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Thursday, September 21, 2017

We won!



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 debunk DOMONO: it starts here


We Won!

By Charles-Edouard!

guillaume dustant mort sida bareback intoxication vih no-kapot MST Hotel-Dieu erik remes act-up
With 120 beats per minute120, the DUSTAN / REMES vs ACT-UP controversy resurfaces. About the death of DUSTAN, Wikipedia tells us:
Autopsy revealed: involuntary drug intoxication resulting in death. So stupid! By 2005, alleviation already exists... Unintentional drug poisoning causing death: see, this is why I am indebted to Leibowitch.

At first, it goes well, then the list goes on, the Rx holds on 2 pages. We add a little, to help a brains that escapes you. The great reaper lurks... The doctor, prescriber of death, will not be worried. Medico-pharmaceutical mob avoids accusation... But you, will you avoid drug poisonning?


Omerta: a reality


They screamed "Scandal!". Rightly so: re-read this post. The presentation by Leibowitch (4/7 and 1/7) was deplateformed, in last minute, without a word of excuse, by a committee co-piloted by ANRS (our good friends!). Once again we saw the power of the anti-ICCARRE clique: friendly and fraternal pressures, obfuscation, and even Stalinist retouching.

Obfuscation consists of mixing the nuggets and the scraps. For a blow snow job, trust C. Katlama! They mixed 4/7 among nonsense, so quickly forgotten.

Stalinist retouching, as we shall see later, consists in suppressing events afterwards. Thus the online video on youtube is amputated of Dr. Turkova's presentation. Well, yes ... They don't make our life easy.

The trick was to entrust the presentation to a pediatrician, without direct experience in 4/7, 3/7, 2/7, 1/7 (relative remission). A scientific congress, in Paris, has ignored the refueled remission, albeit fully demonstrated! And, of course, everyone congratulates microscopic advances... Donkeys scratch each other's backs ...

ICCARRE and the MORLAT recommendation, in front of the world


Download the slides by Dr. Turkova, the complete session here.

The Doctoressa, who, by her own admission was incompetent to speak of the 4/7, was therefore informed, in extremis, of key developments: ICCARRE and the MORLAT recommendation. It was necessary to urgently provide a translation of His Morlesque Holiness, which fortunately was already done. It costs me enough of my time so, when it is useful at the right time, I'm quite happy.

IAS 2017 Paris ICCARRE french guidelines hiv aids Turkova breather Quatuor Anrs



So ICCARRE was exposed to a world, amazed and enthusiastic! The recommendation of its use, MORLAT and ANRS (sic!), was revealed to a world, previously ignorant: Fiat lux! In the scorching torpor, our enemies allowed themselves to be overwhelmed.

The ICCARRE victory and unanimous ovation


The room is full! It's hot! Quickly, they open, not only one but, several adjoining rooms, with television broadcast (broadcast which will be truncated in the official release!). They are under shock! Ovation at the evocation of ICCARRE, general applause!!!

IAS 2017 Paris ICCARRE french guidelines hiv aids Turkova Katlama allegement
Let us not be mistaken, our victory is one of a battle in which the war is going on elsewhere ... We shall have to fight again in a guerrilla war maintained by those who fought against us, in the past, but it is only a question of time ... The final victory is assured, and quasi-remission for all is within reach.

As proof, the ignoble mob-in-white-coats tries to drown the ICCARRIAN universality in a so-called personalized medicine, on a case by case basis, which would be onerous for all. Certainly the Eclipse is variable, but since it lasts at least a week, for the super vast majority, please reserve 'personalized' medicine for some badly treated patients.

Leibowitch, a sought-after, revered, congratulated and even rewarded participant ... He will receive from the hands of Dr. Sidibé, Executive Director of UNAIDS, a magnificent badge. Here is our decorated Leibowitch, lacing up his ribbon beside his Legion of Honor.

Bareback also wins


120 battements minute mort sida bareback intoxication vih no-kapot MST Erik remes act-up
Nearly one hundred presentations about PreP! The medico-pharmaceutical mob has not been idle! Jubilatory ejaculation for barebackers! Sure, Act-up does not find this funny... Their nostalgia ruins our lives!

So, explain us that this PreP attack is not a posthumous victory for barebackers...

