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.

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.

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

As an increasing amount of people with high CD4 cell count and low viral load are treated at an early stage of the disease, the treatment paradigm should shift from lifelong triple therapy to a controlled viral load in the plasma and a controlled replication in the reservoirs. If other strategies with less drugs are validated, people living with HIV (PLHIV) will be less exposed to ARVs and if monitoring is needed less frequently, the cost will also diminish. This is an important paradigm shift that merits strong and considered discussion. This session, aimed at clinicians, policy-makers and PLHIV, updates participants on the most recent results and gives them a better understanding of who is most likely to benefit from such a shift in treatment paradigms.

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

Hello,

I had a VL of 2500 at the beginning of the treatment (genotype = sensitive virus), dropped to <50 copies 3 weeks later, and strictly undetectable since (5 consecutive tests). I am under Eviplera and I have a lot of nausea and weight loss + my cheeks are getting worse. I also have prolonged fatigue and have to rest all the time. Alleviation is out of the question for my doctor. The alleviating doctor I consulted told me to wait 18-24 months before trying 4/7. According to him the benefits to start today would have no real impact on my well-being, while the risk of escape would be real.

How to do? Since there is no objective basis for defining the date from which the risk benefit is balanced.

Charles-Edouard! 15 Aug 2017

The Morlat 2016 report (ANRS) allows the short cycle under conditions similar to the trials. Strictly speaking, within ANRS-4D inclusion criteria, 6 months is a bit short. It should be noted that these are conditions a priori, based on previous studies done on 'chronic' patients, often under treatment for several years.

With immediate treatment, the demand for relief earlier becomes more prominent. The Practical Guide addresses the question:

https://once-weekly-hiv-therapies.blogspot.fr/p/practical-guide-safe-47.html

You do not say which doctor you saw ... I have been told that Dr. Jean Yves LIOTIER is quite willing to use Eviplera (tm); check him out

https://charles-edouard-ma-liberte.blogspot.fr/p/medecins-allegeurs.html

Eviplera (tm) was only used in 4D. Its predecessors (Atripla (tm) for example) were used in FOTO. However, FOTO starts from 3 months of undetectability. But is not a direct 4/7. Morlat says similar conditions, it does not say identical ... So, while waiting to be in the window of eligibility of ANRS-4D, you can refer, during your interview with the doctor, to FOTO and our Guide

Your VL was only 2500 before treatment. If you could negotiate a 6/7 and see when you can start it, that would be good.

The Practical Guide is, like your doctor, a little conservative. But well... an initial VL of 2500 is really very very low ...

We can wonder if the recommendation to treat early really makes sense in this case. The 'scientific' argument often quoted is the START trial, but were there at least patients with VLs that low ???

Indeed, there is no scientific abacus that tells you there or when there is a risk of failure, for the simple reason that in Premium mode, there has never been any failure

Try to find a doctor who looks after you and no protocols on patients who had much higher VLs. This blog is not a medical advice.

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

Hello
If the ratio cd4 / CD8 is always lower than 1 and remains around 0; 7 my cd4 to 430 now 30% Under treatment of tivicay for 1 year and still undetectable ...

Vih since 2008 and beginning treatment 2011..differente sort then mono kaletra and now tivicay always + - well supported ... I did a test of resistance at the beginning that showed at that time that I did not ....

Then I ask for a relief or should I wait for one. Best report cd4 cd8 ... or an ascent of my cd4?
I am followed in barcelona in Spain

Charles-Edouard! July 17 2017

The CD4 / CD8 ratio is never an inclusion criterion for aleviation. NEVER. In ICCARRE 93% of pateints had a ratio <1, at entry. In ANRS-4D, there was no CD4 / CD8 criterion. To believe that the ratio must be greater than 1 to enter the alleviation is absolutely false. The argument circulates but it has no scientific base and besides, under the conditions of inclusion, it is never asked for.

