126

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



DTG-25 mg episode 3

By Charles-Edouard!

In margin of the Lambert Affair (out of our subject, here), a letter of Dr S. PALIARD-FRANCO:

Oh, come on!!! Science and Faith are not in harmony. It is a misplaced trust to place it in those who privilege conviction over proof. Joyeux is a religious activist, almost homophobic... Here is a doctor, writing, in her capacity, to another, Minister of Health, who affirms, right in the eyes (as Dr. Cahuzac would say): by his will, he could have contracted a fatal infection. A deficiency in cellular immunity on demand!!! The proof of his will would be that his immunity, autonomous, insubordinate, works... And, in addition, one could even choose the infectious agent for oneself... One can commit suicide at the first pneumococcus passing by. It is the other side of the same joke that would like the force of conviction to heal, miraculously, a Lourdes in reverse, so to speak.

Many people place their trust in soul supplements (homeopathy, prayer, yoga, overdosing, overprescription...) that viruses, bacteria and macrophages have no use for. We must denounce it. No! criticizing an idea for being false is not a discrimination. Mocking an 'invert' (cf Joyeux), is! To affirm that the Faith of some does not cause harm to others is inaccurate. Misplaced conviction rots everything around it.

Let's go back to our sheep, with our minds cleared of this parasitic nonsense...

DTG-25 mg episode 3: DTG-50 mg, criminal chemical incarceration

This is also a scam of a somewhat original kind. As in prestidigitation, the trick is to divert attention from what is actually happening. The context dazzles us, collectively, and we get distracted, including by the question of Mono or Bi therapy, while the trick, the deception, is right there in front of us.

Their novel is an affabulation for the enlightened. They have committed their crime, before our astonished eyes, and have even signed it: the culprits have named themselves as if to better conceal their cheating.

We had already drawn up the picture:
- the original pharmaceutical sin: the slant and the S
- the escalation test is mandatory but they don't care
- EFV 600 mg an unfortunate precedent
- the trauma of multi-dose rosuvastatin
- DTG and the famous specifications

Our investigation continues...

The curse of efficiency lost but not quite

During pre-clinical development, they will realize something that will satisfy them while posing an unexpected problem. DTG is remarkably well designed... In the laboratory, after many attempts, one always ends up selecting mutants; one cannot think of biology without Evolution. The mutant loses fitness, of course, but gains resistance. It gains more or less resistance. If it gains a little, it remains susceptible to about the same dose; if it gains a lot, the molecule loses its effect, almost completely: the dose must be multiplied to overcome it; this multiplier coefficient, FC for Fold Change, is the indicator of this loss of effectiveness. It is quite well known: the mutation at position 184 confers a resistance to Lamivudine with a moderate FC (ca 3.5): it remains usable. Q148K gives a FC of 83 against RAL and 1700 against EVG: here one should not dream anymore, one would have to multiply the dose to stratospheric levels to overcome it.

Under DTG, and in patients naive to INIs, it is almost impossible to develop mutants with moderate or high FC. Seki explains here:
All single mutants [...] do not alter [DTG] activity by more than a factor of 5.
Fujiwara completes here, I quote:

On the other hand, if you already have a mutant, typically acquired under RAL or EVG, acquired by you (a failure for example), or by whoever gave it to you, this mutant can mutate again and have a moderately high FC, high but not prohibitive: FC between 10 and 20. That's a lot and not too much at the same time. It would have been better if this FC had been a bit lower, but 20 is playable! Hooray! We will be able to bring a solution to the patients of group 2, those who are up to their necks in shit. And at the cost of a higher dose. The FDA will give you anaccelerated MA, which will allow you to exploit the patent for another 2-3 years .

So for group 1, you're going to need a dose for HR < 5, and for group 2, you're going to need a dose for HR between 25 and 50.

A dose for group 1 and a dose for group 2: and these are not conspiracy theories: there is indeed a dose for group 1 patients and another for group 2 patients: this is written in the instructions in the box!

One dosage for some (the vast majority), and one dosage for a few others, perfectly identifiable.

The problem jumps out at you: the requirement is a ratio of 1 to 10, but the suggested dosage is in a ratio of 1 to 2. Can you see the trick? The CF is low for group 1 and ten times higher for group 2, with the icing on the cake that you can't switch from group 1 to group 2. 2 needs, 2 dosages, but the ratio of needs and the ratios of supply differ by a factor of 10!

And the whole aberration comes from there! If your cab chooses a slightly longer route, it passes... If it goes around the ring road 10 times, it's a real swindle. Well, it's the same! At 50 mg, you (from group 1) are swollen by a factor of 10!

The curse of lost-but-not-quite-effectiveness could have been a problem for ViiV, but they're going to pass the buck, and the curse is now on you. We'll see next time how ViiV will succeed in his trick, no one knows...

Towards the obligation of treatment / Judiciarization

David Hynd must attend daily appointments if his HIV levels exceed a certain threshold. Read here. This is the first time that British Columbia has use the courts to force someone to take a treatment against HIV. Let's bet it's not the last... What's up? We didn't tell you about it?

In the news

- DOVATO (DTG/3TC Combo) is announced! What??? The Gilead-o-latre media is not telling you about it ???? Of course, there will always be some idiots who will entertain doubts and lead the poor patient into a daily and deleterious TRI. And others to believe that it will be cheaper. 27,540/year Still!. It's too expensive for Lamivudine ($6600/year for a generic sold for $30/year to NGOs and $300 in India) and 50mg of DTG, which is far too overdosed! Our discussion on DTG-25 mg is very timely!

