130

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



Supersonic Suppression

By Charles-Edouard!

Call unanswered, and for good reason...
Between the ICCARRE, ANRS-4D, Quatuor trials, and the fact that Morlat authorizes 4/7, you have between 1000 and 2000 'official' patients. The ICCARRians' testimony is here, and the others... nowhere... Not one to come and tell about his participation. Not one either to come and tell about a failure, especially as we have been able to highlight the lack of follow-up of the procedure.
The general instruction is to delete again by going back to 7/7, with the same combo. This is with the doctors who 'master' the procedure. There will always be a few who will change the combo, and patients sometimes find this to their advantage. The question of changing or not changing molecules is at the heart of this post.

Close-up CVs: it's essential

I had described here that I had failed the weekly single dose of DTG (150 mg, 1/7). Some readers have come forward and said: 'I can do it'. I believe them. But then again... For me, the use of DTG/3TC in 3/7 or 2/7 (inflated) had already given some warning and the attempt of Mono-DTG (150 mg, 1/7) was a bit of a last try...

Spectacular recovery: I was then displaying my highest CV. On my own, as much as all the other Mono-DTG failures combined! No discussion, but... Shouting resistance would be a bit too fast. With Absolutegravir, you have to expect a rise in CV when the dose is insufficient, a bit like an insulin that is not dosed enough: the objective is not reached, but without prejudice.

By the way, as much as I have a strong opinion on the uselessness of the proviral DNA measurement as a measure of the reservoir(I am therefore an A-Rouziouist), the existence, in my case, of a reservoir capable of restarting the infection is not in doubt. This is an opportunity to challenge some preconceived ideas: one cannot prejudge the height of the rebound(you can imagine that I did not expect this!), nor that one can 'feel' the rebound, as a kind of felt primo-infection(my primo, I remember it, thanks to him...): it is better not to rely too much on the reading of one's body or on luck. Analysis is more useful, as we will see here.

This was the one and only time I deviated from my rule of close CVs (unexpected detention abroad): CV at month-3 instead of month-2. Here again, the lesson is well learned. Afterwards, we do as we can... My new sequence, for example, is, reluctantly, month-1, month-2, month-3, month-6, but it is for professional reasons. So, here, CV at month-3, just after the change to Mono-DTG 150 mg, 1/7, will have been a mistake: might as well remember it!(it may not be Mono-DTG 1/7 that is at fault, we will come back to that). With the years, a certain fatigue to take blood samples every 2 months had been born, by dint of seeing <20 each time. But it is necessary in the initial phase of each change.

Drowning? Recovery? And with what ???

Well... Now you are faced with your $$$ copies (CD4, that's still ok...) and therefore with dilemmas in a drawer: to resume or not the treatment, with or without DTG. Personally, I have full confidence in the long fallow as a method of cleaning up mutants, and do not give any credence to the so-called over-risk of waiting for 350 CD4 as a threshold for resumption(cf SALTO trial, or HIV-CAUSAL cohort). Drowning was an option. Now... Fallowing (1 to 2 years, if you can), then suppression(without DTG, it was long, 18 months, in my case!), then the timid ICCARRian recovery, we took it for 5 years...

So I choose the recovery. But with what? No resistance test at hand. What to do with or without DTG ? Martinez and Lanzafame remove the failures at MONO-DTG and keep DTG. Bart Rijnders, Hocqueloux/Raffi, Katlama, change their approach... We will test if DTG has, for all intents and purposes, behaved like an Absolutegravir.

The virus is smart... So are we!

To the question Cheese or dessert, I often answer Cheese AND dessert! So we're going to develop 2 strategies and combine them.
Strategy 1: Triumeq
Strategy 2: NVP/TDF/F-3TC.

Like the concomitant intake of DTG and NVP leads to a total disappearance of DTGit is useless here. This becomes: combined strategy DTG/ABC/3TC and DTG/TDF/F-3TC, that is, in fact, 2 distinct strategies, combined: namely

Strategy 1: DTG BID 2x50 mg (strong but useless if you are not sensitive to DTG anymore)
Strategy 2: ABC/TDF/3TC (weak, not recommended, but useful in contrast, here).

We will be very attentive to the dynamics of recession. If the descent is slow, we will abandon DTG and quickly put NVP. We will then take note that DTG has become useless. We would regret it a little, but we know how to do the 1/15 without DTG. If DTG is of no use for dynamic remission (1/15 and more), no regrets. If the descent is rapid, we do not change hands, we keep DTG in our remission strategy, but not alone...