Ah, I see ... You would like to know who is this doctor co-responsible for the death of DUSTAN ... Yes ... S/He is still active... We will discuss this one next time.



Feel free to comment, to like to share and to use

Have a good Week, good fuck and do not abuse of meds/drugs

Sunday, September 17, 2017

Mono-DTG: all is fine



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 ...)


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

Mono-DTG: a winner

By Charles Edouard!

In DOMONO, we will find the same failure rate as in BMM + P. Mono-DTG is of little interest to us. In a 1/7 perspective, based on Tivicay®, it can serve as a preamble to a remission strategy. Indeed, if one succeeds in Mono-DTG, one is perhaps in favorable conditions for the ICCARRE descent, either in Mono-DTG or in Bi (BiCycle strategy).


The DOMONO trial overrides proper selection and advice for better bioavailability!

Your Mono-DTG chances can be greatly increased with our Mono-DTG Practical Guide.

No harm to patients


As for the failures in Mono-IP (strategy to be avoided), a viral escape is clamped down by simple return to the initial triple therapy. Patients who fail will have, at the most, to go back, where they were already. And for those who succeed it is just so cool!

In all participants, ART was reinstated and CV was <50 within 12 weeks in all! (see here). The authors of DOMONO (results here), and BMM + P analyze that the attempt at Mono-DTG results in no loss of therapeutic option. And that's what counts!

HUGE benefit, except for ViiV Healthcare


We must admit that, for the time being, the idea of ​​a cyclical strategy (eg 4/7) does not make a good impression on people: they do not understand it, they are suspicious of it. The septists are septists to the marrow, to understand the Eclipse will be difficult for them. At the same time, the desire to take better care, with less, remains very strong: a bi or a Mono-DTG can be an intermediate solution.

The real prejudice is for those who do nothing, and stay in TRI ad vitam.

My readers testify: Mono-DTG is a real relief! I confirm!

A reader reminded me of the benefit when s/he went from Stribild® (4 molecules! And meal obligation) to Mono-DTG, so easy, so small to take, and, above all, so much better tolerated!

What to say to this 72-year-old patient, diagnosed late, with other health problems, CD4 = 1 (!), treatment naive , and that Dr. Lanzafame put under Mono-DTG, successfully? What to tell him? That he should have taken an infamous TRI, then wait a year before doing an ICCARRE descent (as if it were proposed to everyone!). Of course this patient is happy... Because seniors, under 5 ARV molecules, do exist!

Nevertheless, the patient has a choice! Just ban Mono-DTG because of a poorly run trial is ridiculous! Those who have been opposed a rebuke (read here) go elsewhere and they are right!

DOMONO is a useless trial, just good for the trash


It is a bad attempt, not just because I find the conclusion ridiculous and its interruption unjustified, but because it teaches us nothing ... Nothing at all ...

Where is the post-hoc analysis of the Achilles heel (yet incontestable, cf BMM + P)?
Where is the phenotypic (not genotypic) test for patient # 1, as promised in Oct. 2016?
Where is the critical analysis of mutations? And to forget that the R263K is beneficial ...

Ah ... We could identify the Hunchback trap... Well... We?... It's I ... Not the authors ...

Where is the benefit / risk analysis while the benefit is enormous? And the prejudice nul?...

Mono-DTG, it's still a so much better than MONO-IP! (strategy to be avoided, for that matter)

Practical Guide Mono-DTG



The Practical Guide (4/7) has moved the lines: it is copied here or there, and the Morlat recommendation boosted it well beyond my expectations

So I am writing a Practical Guide for Mono-DTG, confident that Morlesque oukase, will go, like DOMONO, to the trash.

Bicycle and MonoCycle Strategies


The Eclipse equation is valid in an efficient medication context, without imposing that it is a TRItherapy

The Eclipse exists whenever the treatment is effective. It does not prejudge "synergies" (there, one will have to explain me the whys and hows ...). The Eclipse results from a burial phenomenon (we'll get to this soon ...) that DTG promotes.

The Eclipse Equation, the deep burial of the proviral sequence, is been worked on, and we can begin to consider a long eclipse for all.