- especially since Mono-DTG just won a landslide victory: Non-inferiority of simplified dolutegravir monotherapy [...] randomized, controlled, multi-site, open-label, non-inferiority trial. The ViiV stipendiaries didn't tell you about that either! We did!!! and we will come back to it in detail! (read also: Predictors of virological failure in HIV-1-infected patients switching to dolutegravir maintenance monotherapy)

- Atripla® in 1/2 dose works as well as in daily dose: We already knew that! We have the confirmation here: Randomized clinical trial of the efficacy of every other day fixed-dose efavirenz/tenofovir/emtricitabine versus continuous therapy. When is regulatory listing expected? Morlat, are you there? Morlat, do you hear?

- Hurray!!! Finally a study that shows that the Eclipse is manipulable: We demonstrate a reduction of the reservoir by measuring what, only, we care about: the Eclipse. The new Gilead's 'shock and kill' clears deadly virus in monkeys. As usual, the natural Eclipse is, in median, 21 days.

The French genius

What is this cool music you are listening to right now? Oh, in its reference version by the lovely Scott Ross, it's a bit abrupt; KEMPFF makes it subtle, audible, invites us to to bird recallby J.Ph. Rameau, otherwise a bit old-fashioned. If you liked KEMPFF, you might like his Bach Sicilienne BWV1031

Feel free to comment, like, share and use

overmedication is an opportunity if you know how to use it!

125

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



DTG-25 mg episode 2

By Charles-Edouard!

You are spoiled for choice! In Paris, there is a plethora:
https://charles-edouard-ma-liberte.blogspot.com/p/medecins-allegeurs.html
You have to wonder where you can be so stupid as to say that Eviplera is not for this: 100% success in ANRS-4D, and very popular practice in Paris/Marais.

The trauma of multi-dose rosuvastatin

This post follows our first episode: DTG-25 mg ep.1

Here is a story that every pharmaceutical manager should know. To get 50% more effect, sometimes you have to double, triple, quadruple the dose. In chronic diseases, this will increase the cost of the treatment quite a bit. And when it's a metabolic manipulation without any proven clinical interest, it may be a problem for the FDA, the health insurance company and the insurance company. To prevent them from looking too closely, the industry has found a way to avoid this: charge the same price whatever the dose. It increases its market share, without any problem for the health insurance company or the patients...

As long as it is reimbursed at 100%.

No chance, the medication is of a questionable and contested utility. It is only partially reimbursed or not at all... This is the case of statins, of which the most powerful(no one says useful) is rosuvastatin, a drug that inhibits blood sugar at a very high rate, but whose effect is not proportional to the dose. It inhibits more at 40 mg than at 5, but not eight times more... Whatever, they will market it at the same price. You can find the prices in the USA, for the different doses, on this comparative site. We can see that, more or less, the 40 mg is at the same price as the 5 mg.

So what did the smart guys do? They were prescribed 40 mg and cut the tablets in 4! And as the association of retirees echoed, all American retirees, forced by an iniquitous system, started to do it! That's as much loss of profit for AstraZeneca: they collected 5-7 billion dollars per year, but the price fouling must have cost them between 500 and 800 million per year! When you like it, you don't count, but when you count, you don't like it!

So, multi doses, yes, at a pinch, but the crushing of the price especially not! do you understand the logic?

You can offer multiple doses without cutting into your profits, what they really need to do is avoid price gouging. ViiV is going to work on this... The same dose/price strategy can be seen in the Bictegravir component (Gilead). To understand how extortion is the order of the day in this industry, just read this article: Decoding Big Pharma's Secret Drug Pricing Practices

DTG and the famous specifications

Reading the FDA document is highly recommended. Normally, the FDA is supposed to protect you. It must also authorize what deserves to be authorized, and not spend ages on it. It is therefore quite legitimate to propose to manufacturers a methodology that allows them to prepare their file in the best way for a faster approval. This is also in the interest of users.

Even if it defends itself for reasons of responsibility, it is, to our knowledge, the only document from an administrative authority that can serve as a guide to the industry. As a result, this document is established as the one and only specification (CoP). If your file is satisfactory according to the CoP, you are in an ideal position to obtain the Holy Sesame (American MA). This is normal, after all.

The French approach, which simply comments after the fact, is doomed to failure: the Transparency Commission will certainly slap you on the wrist, you will be awarded an ASMR that is sometimes very unfavourable, and it will only cost you during the economic negotiation, but your MA will nevertheless be granted. So, because of the lack of construction, the ANSM cannot protect you in any way: they are pissing in a fiddle. The FDA is something else...

The FDA document expresses the expectations, and these expectations reflect the state of the art: it inhibits any progress, including in terms of dose. Under the pretext of protecting you, it protects the FDA, the industrialist, at the cost of an inescapable overdose, because it is the FDA document that orders the overdose.

To be considered worthy of FDA approval, the new molecule/drug must bring an anti-retroviral benefit to 3 groups of patients: these groups are
- treatment-naive, susceptible patients
- multidrug-resistant patients in therapeutic impasse
- multi-resistant with possible options

very precisely:

Group 1: Fully susceptible to all approved drugs, treatments, or prior therapies with a well-documented treatment history demonstrating no virologic failure.

Group 2: Drug resistance to multiple drugs and multiple drug classes. Unable to construct a treatment regimen capable of suppressing HIV RNA to levels below the limits of quantification of the test.

Group 3: Drug resistance present and able to construct a regimen capable of suppressing HIV RNAs to levels below the limits of quantification of the test.

