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



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?