Today, there are enough individual testimonials of success under Bi or Mono-DTG cycles, to be interested in the issue. Especially since the Septists, anti-ICCARRE in their genes and interests, will soon jump on DTG + 3TC or DTG + RPV to lock their patients again in their everyday life straitjacket.

The temptation is too appealing in their camp: it is also in ours!

When you have an Eclipse (and who does not?), why not take advantage of it?

We evacuated DOMONO, that the Medico-Pharmaceutical Zealots will thrive on. Let's put this bad trial to the trash ... Too happy that we have learned some lessons, and better armed to resume our path to remission (refueled, of course...) by integrating this modern and relevant tool: DTG.

In the next few weeks, I will outline what a BiCycle Strategy would be (DTG / x in 4/7, 3/7, 2/7, 1/7 ...) or even MonoCycle (that then rejoins HypoDolu)

These many years to observe the inanity of ANRS convinced me that one does not enter the remission path by kowtowing rue de Tolbiac. Adios non-amigos!!!

We'll resume our normal schedule... Good Weekend, good fuck, not too many drugs, huh ...


Thursday, September 14, 2017

DOMONO and the primary hypothesis

DOMONO and the primary hypothesis

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 ...)


This was originally published here, in French. We provide this translation for your convenience, practical aspects may differ where you live.
At first, we provide a Google translation, then we work on proper translation, which will come soon.


Patients lose confidence in medicine ...


Overmedication is on! Be confident... Inhibitors are not toxic, taking a treatment in advance is safe. Then comes the obligation to get tested, then that to get treatment. The same drama as with vaccines! And, it is much more profitable!

To make believe that it is necessary to treat at any level of CD4, one has adulterated a trial: START. By construction, it could produce no other result than the advantage to early treatment. The trick? Introduce a large group of pre-tuberculosis patients. If we exclude them, the result is reversed, as had been shown by years of British practice to initiate only below 350 ... CQD


S230R in DOMONO


The S230R mutation is associated with resistance only if it is associated with others. All of them do not necessarily confer resistance ... According to Stanford, here: S230R is a non-polymorphic mutation [...], which seems to have minimal effect, if any, on INSTI sensitivity.

It is not causal in the VL rebound, and, alone, does not confer resistance (cf: here). It has a NUL score for DTG, but not for RAL or EVG (see here). Achilles' heel? Go figure...

S230R can only be identified as RAM (mutation associated with resistance) only if it is not alone; But here it is alone! So, not a RAM. VL rebounds, it calls for action. Which? A resumption of TRItherapy (Eviplera®), as the authors did ? Or an addition of 3TC, as they recommend at the end of the trial? In the long run, ICCARRE still remains possible.

Here, it was not a RAM justifying a trial interruption...

More than 50% of failures are preventable


As with DOMONO, the BMM + P study excludes patients who had failed INI; BMM + P shows that more than 50% of failures are avoided by using the Achilles' Heel selector, which DOMONO does not. Unsurprisingly, we get as many failures as in BMM + P? Mostly avoidable failures!

The primary hypothesis is validated

Despite this, the non-inferiority hypothesis is validated! If the Morlat group is consistent, it could allow Mono-DTG in its next revision ;-)

Lorgeril explains, here, that we must define the primary hypothesis, in advance, and stick to it! And concludes: A trial stopped prematurely is worth no shit! Trash !

Fatal error: the undue safety interruption


The trial has been interrupted due to a safety trigger, on the pretext that the number of RAM exceeded the number of allowed RAMs, as per predefined safety conditions. Predefined conditions that we could not find anywhere... It comes out of nowhere: it is done with a wet finger.

This is quite debatable: indeed, the S230R, seen at S30, is not strictly speaking a RAM. But the two other resistances N155H and R263K are seen at S60 and S72, ie while the patients, technically, are no longer part of the study, which lasts for 48 weeks.

The error originates from that patients remain in the study beyond the time allowed, without releasing the bridle. This safety constraint is calculated from a permissible frequency, say 2 per year, that is multiple by time (1 year), which gives 2 ... But if the study lasts 2 years, then the trigger should be set at... 4.

Why are there S72 patients in a 48-week study??? They had difficulty recruiting: the recruitment was spread over approx. 1 year!!!