(In some ways groups 2 and 3 are somewhat confusing)

In addition, the FDA does not consider that a new ARV can be used alone. All this is very restrictive and DTG developers will have no choice but to comply...
To be convinced, let's take the example of an Absolutegravir, whose definition we recall: a molecule against which no resistance develops, whatever the dose. An Absolutegravir is used like an insulin... Too low a dose, the CV goes up without developing resistance. In other words, the barrier to new resistance is infinite in height.

This Absolutegravir is an ideal situation and allows us to imagine variants. Here is a definition for a type of Quasi-Absolutegravir.

Under this QAG, and even in case of under-dosing, it is impossible to develop a new AMR (mutation associated with resistance); the eventual rise of CV only reflects an insufficient dosage. On the other hand, it has a (small) defect: there is a mutation that makes it 100% ineffective. This mutation cannot be acquired under QAG but may have been acquired under earlier, weaker X-gravir.

Such a molecule would be of phenomenal interest for Group 1, but of no interest at all for Group 2: this hypothetical QAG does not meet the CoC of the FDA: it cannot be marketed!

What a shame! Because it would be damn useful ! But even if it did exist (and we can even reasonably assume that it does) it would, in the long run, mark the end of profits for the manufacturer, who will only offer it as a very last resort.

Let's take another QAG-2. With this QAG-2, and even in case of under-dosing, it is impossible to develop a new AMR (mutation associated with resistance); the possible rise in CV only reflects an insufficient dosage. On the other hand, it has a (small) defect: there is a mutation that makes it 50% ineffective. This mutation cannot be acquired under QAG-2 but may have been acquired under earlier, weaker X-gravir. Here, this QAG-2 will meet the FDA CoC: it meets the needs of group 1 but also of the other groups, even if only partially. It will pass the review with flying colors. Obviously, we have to propose a dosage that meets the needs of group 2&3. This is exactly what the development team is going to do: in a presentation (see here, the source is here), they explain perfectly this double objective:

The dose proposed to the FDA serves a dual purpose. Well... We understand... but what if this second objective (efficacy on resistant mutants) does not concern you at all? Why on earth would you take a dose of rescue therapy (second line) when you are not concerned by anything? Why repeat at auction(brazenly and stupidly): we are all different, if we forget that we belong either to one target group or to the other and that we can know it.

Frankly, you don't care about taking the right dose for a Genvoya® -resistant patient(and even then... it's not always right) when you don't have to!

Do you want to go into treatment with rescue Pentatherapy? No, that's ridiculous... So why take such a huge dose of DTG?

We'll see in a future post, how ViiV went about maximizing, at your expense, its financial efficiency, with impunity...

Judiciarization

Opioid crises in the United States: pharmaceutical officials prosecuted(Le monde)

In the news

- Plosmedecine protests against trials for the sole benefit of industry and to the detriment of a healthy scientific discussion: The Ethics of Switch/Simplify in Antiretroviral Trials: Non-Inferior or Just Inferior?

- Doravirin ® is ultimately not terrible: DRIVE-AHEAD Trial's results and the need of a right comparator drug.

The French genius

The Goldberg variations are a hymn to silence. The interpretations by Glenn Gould are unforgettable. Unsurpassable? Not sure... We were missing a genius interpretation, on the harpsichord. Did you dream of it? S. Ross didn't do it, Jean Rondeau did! And you will find it on YouTube

Feel free to comment, like, share and use

good weekend, good stuffing and not too many meds ... Huh?

124

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



DTG-25 mg episode #1

By Charles-Edouard!

From an astute reader:

The discussion on DTG 25mg will be interesting, and, super important with the announced arrival of the injectables, where you will be able to take half a dose, without risk of forgetting...

DTG 25mg: it's time to open the debate!

Science is the approach that keeps us from getting it wrong. (inspired by Carl Sagan) Science is the honest search for knowledge about reality (PZ Myers)

It is the art of asking questions, good questions. Let's open the debate on an inspiring, edifying, exciting and life-saving subject. The doctor has the privilege of prescribing: choice of molecules, dose and rhythm. This privilege has been distorted by not using it. It has become unbearable and will become even more so: the combos are constructed at the sole whim of the industrial and financial Lego, the doses chosen in spite of common sense, and the rhythm, without even taking into account the chrono-physiology of the virus.

While the overmedication is obvious, since the arrival of Tivicay ®, nobody asks the question: but why the hell so many milligrams: 50! only that!!! There is no justification for such a choice. However, the drop-out rate, due to side effects, is 10 to 15% after 3 years, while on the other hand the antiviral power is unequalled, and purely virological failures are rare...

When one is so close to the ZeRo-failure, one can legitimately ask oneself the question: have we not put ourselves too far from the cliff...

We open the debate with this simple question: where do you get the idea that 50 mg are necessary? (in general, and for me, a patient, in particular)

One of our allies laughed at his colleagues who poison their patients with DTG triple therapy, while he does bi and mono. To which I replied that he was just as much at fault for never having asked himself the why and how of this 50 mg...

Here is how we will explain the question:
- the original pharmaceutical sin: the slant and the S
- the escalation test is mandatory but they don't care
- EFV 600 mg an unfortunate precedent
- the trauma of multi-dose rosuvastatin
- DTG and the famous specifications
- DTG exists in 4 doses
- DTG-25 mg has been evaluated and we don't tell you about it...

