full of potentialities, accessible to everyone.

I'm going to 1/12!

My 1/10, in extra-Leibowitchian formula, this time, has been validated. The NFC-3 suits me very well (Charles-Edouard's New Formula!), so we're moving forward, carefully, as usual, and we'll come to complete, without batting an eyelid, new molecules, when the time comes. We are completely free from the goodwill of the medical-pharmaceutical underworldof all those pretentious people who never did anything. Free, finally free... And soon (semi-) cured!

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

131

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



Discovering Islatravir (ep.1)

By Charles-Edouard!

From a well documented veteran:

We've heard it so many times, you'd think the argument was legitimate... It is easy to lose sight of the fact that the aim of a treatment is to cure, not to confine. Especially at the cost of such a devious over-medication, of which one is only really aware after 2/7. Look at what those who take ABC in 2/7 (or even less) say: they complain about it more than those who take it in 7/7. Does this mean we should go back to 7/7? I have never seen anyone go back. The bomb-silence cycle (aka choke-and-mute) creates, as such, a selection pressure that is all the more exploitable and beneficial as the bomb is strong and the silence long. Mini-bomb-mini-silence? Mini-bomb-long-silence? I prefer Maxi-bomb-maxi-silence: my day of liberation is (will be...) the 30th of January 2020. I can't resign myself to life imprisonment, nor to sentence adjustments. Especially since we'll be able to build super-bombs, really well.

Islatravir: Finally the Weekly stamp!

A new chapter in intermittence is opening, and what a chapter it is!

Misconceptions but favorable ones. Believing that one can do 5/7 with EFV, limitingly to 5/7, due to the favorable pharmacokinetics and obvious overdosing of EFV is an original mistake. The first successfully tested intermittence is 7 ON, 7 OFF. The fact that we know how to do the 7 OFF should have opened our eyes to the supra-kinetic character of the cycle. Anyway...

The history of intermittence was built on a misunderstanding, certainly, but it was built. With a very very confidential success. The persistence of the effect of DTG for 3-4 days is registered in the Vidal: patients have started to understand. DTG allowing for 4/7 (or even much less), Dual Therapy and Mono-DTG (not counting DTG-25 mg) opened the Pandora's box to a wider, more receptive audience. With the success that we now recognize to 4/7, with or without DTG, by the way...

And here is: Islatravir. With 2 'favorable'(and antagonistic?) characteristics: It is ultra-nanomolar (EC50 at 50 pmol/l) and it is very persistent. We can afford to put only a very small dose (2 mg?) and the intracellular persistence (of the triphosphate form) lasts a week... at least... Let's bet that the marketing phase will have 2 objectives: to exploit the mini-dose to the full and to mask, as much as possible, the weekly persistence.

Islatravir: a chemist's vision

The story of islatravir deserves to be told, even if it is at the cost of inevitable approximations. Unlike DTG, which was designed by computer, specifically targeting the catalytic pocket of integrase, this discovery was made more by chance and by the intuition of skilled chemists.

In the cost structure of a chemical, the most important contribution is the manufacturing cascade (usually a synthesis). If it is simple, it is inexpensive. To make a nevirapine, take 2 industrial pyridones, mix, precipitate with acid, wash, filter, done. On the part of the industrialist, there is not much intelligence nor deserving work... Let us pass...

But this alone leaves the product unaffordable for the poorest countries. However, to obtain a desired molecule, one could go about it differently: take a complex but cheap molecule and split it to keep only the structure that interests us. Complex molecules at low cost? Yes... vegetable or animal proteins, by-products of the food industry, looking for juicy outlets, and even more, if affinity... We take a cheap protein, we cut it (which requires less energy than assembling it) and if we fall right in the middle, it's bingo! The problem is that we will try dozens of sub-proteins with thousands of potential applications (e.g. egg shampoos), sometimes with a little luck. Originally, an envelope from the JSPS, an agency attached to the Japanese Ministry of Education, to animate institutional university research and facilitate collaboration with industry around amino acids.

A precedent: RALtegravir

Even if there are some notable exceptions (e.g. fosampenavir), the vast majority of molecules useful to pharmacists follow the rule of 5. There are as many possible combinations of C, H, S, N, O and F atoms, which follow Lipinski's rule, as there are stars in the universe: billions of billions. It is like looking for a needle in a haystack. Now, if you have a good hundred thousand... So people like Merck, who have already synthesized so many things, spend their time (and your money...) making trays with little wells, pour in cultured HIV(but also Ebola, Marburg, cancer, whatever) and come and dip a little bit of the AX10295 molecule in one well, then the neighboring AX10296 in another, etc.

It costs a lot of money. Until one day we have a touch. In this case the diketo acid, which has a modest activity but stands out. We look, we study, we create variants, etc. and we arrive at a not too bad drug: Raltegravir (1200 mg anyway!). And a monopoly on the market until the other zozos manage to manipulate the diketo acid to produce something passable (EVG for Gilead and... something as toxic as possible for ViiV, which ended up in the poo, we've already talked about it)

This first touch has, except for extraordinary luck, a mediocre activity: you have to put a huge quantity of it to get the virus out of your well. Not possible for a drug, but it's a starting point. We improve a little, and we only need millimoles, we improve a little and we only need micromoles, we are on the right track. We improve a little more and we hardly need more than nanomole: here is the Grail: we succeeded, we go...

Will ISLATRAVIR kill the 7/7, the 4/7 and even the 1/7?

There is a lot to think about... In a next post: how ISLATRAVIR was conceived and how it can help us break the 1/7 barrier... To be continued, as you will not read this anywhere else...

Obligation of treatment / Judiciarization

- the last straw: Mediator: Servier asks the State to reimburse compensation paid to victims

- Camouflet for the cretinous rouziouists: In France, the (too) early treated give the finger of honor and abandon the treatment in majority. A little common sense in a world of bullies? Too early to stay on track? Shorter time to first antiretroviral treatment is not associated with better continuation of care (here) (sweet euphemism!). This is a FRENCH study! Oh, they didn't tell you about it? Well, let's see...

The only interest in treating (too?) early, in our tropics (cf HIV-CAUSAL cohort), is to be non-contaminating. Obviously, and at the time of PreP (i.e. the shift of responsibility for protection), being non-contaminating is not a decisive argument for everyone... The IST obsession (Everything but Intermittency) is failing after failing and is reaching the end of its logic...

In the news

- The systematic use of dosing in order to adapt to the 'recommended' doses has no effect on undetectability. Another euphemism... Why not say, in good French, that the registered(prescribed?) doses are useless, which is normal, since the concept is biased and the values are false(we will come back to this perhaps). It is in France, but not published in French, and it is here:
In other words, the Morlat dosing recommendations were followed and there was no therapeutic benefit. The concept of threshold dose, in the hands of people who do not understand it (patients and doctors) is a real catastrophe: we could not hope for a better demonstration... It is a FRENCH study! Oh, they didn't tell you about it?Well, let's see...

- Discovery of a second genetic mutation resistant to the AIDS virus: it' s here

Good weekend, good stuffing and not too many drugs ... Right?

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!

Feel free to comment, like, share and use

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!

Feel free to comment, like, share and use

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?