The main reason for stopping the trial was that there were too few participating centers, and that the investigators, who have defulted their expectations, had not reassessed the safety conditions to take into account the delay. Hopefully Hocqueloux, in MONCAY, who also has trouble recruiting, will be smarter!

All the statistical analyzes are based on the (doubtful) hypothesis that resistance is random, with randomness constant in time ... Therefore, advancing the date of initiation of treatment increases the time the patient is exposed to risk of resistance or suicidality. But, no one talks about it ... Of course...

The summer is coming to an end, our summer series will have one last episode, and then it's back to scholl, full lights on our victory, remissions, post-treatment controllers, bi-cycle short cycle (BiCycle Strategy), new results with Mono-DTG ... Oh, we'll have fun!

Hurry to the sea, the beach, sun and Love!



Wednesday, September 13, 2017

NVP, DTG: the Hunchback Trap



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 ...)


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

NVP, DTG and the Hunchback Trap

By Charles Edouard!

An alarming testimony on drug availability, here

Plan ahead! We must plan ahead! Physician: Retirement or dispute, drugs: rupture or obsolescence; Insurance: loss or cancellation; treatments: escape or interactions, etc. It is the doctor who writes the prescription (and the patient who throws it in the trash)! In 2/7 one easily builds a comfortable stock (I have 5 years!), And then... DTG / 3TC is nice because it will be coformulated and widely distributed.
We're no longer alone, it's over! We have a community (see friends of ICCARRE), ICCARRE-friendly physicians, serious clinical trials and especially an ANRS recommendation (Morlat 2016). Even so, we must plan ahead!

For Switzerland: Dr. Jean-Philippe Chave, chemin Porchat 24, 1004 Lausanne, Switzerland (tel. +41 21 648 38 38) (limited Short Cycle experience)


NVP, DTG: the Hunchback Trap


We had seen (Dolutegravir, R263K and DOLUMONO) that R236K may appear or reappear with a drop in pharmacological pressure. It may 'be born' on this occasion; it can also be a vestige of the VL descent, and come back, on the occasion of an incident.

In the present case, for the R263K (a rather beneficial mutation) resurgence, replication would be necessary. However, this patient is supposedly undetectable ...

We have a replicative event, at S 60, certainly ... To be a vestige of the past, there should have been another replicative event! We do not see it ...

Well ... I was wondering about... You do not see it! This is a detective novel, the clue is somewhere.

Damn, but of course!!!



video Nostalgia

It is difficult to imagine how a patient, in continuous virological success, may have had a hidden replicative event ... And yet ... So in the middle of the night, it wakes me up (yes, yes...). Of course...

Come on...
Has the cat got your tongue? S/He originates from Nevirapine.

A new suspect... Already seen in: Dual therapy Guide: Coadministration of NVP / DTG lowers the concentration of DTG, the same magnitude as the bad absorption that happens at S60. Yes, but s/he did not take Nevirapine and Dolutegravir at the same time!

Let's have a look at Influence of nevirapine administration on the pharmacokinetics of dolutegravir..., by Eric Dailly, François Rafi (hi, hi, hi ...) et al.

It is explained that the coadministration reduces the concentration of DTG, at the same level as at S60. Certainly ... But there is no coadminstration ... So, you have to read carefully...

In stable patients under NVP + Kivexa, DTG is added for 5 days, followed by a noticeable decrease in DTG. NVP accelerates hepatic DTG metabolism. As expected.


What happens 15 days after stopping Nevirapine? The same effect is still clearly visible!

So you take your TRI-based Nevirapine, you switch to Dolutegravir in mono, and you have a window of at least 15 days where the concentration is greatly reduced: in a nutshell you can have the ideal conditions for the selection of the R263K, this fleeting resistance.

And the authors conclude: A small subset of individuals may require a doubling of dolutegravir with a twice daily dosing.

While we are at it, we look at our table and we see that 2 of the 8 failures occur with patients previously under NVP, whereas, typically, patients with NVP are rather few, and conversely, there are has no patient from an IP-based regiment (while typically representing 30-50% of patients)

And to conclude, wrongly maybe, that following a 1 NNRTI + 2 NRTI strategy (eg Atripla, Eviplera, etc.) with a MONO-DTG (or even a DTG) may present a risk.