The abuse is so blatant to our readers that the feeling of a plot against us and our finances overwhelms them. Let's stick to the facts:

The original pharmaceutical sin: the slant and the S

The pharmaceutical grail: the S curve. Galen is credited with formalizing the following observation: the slave prepares opium for his master, who is insomniac. Too little, it has no effect, the right dose, he sleeps well, too much, it kills him. Over a certain range, the effect is in proportion. 2 times more and the effect is doubled. Hence the idea of an oblique line, with, at its foot, a gentle slope, and, towards its highest point, either a saturation (it is then a medicine) or an explosion (it is then a poison). It is basic and primitive, of course, but that is how it works, in general. From the name of Galen, we call the art of preparation: galenics...

The Grail for the pharmaceutical industry is to find this S-curve: once they have the curve, they are almost sure to succeed, especially in terms of regulatory approval: it is so canonical that their presentation to the authorities will go smoothly. Of course, after the first obstacle: toxicity.

In the Dolutegravir story, you may have missed an episode: ViiV (GSK) had, initially, a very different plan ... The basic idea was to put on the market a lambda INI, like Raltegravir or Elvitegravir. But it was too toxic. That's why ViiV is in trouble... Nothing but old molecules in the portfolio and nothing to renew.

Another company, unknown to ARVs, but known elsewhere(we'll come back to this), Shionogi, Osaka, Japan, has a 2nd generation INI, a good candidate. Shionogi: Kadors of inhibition! ViiV buys the rights for 10% of its shares (estimate: 2 billion dollars, anyway...) and royalties (unknown percentage, probably high). Who from Renault or Nissan has the power? In practice? Here, it's a bit the same... ViiV is rather the false nose of Shionogi. The introduction of Dolutegravir must be successful at all costs, the survival of ViiV depends on it.

The S-shaped efficacy curve means that beyond the linear zone, when the dose is doubled, the effect is not doubled. But, it costs twice as much... You have a little hunger: you eat a small banana, it does it... But well... Just... So you eat a second small banana, just to be safe. We all get trapped... Eating a small banana was a great plan. The second one is an extra soul, the angel's share. For a very marginal benefit, it cost you twice as much.

The cost increases linearly, in proportion; the desired effect saturates.

the escalation test is mandatory but they don't care

Once the phase I test (toxicity) is over, the regulations require a phase II test: dose escalation. In practice, the dose that will be retained is part of the tested doses. If there is no additional benefit to increasing the dose, there is no need to increase the dose.

The FDA, which was historically established to protect the patient, imposes this formalism. However, in view of the results, it is not the FDA that decides on the dose... The industry proposes, the FDA disposes. So the FDA does not formally impose the optimal dose.
The manufacturer can choose to market one or more doses. Faced with several possible dosages, the manufacturer(we specify the manufacturer) makes choices, choices that he will optimize in order to maximize his financial income. In principle, he will be cleared of these choices by the presence of two recourses: the FDA (or the ANSM) can refuse, and, in fine, the physician can adjust the dose. The FDA sets the rules of the game in advance: the document is here...

The industrial pharmacist only proposes... The responsibility of the dosage is medical, not pharmaceutical. In practice, the only last line of defense against poisoning by cumulative toxicity is the patient herself.... So the escalation test is only a formal exercise, whose conclusions the manufacturer can easily, under some excuse, ignore.

EFV 600 mg an unfortunate precedent

I must be about the only one to report this sad case: see here or this raging article: Dose optimization: a strategy to improve tolerance and reduce the price of antiretroviral drugs, by Hill, Ananworanich and... Calmy! (sic)

The phase 2 trial clearly indicated an advantage to the 200 mg dose. There was no objective reason to choose 600 mg. Apparently no one can say who chose 600 mg, under what circumstances, and on what authority. Every time you brought it up, you were sent back to your 22m. Until the ENCORE-1 trial, its validation by the WHO, and the marketing of the product, which nobody, nobody talks to you about! They are all walled up in a complicit silence... With DTG, it's the same thing again, but we know the actors and their role... How much is EFV overdosed? 2 times? 3 times? 6 times? Who knows... With DTG, we go to frightening multiples: 2 times, 5 times, 15 times, 25 times ... Amazing!

Well, let's continue next time...

In the news

- Levothyrox: the study that proves patients right: a simple re-analysis of the trials. We do the test, we let the manufacturer do the interpretation, and bam! the disaster. See our analysis of Isentress HD and its 1200 mg!

- HIV infection is no longer decreasing in France. Repeating the same mistakes leads to the same failures. Targeted screening has reached its limits... Adding another layer will only have a marginal effect.

- Colorectal cancer screening is so boring that it is being abandoned. We are sorry in advance about the 'sales' of the reimbursed condom. A good intention, ridiculed by the administration...

- We learn, thanks to an Actupian document, enlightening and staggering at the same time, that Gardasil, this unfortunate vaccine so expensive and so controversial is now free in CEGIDD. If you are at risk (e.g. young gay man), this is to be considered carefully. The benefit/risk ratio is crap for the general population (girls and/or boys, who cares), but for a person at proven risk, it's another matter.
For my part, being at high risk for Hepatitis B, I am vaccinated. Not to the point of demanding, loudly and clearly, the vaccination of infants! Forcing a medical intervention for the sole benefit of others is a crime against humanity (Nuremberg jurisprudence)

- One learns, by the way, a decision taken in secret: the BCG vaccine, whoseinefficiency will have been demonstrated only later, is no longer compulsory for the health workers. The scandal is so huge that we wanted to get out of it by the back door, touch by touch.
Today the BCG is buried! But they are not going to trumpet it from the rooftops. Some vaccines are useful, others not! You have to stop talking bullshit... Forcing people to take useless or even dangerous vaccines is putting gas on the fire and feeding the anti-vaxers.

overmedication is an opportunity if you know how to use it!

