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Friday, July 28, 2017

R263K and Darwinian sink



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

Summer 2016: we offered a serial: ANRS-4D and the cheaters

Summer 2017: we will debunk DOMONO:
- Dolutegravir and R263K
- R263K: new scenario (DOMONO)
- N155H: new scenario (DOMONO)
- Nevirapine and Mono-DTG Switch: the Hunchback Trap
- calculation error in the primary hypothesis
- DOMONO and the benefit for the patients (not for BigPharma ...)


R263K and Darwinian Sink

By Charles-Edouard!

Here is a testimonial DTG 100mg / week ...

With Dolutegravir, as a monotherapy, we have opened the Pandora's box: some will not get there (eg DOMONO), others will get there (eg DOMONO, again), and even go further in aleviation! There must be a limit ... How far can we go?

Dolutegravir and the Hybrid Behavior


It is difficult to understand: mono-DTG has given excellent results in many patients, and some discordant results, including, in DOMONO, a patient with a surge at 70,000 copies, without mutations, and with, so we are told, a good adherence: it is hard to believe!

Dolutegravir HIV tivicay resistance R263K HIV darwin mutation reservoir cure

For some, DTG is an Absolutegravir, for others, it's just a powerful ARV, no more. Absolutegravir has a unique mode of operation: it never give resistance. Dolutegravir presents this mode (pseudo-Absolutegravir) for some, and commonplace ARV for others...

The Darwinian well separates 2 modes


Whenever the Darwinian sink separates the two modes, there is an Absolutegravir side and a trivial side.

Dolutegravir HIV tivicay resistance R263K HIV darwin mutation reservoir cure
The maintenance patient can either maintain maintenance, stay at the starting point or even drop his virus into the Darwinian sink (orange path) or fail with a mutated virus (green path) or even a non-mutated virus (in appearance) (red path).

There are therefore 3 types of results (and not 2): maintenance (or even improvement) of the control, escape without mutation, escape with mutation.

Let us keep this pattern in mind: we will see scientists and clinicians throwing at each other okases and anathemas, to the great detriment of patients and the benefit of Big Pharma, with usual useful idiots as a megaphone.

Dolutegravir, R263K and Darwinian sink


Dolutegravir HIV tivicay resistance R263K HIV darwin mutation reservoir cure The naïve patient, having a virus, as wild as possible, has everything to succeed his/her attack treatment, in mono-DTG. For now 100% success at Lanzafame: he has an Absolutegravir.

One raises the pharmaceutical pressure: the virus descends, without mutating or even mutes (R263K) to fall into the sink.

If one reduces the pharmaceutical pressure, the virus goes up, exhibiting, for a while, a R263K mutation (possibly), and if one lets go, it goes up further, and the mutation might become invisible (while remaining present? )

The well, the 3 zones and DOMONO


Now that we have more baggage, we can get to DOMONO. An intermediate presentation of DOMONO is available here (presentation at Glasgow 2016), the poster with conclusions was presented at CROI-2017. You can take a step ahead of our summer series, by identifying the 3 areas of results: success, failure without resistance, failure with resistance. Our next episode: Is a failure with the R263K a resistive failure?

This story is rather complex (I simplified a lot ...). You may want to read:
Monotherapy with either dolutegravir [...] in humanized mice (you have to read the complete article to see that the failing mouse was underdosed, otherwise it is misunderstood).

Wainberg and Mesplede explain that the R263K trick may not work in 1-10% of patients: Polymorphic substitution E157Q in integrase increases R263K-mediated DTG resistance

The Achilles Heel is well detailed by Dr. José Moreira in Dolutegravir monotherapy as a simplified strategy in virologically suppressed HIV-1-infected patients.

Patient selection will be crucial


Careful patient selection will be an important aspect for mono-DTG (attack or maintenance). To note this Saturday 22 July the conference: Global HIV Clinical Forum on Integrase Inhibitors (sponsor ViiV Healthcare ...) with a program denser, in fact, than the one published.

Good ... Work in progress ...

Good Week-End and Good Fuck!




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

Summer 2016: we offered a serial: ANRS-4D and the cheaters

Summer 2017: we will debunk DOMONO:
- Dolutegravir and R263K
- R263K: new scenario (DOMONO)
- N155H: new scenario (DOMONO)
- Nevirapine and Mono-DTG Switch: the Hunchback Trap
- calculation error in the primary hypothesis
- DOMONO and the benefit for the patients (not for BigPharma ...)


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