This risk is neither confirmed nor quantified, however it is very easy to cover: just take 50 mg twice a day for a reasonable time, which is all the easier as this eventuality is written on the Tivicay® label.

It costs nothing, and can prove useful in increasing the success rate of Mono-DTG.

Why "Hunchback Trap" ?



It's simple: it's a trap from N. (NVP) to D. (DTG), a trap N.D. (Notre-Dame, Our Lady), a play of words that works only in French ...

Where you hoped for a double bevel, where one goes down while the other goes up, you can have a trap, during which the situation is not optimal.

Even if it is not true, it is well found!


Especially it is very easy to guard against it, so we will include it in the Practical Guide to Mono-DTG (under writing). Two precautions are better than one ...

Indeed, we want to put all the chances on our side, to be in the best conditions to address what really interests us: the short cycle in either Bi-Cycle (BiCycle) or Mono-DTG.

When we think that the secret desire of subsidized virology is to switch patients from NVP to Genvoya®, then going to 4/7 direct, it's chilling!

Our summer drama shows that Mono-DTG is more viable than DOMONO lets think!

Enough with brainstorming, let's go to the beach! Good weekend and good fuck!



https://charles-edouard-ma-liberte.blogspot.fr/p/essai-clinique-anrs-4d.html

Friday, September 1, 2017

N155H and DOMONO



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 ...)


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

N155H in DOMONO

By Charles Edouard!

Testimony of by a sucker:


Genvoya® ... When patients discover that with Genvoya® they can not consider 4/7 nor the mono-DTG, they mare not too happy... What can I do? The error is in the choice of the virologist. In a predominantly feminized profession, we find that all Tempists are men (except for Breather where they are ... pediatricians ...). However, about 20-25% of the candidates to 4/7 (ANRS-4D and ICCARRE-2) are women. This sexual tropism of virologists deserves further study.

resistances shooting-gallery


In the ten green bottles, we had worked by elimination. There are several types of failure: random failures that reflect a random risk and predictable failures, therefore avoidable, which constitute a prognostic element in order to avoid the risk. This knowledge is obviously crucial for effective selection: it therefore does not contribute to rincrease isk but, on the contrary, reduces it.


When they launch DOMONO (DOLUMONO), they do not yet know the risk identified by Prof. Katlama: the Achilles' Heel. It is defined by the prior use of RAL or EVG. It is the prior use that constitutes the risk; A simple failure with RAL or EVG is not a satisfactory description of the Achilles' Heel. Of course, if one has failed with such an inhibitor, it is because one has used it ... Let's state it clearly: the Achilles' heel is the prior use and not the previous failure.

Unlike Barcelona Munich and Paris, those in Rotterdam absolutely did not understand the Achilles' Heel: they turn their backs to it, deny it, do not want to document it. Unlike the collaboration between BMM + P. The risk could not be known before it is identified ... By Oct. 2015 ... From then on, they had the opportunity to rework the files, document the Achilles' Heel and provide a constructive discussion . To this day, they have not done it!

N155H: What are you the name of?


One can only turn to BMM + P. There are 4 failures with emergence of N155H: B001, B004 (poor adherence and AH), B007 (AH), B008 (poor compliance). A selection algorithm that includes AH (Achilles Heel) and adherence reduces risk by 75%.

dolutegravir HIV tivicay resistance N155H VIH mutation reservoir observance adherence
In the absence of information on a possible Achilles heel, one can only speculate. Therefor, why blame Mono-DTG?... It's a little too fast!

At no time do they question their selection criteria or improve the selection of patients. It is therefore a trial for nothing, not by the methodology but by the obstinacy of the investigators not to question their hypothesis. So much the worse for the patients, who will henceforth be rejected indiscriminately. Fortunately, we still have Hocqueloux, Lanzafame, Oldenbüttel, Blanco and Katlama.

Alternative scenario and choice of patients



One can make the Achilles' Heel and / or non-adherence an alternative scenario.

The failure is at week 72! It is a long way, however ... One can ask a few questions and recall that ICCARRE 4/7 is, de facto, a PreP: Mono-DTG, no ... The re-exposure to an already mutated virus is a possibility (Ah! The sexual promiscuity of Rotterdam!) to which Mono-DTG may not protect. Ah ... Bah ... Yes ... We have to dig a little ... And maybe put the risk of reinfection in a potential risk in Mono-DTG. Who knows...