123

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



relief and intermittence

By Charles-Edouard!

A reader asks the inevitable question:
This is the question everyone will ask... Almost everyone... Others will go for 3/7. It is the purpose of the OMNIBUS project to answer it. Reminder: this blog is not a medical advice

relief vs. intermittence

Since our Staff at the Salpêtrière (Sept. 2018), it is agreed to call lightening, which uses fewer molecules and intermittence, short and ultra-short cycles. Reducing the concentration of EFV from 600 mg to 400 mg (or even 200 mg) has no other name than 'correction of methodological error' .... Obviously, there are people who will want to do both ... Especially since the 4/7 in commercial dual therapy is inevitable... Inevitable, because the only advantage of MK-8591, the EFdA marketed by Merck is its half-life of ... 168 h! To think that the 4/7 in BI will not be done is a nonsense... It is quite legitimate to ask oneself, as of now, the question.

For carefully selected patients, MONO-DTG works very well, and I can assure you that it is very pleasant, since the tablet is very small. I have had it work in half (7/7) and quarter (7/7) tablets! I assure you that when you take your quarter of a tablet in front of a witness, she is amazed... Mono-DTG has a remanence of 3-4 days, it is written in the Vidal, and tested in the ING XXX trial; So people who succeeded in their Mono-DTG in 7/7, went to 4/7, including my excellent friend jesuisdutreize. The weak point of this strategy is that there is an Achilles heel if the virus has been treated, at some point, by RAL or EVG. For those whose virus is old (pre-2007), just look at the prescription history. For the new ones, it is a bit different, because their virus could have been treated (badly) by the person who gave it to them. However, we do not know how to make a relevant genotype for this case, so there is a random risk, all the more so since Isentress ® (RAL) was used liberally, as in Holland or in the West of France...

So, before considering a MONO-DTG in 4/7, one must be sure that one is on the right side of the handle... The passage by 7/7 is thus rather a good idea. It is necessary to be perfectly compliant during this first phase. Then you can work on intermittence, under close biological monitoring, as always. MONO-DTG in 4/7 is great. Today, in Paris, Prof. Katlama is the reference for Mono-DTG.

OMNIBUS-Bicycle

Once we understand the process that leads to MONO-DTG 4/7, we understand better that the process that leads to Bi-DTG 4/7 requires a good real honest validation of DTG/x, in 7/7, for a while. From this point of view, the process is the same, whatever the x in DTG/x: either 3TC, or RPV, or ATV (boosted or not), or nothing. The cause is this Achilles Heel, identified by Katlama and confirmed by subsequent explorations.

Then there is the choice of the second molecule (or not). The undeniable advantage of Mono-DTG is that in case of failure (apart from the Achilles Heel), there is no resistance to DTG. Let's say, in any case, that DTG can continue to be used. Martinez, Lanzafame, and personally, myself, believe that it is enough to reinforce, without making a cross on DTG: that's pretty cool!

3TC: In case of failure under DTG/3TC 4/7, the weak link is not DTG but 3TC, in other words the M184 mutation: this one is a pain... It is easily eliminated by fallowing (1 year off treatment) but you will be bored for the rest of your life and you can say goodbye to dual therapies, to 'classic' intermittence, etc... The objective of DTG/3TC in 4/7 is good if it works, and then what do you do?

RPV: better not to be susceptible to drug-induced depression... DTG on one side, VPN on the other, there are many who can't stand it. As always, if you can handle it, it does, and it's Juluca®, in one pill. If there were no alternative, it would be attractive.

ATV: This is the stuff we're talking about. The highest strength barrier is DTG and ATV is right behind it, so it's concrete. I'm very happy with it, no liver problems, and it's a good way to get to 3/7. Leibowitch and Katlama agree, for once... and consider it for 2/7. That's really cool. Katlama says with booster, Leibo says without...

As long as I have to choose between MONO-DTG 4/7 and DTG/ATV 2/7, for me it's all clear: DTG/ATV 2/7... And there's nothing to stop you from starting MONO-DTG --> MONO-DTG 4/7 --> DTG/ATV 2/7, with Katlama for example.

OMNIBUS-3D

You can also consider, and this is the easiest way, to advance to 3/7 with your Triumeq®, it is eligible for the OMNIBUS-3D trial and so are you, since you are successful in 4/7. OMNIBUS-2D is not yet finalized, but Triumeq® is definitely in! Triumeq® 2/7

My personal experience includes 4/7, 1/7, 1/15 (modified Leibo method), Mono-DTG, in 4/7, in 1/7 (failure), Bi DTG with 3TC or with ATV. The only thing where we have the satisfaction of moving forward is 4/7, 3/7, 2/7, 1/7, etc

Strategy	Toxicity Unit per week	commentary
Bullshit IRR (7/7)	21	if you have shares in Labs...
Bi: DTG + 3TC, 7/7	14	validated (Lamidol)
Any classical IRT 4/7	12	soon outdated?
Bi: DTG + 3TC, 4/7	8	Omnibus-Bicycle, not started
Quadri-Leibo (2/7)	8	rigorously demonstrated, but Videx® unavailable
Mono-DTG 7/7	7	caution (Achilles heel and compliance)
Mono-DTG 4/7	4	caution (Achilles heel and compliance)
Quadri-Leibo (1/7)	4	rigorously proven, but Videx® unavailable
Charles-Edouard formula!	3	new 1/7 (1/15) under exploration

Who to consult

In this case, it's not the doctor that matters, it's the close CVs: if the doctor gives you the prescription, it's free, otherwise it's 70 Euros per CV: not the end of the world... This is the big advantage of Triumeq ® 3/7 or 2/7! You don't have to worry about it! The caution is to make sure that the CVs are close together

That's how I keep the same doctor: he is not at the forefront, that's for sure! In the worst case, no doctor would be suitable for me... Leibo is out of the picture, since he has announced to leave the case(considering his age, it's understandable and inevitable). Katlama, hurry up, retirement is coming soon, but once the plan is made, it's made.