In Barcelona there are doctors very aware of aleviation (Dr Martinez and Dr JL Blanco), it is very favorable!

https://charles-edouard-ma-liberte.blogspot.fr/p/medecins-allegeurs.html

It is not clear whether you are under Tivicay (tm) in mono, bi or triple therapy. Aleviation trials with Triumeq will begin. For now, we only have scattered testimonials on the Internet. Prof. Katlama iditifies the achilles heel as a risk factor (a risk factor that can be seen in the patient's history but not on the genotype); A priori you do not have it. So we do not quite see what relief you want. Bi (DTG + RPV or DTG + 3TC) lightening is well documented to consider it under medical supervision. Also for mono-DTG; 4/7 with DTG / 3TC / ABC is documented only through testimonies that are consistent; Even for the 4/7 schedule with mono-DTG.

Tivicay (tm), can, in the long run create a depressive effect. It is more and more reported, eventhough initially we did not know it.

The pillars of the aleviation are: Efficiency, progressivity, frequent VL. It is necessary to verify the effectiveness using VLs (2 months)

We must not depart from the frequent VLs. How are you going to organize this in Spain? In France, it can be done without a prescription (60 Euros).

Thank you for sharing your Spanish experience.

Besides, if you can, try to help us. We hope that one of our readers will be kind enough to translate this document into Spanish:

https://charles-edouard-ma-liberte.blogspot.fr/p/guide-pratique-safe-47.html

Testify, share, translate, etc! Keep us posted!

This blog is not a medical advice

Anonymous July 17 2017

Thank you for your quick reply…

In fact I take that tivicay 1.cp a day ... I want to reduce the quantity and get to 4 dosage a week or less ... like you ...

I feel fatigue and muscle aches ... especially after sleeping ... I feel like I did in marathon the day before!

I try to do a lot of sports ... I am 54 years too ... then ... the pain can come from non age but well .. Many younger people do also complain ... so I start thinking that these drugs have toxicity ...

I will see my doctor with him in October I will talk to him about it trying to prepare a little with some reference in terms of alevaition ... I will see how he reacts. Already the tivicay (tm) was prescribed on my request and my doc had to insist on not missing any pill ..

After that there are private labs here too ... If not I can consult or ask for an opinion in France because I have a French Health Insurrance too ...

Thanks in any case for all this info ... till now I was blind and trusted the system ... but as I started reading this blog I am shocked ..

Charles-Edouard! July 17 2017

The mono-Tivicay (tm) is already an advanced alleviation. I'm currently writing posts on how DTG works (which can be tricky, due to its dual operation, see next post) I also have some news regarding its pharmacokinetics and it is rather favorable. I am writing the practical guide Mono Tivicay. The DOMONO trial is double-sided, successful for some, failure for the others ... It shows very well that the initial validation of the monotherapy is 12-18 months, and that the recommendation of your doctor is very just ; Me, I take Tivicay (tm) breaking it with a blow between the teeth and with a meal: it increases the bioavailability.

As for the Mono-DTG aleviation in 4/7 (for example), to my knowledge, only Dr. Lafeuillade (Toulon) said he was going to try. When you see my guide on the mono of Tivicay (tm) you will see that there are traps. So a validation over 1 year seems a good idea. In addition to me (DTG 50 mg + 3TC 300mg, Saturday and Sunday (5 months) or DTG 100 mg + 3TC 600mg, Sunday (1 month)) I know (credibly) of the users Mono-DTG 50 mg 4 / 7 and Bi users (DTG + x) in 4/7. I remember one thing from their testimony: they advanced very gradually.

And what concerns the joint pains (welcome to the club! ...) I made a few pesonal findings, which I prefer to share by email than on the blog.

Yes the blog is surprising! If you knew how I was shocked when I discovered ICCARRE! Everything is well published in a scientific literature that other media 'forget'; too bad. Hence the importance of sharing.

You saw that we have a version in Portuguese. I call for a Spanish version

This blog is not a medical advice

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

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Friday, July 28, 2017