Conversely, for the polysexual patient, DTG + 3TC or ICCARRE (4/7) are interesting alternatives.

Hopefully, Dr. Hocqueloux, in charge of the Moncay trial, will be better inspired.

In The News, Statins: The French Guidelines U-turn


Reminder: ANSM recommended statins, as prevention, so called primary. 6-7 million French were statinned (how many deaths?), Including 25,000 HIVers (albeit having already 3-4 molecules). The recommendation was voided by the Council of State (upon request by FORMINDEP) due to conflicts of interest of experts. The analysis of the studies, already old, and widely disputed, led the HAS to withdraw this deleterious recommendation. Le Figaro, a French paper in this article , clears, somewhat easily, its historical contribution to over-medication, to collective anti-cholesterol hysteria, by making false accusations to anti-statins. Yet what could they do but to bring to the public's attention the uselessness and dangerousness of statins, and the apparent bad faith of the industrialists? (So says Le Figaro)

Conflicts of interest? Bad faith of the industrialists? Toxicity concealed? Overmedication? Over-prescription? Misleading official recommendations? Turning into sneaky? Legal irresponsibility? Doesn't that remind you of anything?

Mutatis mutandis ... Ad nauseam

All this reveals the deception on a large scale, of which nothing (or almost nobody) has protected you. Are you taking statins? Go to an Independent and Caring Cardiologist!

Personal note: I started (100 mg DTG + 300 mg 3TC) in 1/7 (that's 1 Lamivudine less ...)

Go ... It's summer ... Enjoy the holidays, fuck, freemindedly!


Sunday, August 6, 2017

Dolutegravir, R263K and DOLUMONO



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 ...)


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

Dolutegravir, R263K and DOLUMONO

By Charles Edouard!

Pr. Philippe EVEN: Each clinical trial is a detective novel, it is first a novel because it is false, and, it takes a detective mind to detect all maneuvers.

At the min. 53:30 of the Even video.

In order to better understand this post, please read again DTG and R263Kand R263K and Darwinian sink

R263K is beneficial, it amplifies the effect of Dolutegravir, and can even explain an Absolutegravir-like effect. This is a beneficial mutation, which is not the stepstone to others.

It is also beneficial to the reservoir (post to come). And it is, at most, commensal of the VL decay. When the pharmacological pressure is lowered, if it is there, well ... As the rats leave the ship, it comes out first ... Even if it quickly becomes invisible, drowned by the fittest virus (the original one).

In the table, a patient is identified with R263K; The authors, by their decision to stop the trial, consider that R263K appears, in a way, say, of a random event, and creates the VL raise: it would be the cause. This is consistent with the idea that the R263K mutant shows resistance to DTG. However, this resistance is very very modest, hardly measurable, and is accompanied by a significant loss of fitness. And also, why does it appear now, after more than a year ?? ...


Ah! They have an explanation: the dose of DTG was lowered by malabsorption: Probably suboptimal gastrointestinal uptake of DTG during 10 days due to gastro-enteritis

Here is our alternative scenario, more credible:


The patient has a gastroenteritis, takes none or little or inefficiently, the medication pressure decreases ... Dosage at 13h is 0.7, ie as my mini-Dolu, so, as expected, the virus takes up, with its commensal R263K, as a signature, not as a cause. Hazard of things, it is seen at this time: what happens if the situation persists: the virus continues its raise, the wild-type (or historical) virus, fitter, overcomes, very quickly, and the R263K fades out, relatively to it: it will become invisible. No visible mutation and a virus on the rise, but not too much... Does it remind you of anything? Look at the table...

In mono-DTG, to optimize the bioavailability, one takes with a meal. As for myself, I also break the pill between the teeth: broken, it disolves better.

Elementary, my dear Watson! Elementary???


The event does not arrive stochastically (randomly in time) at week 60, it arrives with ... the winter and gastroenteritis! Bravo!! The authors have just invented the rain! Well, that's too sad!

There you have it! All ? Absolutely everything ?? All ???

Oh really? The virus goes up with its commensal R263K, along with an accidental drop in drug pressure ... Certainly ... But was it doing there in the first place?!