I have published a list of caring doctors, you choose...

Obviously, the alter egos of de Truchis, like Landman or PM Girard, will not be an interesting second opinion for you, it's kif-kif, besides, they are bound by the ANRS trials...

For an enlightened strategic definition Katlama(or maybe Valérie MARTINEZ) at the Salpé, and you also start to take issue with Jean Derouineau, who had the good and nice idea to ask to be part of the list and who does a little bit of everything, in town medicine.

News from Omnibus

It's finally happening! The consultation period around the protocol is coming to an end and it is finalized: we still have to convince some clinicians, and this is well on the way. Well... It's going on... As for the financing, I'm making progress too... Well... Needless to say that the winds are against me, but well... I've just succeeded in an absolutely smoking coup, in a related field, and, moreover, I've been told that the financing is on the right track. And it's a nice funding! I'm going to have the approval letter framed, I'm so happy!

In the news

122

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



Toxicity? In your dreams my good lady...

By Charles-Edouard!

Here's one who's had it! One must be quite unconscious!

The worst thing about this sad affair is that there are patients with 800 CD4 before starting a life-threatening treatment. If the U=U is an undeniable benefit of the treatment, it is still necessary to use it! In our tropics, the HIV Causal Cohort clearly shows that there isno excess risk in delaying treatment until 350. The same is true for START, where the excess risk measured is in exact proportion to the participants in the South (where the excess risk is real, as we know thanks to TEMPRANO) and those in the North, where the excess risk is nil, as we must remember. (see my post Early treatment: How Morlat is misleading.

At the very least, he could benefit from the LOTTI trial, which the parrots talk about here, the original article is here. Personally, my natural inclination invites me to treat, but to mistreat in this way the poor basic homo, already an outcast of a society that rejects him, not to mention professional circles, ah bah NO!!!

Toxicity vs. benefit

When the benefit is real or imperfect in the face of a situation of real danger, significant toxicity is acceptable: e.g. AZT, in its time, certain chemotherapies, etc. When the benefit is putative or even illusory, on the other hand, acceptable toxicity cannot be 10-20%, but at most 1-2%. Dr Marc Girard gives us a vitriolic analysis of Gardasil, for which we are still waiting for proof that there is a benefit or that immunization is lasting. Some dream of mass vaccination of young girls (and even young men)... Here, one of the problems is that it is absolutely impossible to identify with certainty a 1% toxicity, but multiplied by the number of innocent girls thus raped, it will make numbers!

In the same vein, let's demonstrate the real benefit of vaccinating infants against an essentially sexual disease, whose immunization duration is only 10-15 years (I speak with full knowledge of the facts, I have been vaccinated, with booster shots, and I keep an eye on them): once they reach the age of risk (say 15-45 years old...) they are no longer immune! The vaccination coverage against hepatitis B in children of 24 months (87% in 2015) is very high, but less than half of the adolescents are vaccinated. And the vaccination of ... infants is mandatory: look for the error! Will we have to wait 40 years to realize that the vaccination of infants has no effect on the incidence? If there was a vaccine against HIV, with an immunization period of 10-15 years at the most, like for HBV, would it occur to you to compulsorily vaccinate the very young?

There are toxic ideas, toxic characters...

When you invite to the debate the Rouzioux ®, the Raffis ®, the Peytavins ® (and I go on...), you spoil it: here are people from whom you have to stay away! I am not even talking about statin spreaders like Danchin ® or Steg ®... And our poor patient, don't you think that a good kick in the ass of his doctor would not be deserved ? Anyway, as soon as you hear Genvoya ®, run away and go read what the transparency commission said about it...

In the news, the French genius

Apparently, there are still a lot of people to pay tribute to him, week after week. I liked the character, even if I buy elsewhere...

overmedication is a chance if you know how to use it!

Comments

Pierre1 March 2019


AnonymousMarch 2, 2019

121

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



Sonigo and Darwin: neural pleasure!

By Charles-Edouard!

February 12th: It's Saint Darwin's day!

In my previous post, I put some pretty powerful stuff! First, this picture of the shift from risk and non-risk, which maps the path to remission (Infinite Eclipse): we'll exploit it further. Also that Darwin is the greatest scientist of all time: this has only recently come to my attention. Before, I would have put Copernicus, Galileo, Newton, Einstein or Dirac... It turns out that the problem to be solved, which is here, there, in front of me, is biological and thatone cannot think of biology without Evolution.

Darwin is a man of his time. If it had not been him, it would have been Wallace (whom Darwin himself refers to as a co-inventor). Mendel had already discovered the granularity of heredity (hence the gene). Darwin was already a widely read author, on a par with Dickens, even before 'The Origin of Species'. Let's not make him a hero but a beacon and an inspiration.

There are at least 2 major scientific problems: how to get rid of the virus (or at least its effects) and why it has such a deleterious effect (for a virus so sickly, so slow, so not adapted): once these questions will have been answered, all that will have been said before will appear irremediably false. The Siliciano, Rouzioux and other people who prevented us from cycling in circles, will be ridiculed. Rouzioux will have the double punishment, because notwithstanding her hysteria of the immediate resurgence of the reservoir(invalidated by the analytical interruptions) she will also have argued against the Swiss opinion, delaying as much the inevitable admission of the U=U: as much to say thatit will have ruined the lives of many people!

