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?