It is the summer, we take our time: it will be for a next post! It's fun, isn't it?

In the news: DTG + 3TC, in first line, <500.000 and an overwhelming VICTORY


B. Taiwo presented the results, at S24, of ACTG A5353: phase II DTG + 3TC, in first line. It is a little more ambitious than PADDLE (20 patients under 20.000 copies), but less than Lanzafame (20 patients <100.000 copies, in Mono-DTG, with selected patients).

IAS-2017: the consecration of 4/7


For the ICCARRE session, the conference room was full and many screens had to be installed outside. Standing ovation at the evocation of Leibowitch (ICCARRE), a sought-after participant, adulated, congratulated and even rewarded: the victory was such, that we will make a jubilatory post, at back to school! , that was sooo enjoyable

Tiring but victorious week: Good Weekend and good fuck



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 ...)


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

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 ...)


Friday, July 14, 2017

IAS-2017-Paris, ANRS-4D



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 ...)


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

IAS-2017 in Paris, ANRS-4D and 4/7

By Charles-Edouard!

After Durban (2016), Paris hosts the IAS-2017 congress. A trimmed, more scientific edition!

ANRS is a co-organizer. Its only relevant contribution to history was ANRS-4D: the rest is of no interest, others would have done anyway, or appaling fiascos (eg Mobidip or Ipergay, so quickly forgotten). ANRS-4D, as an unfinished version, was presented at DURBAN.

There will be an ANRS-4D poster, announced as: MOPEB0321, ie Monday (MOnday) Poster Exhibit session B; details are not yet available.

It is not very much, but apparently they had to struggled quite a bit to get something!

IAS-2017: alleviation session


There is a session devoted to alleviation:
IAS 2017 ANRS allègements international AIDS society Paris Durban poster ANRS-4D


Professor Katlama will talk about initiations under mono and bitherapies, normal ...
IAS 2017 ANRS allègements international AIDS society Paris Durban session  Turkova Anna Katlama
Dr. Pedro Cahn, bitherapies (father of GARDEL and PADDLE), normal, a Thai doctor of reduction, good, why not ...

For strategies 4/7, there will be ... Discussed by Dr. ... Discussed by Dr. Molina Anna Turkova !!! Paris will discover her. Unknown? She is coordinator and author in the BREATHER trial (5/7), her topic is: Treatment four days a week: for whom is it an suitable option

She may not be aware of ANRS-4D: even the press release has disappeared from ANRS site (see a back-up here)! Has she gained experience on the 4/7 somehow ??? (Or Penta-15?)

The situation in the fields has changed quite rapidly:

In Garches, data are collected from 114 patients (FASEB J, 2010 and 2015): no failure over more than 600 years of treatment in 4/7.

ANRS-162-4D, enrolled 100 patients (see IAS 2016, Durban, manuscript submitted for publication): no failure in eligible patients who adhered strictly to the protocol, ie, zero intrinsic failure.

As of November 2016, French Guidelines, quoting BREATHER and ANRS-4D, authorized the free practice of 4/7, outside of clinical trials.

In addition, 2 patient associations collect clinical data, in parallel and independently, from conventional clinical trials. A list of doctors is available.

Today, patients under treatment 4/7, in France, can be estimated at about 500 ... And counting! Paris follows trendy fashions !

A large, controlled clinical trial, ANRS-170-Quatuor, will soon begin in 62 French university hospitals, with 640 eligible volunteers.

It can be anticipated that this presentation, at IAS-2017 in Paris, will have a significant impact on participants ...

Has she had a chance, at least, to discuss this with investigators involved?

Breather: a good trial, a bad theory


I have echoed BREATHER, here, in details! This is the only place.
Unfortunately, the authors theorize, speculate, wrongly. The weakness of the authors of BREATHER is to theorize around a pharmacokinetic specificity of EFV (whereas the majority of children take AZT, with a short half-life ) There are reservations here, and there, that have been added by castrators, on a very undefendable argument. It is a shame because it deprives hundreds of thousands of children of a salutary strategy. I would like to remind you of a fundamental difference between BREATHER and ICCARRE / ANRS-4D / Quatuor: the lack of prognosis on genotype!

4/7: for whom is this a suitable option?