It is necessary to find another theoretical corpus. Faucy observes and exploits the Eclipse of at least 7 days, Sonigo explains to Leibowich the slow resurgence curve. Charles-Edouard! himself presents Pasteur with the Choke-and-Mute as a workable route to remission(watch the video again!). Darwin took 40 years to perfect his trick: the choke-and-mute needs to be perfected too. It is the basis of dynamic remission, the 1/7, the 1/15. Sorry, it's the attrition (erosion) of the virus (over)life expectancy distribution that counts. Theoretical variants have been presented: Ptolemaic(Leibowitch, the eternal (non)-return), Newtonian(Weinberg, the burial of DNA); there is also the Darwinian(Sonigo, the population burial). The latter is perhaps the most interesting, but rarely well introduced.

Leibowitch tried it in 'En finir avec le Sida', but his chapter with forests and rabbits is unbearable. It comes from Sonigo, co-author of Kupieck, and the story of the rabbits comes from Lokta and Voltera, which I will, one day, demonstrate is the solution to the above problems. This is unbelievable because the allegory is not accessible to the common man, as Evolution and population dynamics is little or badly taught in high school. The West and its medicine remain impregnated with Creationism and Lamarckism.

Pasteurian News

The publication of Asier Sáez-Cirión (Pasteur), that viral persistence occurs in cells with low glycolysis, thus with slow metabolism, has made a lot of media noise. Theannouncement is here, the original article here. So it would be enough to wake them up a little to release the virus and to zap it by tritherapy. Frankly, this obsession with waking up what will inevitably wake up goes against my propensity to sleep in when I feel like it. The Pasteurian news has the remarkable feature of being, in fact, a re-discovery of the fact that the residual virus hides in cells with a low metabolism/rotation (thus long half-life, hi, hi, hi...). Re-discovery then... A discovery of the Golden Boy of Pasteur: Pierre Sonigo. Well... At least this allows us to put the spotlight back on... the rabbits in the forest...

Sonigo comments on this news

Me: The Origin of Species has matured 40 years of epistolary exchanges, always useful in the formation of the scientific idea, to the point that the paternity (therefore the Nobel...) is problematic. I have revealed a bit of OMNIBUS, because I am sure that it will happen, without delay. So, Sonigo graces us with a commentary all the more expensive because he has the rare and fundamental word to the advent of 1/15 (or even better), which is only a matter of time and perseverance. Hidden in this short Sonigo commentary are the pillars of modern biology:carrying capacity, selection by capacity (more subtle than survival-of-the-fitest), a Lokta-Volterra, all concepts that will be explained further. Without further ado, here is the Sonigo-in-the-text, unedited:

120

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We provide this translation for your convenience. Practical aspects may differ where you live.



Why OMNIBUS-3D? Because ...

By Charles-Edouard!

OMNIBUS to 1/15: you'll have to be flexible and motivated!

Well... To get as close as possible to remission, you have to be smart! ICARE, the cuckoo with the gummed wings, didn't go very far... It was 2000 years ago!(besides, it is a fable). Today we fly everywhere, including to the moon, and even behind!...

On the road of progress, follow the green boxes, diagonally...

Special feature	5/7	4/7	3/7	2/7	1/7	1/15
broad eligibility
Selection on genotype	No	Yes	Yes	Yes	Yes	Yes
Bi: DTG + 3TC	Yes ?	Yes ?	No?	No ?	No	No
Any conventional TRI	Yes	Yes	No	No	No	No
TRI selected				Yes ?	Yes ?	No
Quadri-Leibo	No	No			Yes ?	No
Charles-Edouard formula!	No	No	No	Yes ?	Yes	Yes ?

A case for OMNIBUS-3D

OMNIBUS is moving forward... The definition of the first component, OMNIBUS-3D, is nearing completion and we are recruiting clinicians and collaborators. To finance it, we will have to apply for funding(grant application) from various organizations. We must be prepared to present the project to decision-makers, who must not miss the substantiated nature of our application. So, we work on a digestible and relevant argument. From there, all variants are possible... The substance of the case is presented here. Once refined, it will be integrated into the financing file.

Argument of the viral dynamics: The Eclipse

HIV infection is chronic. The treatment is in 2 phases: an initiation followed by a maintenance, defined here as starting 6 to 12 months after the undetectability is confirmed. The recorded practice is to extend the initial prescription scheme to the maintenance phase (ref HAS). It is however established (ref Autran) that lymphocyte activation, which is essential for active viral replication, disappears in the 3 to 6 months following undetectability. It has been observed that poor compliance is adverse to the success of the initial treatment and it has also been observed that poor compliance, beyond the initial phase, is not detrimental (ref Lima). Trials of interruption with a view to eventual remission in patients with a favourable profile (SPARTAC trial) or interruption guided by CD4 count (SMART) show an inevitable resurgence of the virus, contrary to the therapeutic objectives. Conversely, analytical interruption trials in patients with a favorable profile (SEARCH 019, ULTRASTOP), as well as in unselected veteran patients ( Rothenberger ref), show a time to rebound (aka Eclipse) of 2 to 3 weeks on average, without it ever being less than 5 days.