The question is interesting and falls right to the point: we will listen to the arguments of the restrictive clan, and dissect them! Remember to record the arguments of this session.

It was a tiring week! So, Good Weekend and good fuck!

Comments


Anonymous 15 Aug 2017


Charles-Edouard! 15 Aug 2017




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 ...)


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

Friday, July 7, 2017

Dolutegravir and R263K



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

Our Summer 2017 series: DOMONO will have been, in fact, a real SUCCESS!
- Dolutegravir and the R263K
- the R263K: new scenario (DOMONO)
- the 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 ...)


Absolutegravir, Dolutegravir and the R263K

By Charles Edouard!

Some news from Backy:
A small pick up in ASAT is not a cause for concern; At 5 or 10 times the limit, yes, this would be worrying; You are far from that! This is a successful case of Tivicay® monotherapy; Once settled, you can watch what others do, such as jesuisdu13 who uses mono-Tivicay ® at 4/7 ...

When Dolutegravir mimics Absolutegravir ...


Here, I simplify greatly ... also reread our post on : Absolutegravir, a fantasized molecule.

Absolutegravir is computer-designed on a digitized 'Wild-type' Integrase; a docking software tests millions of configurations. Then, they rerun on mutated, digitized integrases; Finally, on common enzymes to avoid side effects.

dolutegravir HIV tivicay resistance elvitegravir raltegravir genvoya
In the computer-aided design of DTG, we do not yet have the digitized mutated integrases (besides, which mutations?). So DTG is designed on 'wild-type' integrase and confronted with known mutations of RAL and EVG. Its efficacy, which is assumed to be absolute, is specific to the unmutated 'wild-type' integrase. It is a good start, and more effective than the usual cuisine that gave birth to Raltegravir. Everything is a matter of timing ... I simplify to the extreme, in fact, it's a huge job!

The R263K: a deep Darwinian well


In the very first trials, we observe (by luck or design insight), a phenomenon quite unique in its extent, not seen in test tubes. The mutation of choice of DTG is R263K. It is hard to find in tests tube (known as 'passages'), but it is found in the VIKING trial and in tissue passage tests (a McGill, Montreal, exclusive)

dolutegravir HIV tivicay Darwin puits trou noir évolution monotherapie HIV black hole
This mutation has two characteristics: it confers a very modest resistance, almost nothing, and the mutated virus has only one desire: stay home: it has no ease to replicate: its low fitness makes it unfit. It's almost a 'Junk'. It falls in its hole and stays there, happily: Let's call this a Darwinian black hole or Darwinian well.

When the pharmacological pressure acts on a wild-type virus, it decreases (without mutating) or mutates with the R263K, which, remarkably, makes the pharmacological pressure even more effective. Conversely, when the pharmacological pressure decreases, the virus regains vigor, including, in the first instance, its R263K mutant. Further, by the effect of "survival of the fittest', the historical virus, wild-type, takes over and we lose track of the mutant.

On a wild-type virus, DTG acts as an Absolutegravir


As long as one remains within this binary system, R263K mutation is beneficial. It is a marker, an epiphenomenon, and it is not the cause of a VL increase (whereas the drop in pharmaceutical pressure is); It accompanies it, kicking and screaming, to finally disappear.

As long as you have a wild-type virus, especially on integrase, Dolutegravir acts as an Absolutegravir. The owners of Absolutegravir will want to keep their trump card until the end, and ViiV HealthCare is not going to come and explain that the naïve patient, with a wild-type virus, has a molecule that has all the advantages of an Absolutegravir.

This is how Lanzafame succeeds with his DTG monotherapies on naïve, selected patients, how I managed Hypodolu (overdosed), Minidolu (Tivicay® 1/4 of a pill, daily) and DTG + 3TC in 1/7

Here is a first clue for reading DOMONO, our summer serial!

Good holiday, good fuck, beware of the sun, and long live the Eclipse!

Comments


Anonymous July 17 2017


Charles-Edouard! July 17 2017


Anonymous July 17 2017


Charles-Edouard! July 17 2017




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

Our Summer 2017 series: DOMONO will have been, in fact, a real SUCCESS!
- Dolutegravir and the R263K
- the R263K: new scenario (DOMONO)
- the 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 ...)