The existence of an early reservoir in cells with low turnover/metabolism (ref Pasteur + Sonigo) is the accepted cause of the practical impossibility of obtaining a cure by the classical means of antiretroviral therapy. The latency of the reservoir is maintained by its presence in slow cells. The low dynamics of resurgence, repeatedly observed, and the persistence of the reservoir are two sides of the same coin. We do not know how to purge the reservoir because it has no dynamics, on the other hand, we know how to take advantage of this absence of dynamics.

The first short cycle tests (7 days ON and 7 days OFF) followed by 5/7 tests (Dybul/Faucy test, FOTO) have confirmed this opportunity. The rare failures observed with some combinations, in particular IP, contrast with the renewed success with NNRTI (FOTO, BREATHER): there are rules to discover. The exploration of these rules (FASEB-1) has made it possible to delimit the favorable synergistic combinations, on the one hand, and highlighted the possibility of extending the strategy to 1/7, on the other hand (FASEB-2). The virological failure rate published at the time was 2 per 100 years of treatment, out of a total of more than 10,000 cycles, for the best synergies. These observations, confirmed over time, invalidate the classical pharmacokinetic argument and force a paradigm shift. The appearance of more powerful and more persistent molecules has strengthened the therapeutic arsenal in this respect. As an example, the persistence of the effect, beyond 3-4 days, was observed in the ING 111521 trial (initiation monotherapy with Dolutegravir). So there is also a change in time.

A challenge for EvidenceBased

Medicine
The OMNIBUS family of trials aims to scientifically establish these rules, for the benefit of the greatest number. The supervised practice of 4/7 is now included in the expert recommendations (Morlat report 2017). The robustness of the method is based on 2 observations: the follow-up of the Garches cohort concerns 94 (?) patients and 10,000 cycles; the post-hoc analysis of the 3 failures of the ANRS-4D trial attributes them to the sole failure to follow the regimen: as a result, the intrinsic failure rate is zero (ref de Truchis - Le Figaro). For some, this evidence is not sufficient to consider entering the intermittent treatment with confidence, for others it is an incentive to explore further, without any safeguards and without medicine based on evidence being able to shed any light. The weakness of the evidence in terms of robustness is an obstacle to deployment, and the Quatuor trial only partially compensates for this. Distrust of the medical technostructure has been present since the beginning of the epidemic and is reinforced by the delays and the active debate among patients (Internet, SNS).

Heuristic, Darwinian, incremental, autonomous exploration is within the reach of informed patients who are progressively pushing back their horizon while sharing their success. Academic medicine is challenged to propose eligibility criteria and safeguards. The search for a better modus vivendi is legitimate, in the face of the proposal of pharmaceutical incarceration, early, in perpetuity, perceived as unfair and unjustified. Some people, informed and educated, will be able to do so, while others will be kept away, thus breaking the principle of equality in access to care.

A strong economic incentive

For France, the cost of the salaries is about 1.000.000.000 (1 billion) Euros or 50 Euros per year and per household. At the current rate of contribution, 7 billion of gross salary must be mobilized to finance them, i.e. the salaries of 345,000 people! Arithmetically, each day saved represents a saving of 150 million Euros per year. The delay in the adoption of the 4/7, which appeared quite early in the Morlat recommendations, is detrimental. The validation of 3/7, envisaged by OMNIBUS-3D, in addition to its own gains, will contribute to a faster adoption of 4/7. The gains are therefore greater than the 3/7 strategy alone.

The strategy of reducing Efavirenz from 600 mg to 400 mg results in a saving of 100 million dollars for the CHAI Foundation alone, and already has more than 1 million users (ref Mylan). It is included in the WHO treatment guide. The Quatuor trial will enable the savings to be amplified in areas where the technical means are adequate. The technical means required for the OMNIBUS-3D trial are the same as for the 4/7. All eligible molecules are either free of rights or promised to be widely and inexpensively disseminated in countries in need. 3/7 would therefore represent a 33% increase in savings where 4/7 is deployed.

The financial means provided by donor countries are constantly being eroded while the number of beneficiaries has increased dramatically, following the adoption of the non-distributed treatment strategy. Industrial production capacity is stagnating, depriving 10 million patients of treatment, at the cost of more than one million deaths annually, including 250,000 children and adolescents. Short-cycle strategies will rapidly free up this industrial capacity for the benefit of millions of people: for many countries, this is the only way to achieve the second and third components of the 90-90-90 eradication strategy adopted by WHO.

Arguments against the OMNIBUS-3D trial

Currently, we do not identify any... The 5/7 trials did not identify any limits to the cycles, nor any limitation in terms of molecule (except for the old PIs). If we had stuck to a pure pharmacokinetic vision, without taking into account the pharmacodynamic effect, we would not have dared to try 4/7. The unquestionable success of ANRS-4D shows that it would have been a great mistake not to try to go beyond the pusillanimous 5/7. It would be the same not to undertake OMNIBUS-3D.

In the news

- Lanzafame published 2 articles: Dolutegravir Monotherapy's Virological Efficacy in a Highly Treatment-Experienced Patient and Dolutegravir monotherapy: an option for highly adherent HIV1-infected naive patients [...]: we'll come back to it...

- I wanted to point out a video of a meeting at the LGBT center, posted on: facebook.com/seropotesparis/...
with De Truchis and Landman... Finally, what is more and more amusing: everyone is starting to rally around the idea of ICCARRE. Well, take the time to watch it, we'll discuss it later.

The greatest genius of all

Yes, yes... It's Darwin and soon his birthday... Valentine's day? Well, yes... OK for fun and sex... Why not a Darwin's day? He's the one who freed us from all those bastards... Well... They won't canonize him anyway... Think of making change your treatment, it will be better adapted (hi, hi, hi...)

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