Admire the work...

Intake scheme	rhythm	duration	result
DTG/ABC/3TC in the morning DTG/TDF/F-3TC in the evening	7/7	1 month	<20
DTG/TDF/F-3TC	7/7	1 month	<20
DTG/TDF/F-3TC	5/7	1 month	<20
DTG/TDF/F-3TC	4/7	1 month	<20
DTG/TDF/F-3TC	3/7	1 month	<20
DTG/X/TDF/F-3TC	2/7	1 month	<20
NFC-1	1/7	6 months	<20
NFC-2	1/9 then 1/10	6 months	<20 (*)
And in project...		(*): last validated tag
NFC-3	1/12	6 months	start: Sept 2019
NFC-3	1/14	6 months

Supersonic descent offers new perspectives!

It is observed that the virus should have maintained a normal sensitivity to DTG. For a susceptible virus, DTG works equally well at 2 mg, 10 mg, 50 mg, in monotherapy of attack ( ING 111521 trial). It is a methodological error to confuse efficacy and speed(obviously, for a molecule with 1 LOG, e.g. AZT or 3TC, the absence of speed leads to inefficacy, but with DTG we are not in this context). So with 100 mg, on a susceptible virus we should have a very good speed of descent: this was the case. 2 x 50 mg, it's worth it at the initiation, during 1 month, but it's unbearable: depressive effect guaranteed! I endured, but the effect was perfectly visible, what a horror!

If DTG had lost all its efficiency, ABC/TDF/3-TC would have given us a flat kinetic. In the intermediate case, we would have jumped on the way down.

We will never know for sure! But DTG remains in our toolboxwhich is an excellent thing. We'll complete it, for sure, but it stays there. It is ABC that is on the hot seat, and will disappear, phew...

The attentive reader will have noticed that we went from MEGA-Copies to 1/7 in ... 6 months! If with DTG/ABC/3TC/DTG/TDF/F-3TC, 7/7, we did not succeed in the first month, then we could fallow (drown) and then NVP/TDF/F-3TC 7/7. Compared to a fallow (1-2 years)/Tradi-TRI (1 year)/ ICCARRE (4 years) strategy, we win!

Fallowing is the ultimate catch-up net: you have to make sure you have 12 to 24 months to go. Many patients start too early, but if they start when they could have reasonably postponed, it also means that they can afford to fallow. At the time they make the decision, which is too early in our tropics, they are not aware of it, but it comes naturally with time... The exploration of the Eclipse has several nets of catching up. Especially since the close-up CVs are easily accessible and DTG-double dose (or even triple dose) will shoot down any CV in no time. The mega dose to zap the asshole works, of course, what is stupidis to keep the same overdose once the undetectability is reached. This is silly.

And ... Hop!... Forward to the 1/15 (again)

Now, for my descent to 1/15, I'm going slower, since I made the descent to 1/7 in supersonic mode.

In the news

- You are indebted to him and he is dead: Kary Mullis invented PCR, won the Nobel Prize in Chemistry(just that... ). PCR has many applications, including one that concerns you: CV. There is a before and an after to PCR... Dr. Leibowitch, who has always been opposed to double-blind placebo trials, has finally been listened to since he demonstrated the possibility of obtaining an undetectable load(Stalingrad trial in 1995). Before the CV, we went in blind, using the 'guinea pig' patient. No CV, no intermittence...

Once a scientist, always a non-scientist... We make fun of his allegory on the luminescent raccoon, which he commented thus:

Hi, hi, hi...

- Offshoring at the root of the drug shortage in France. Offshoring ??? Ah Bon ??? Does it exist??? Until recently, ARVs were still produced in France. In Auvergne, precisely... And why on earth in Auvergne? Because it was the price to pay to the Chiraquie to obtain the authorizations without too much trouble. Since then, Brussels, Hollande and Macron have been there: nothing grows back!

The French genius

We had exposed, right here, (a little before everyone else...) that the Levothyrox scandal is due to a methodological error: Indeed, one should not compare Mean-to-Mean when the standard deviations are important! Especially not! This allowed us to point out the aberration that is Isentress® 1200 mg(1200 mg! where do they get the idea?) and which has its MA(yes, yes...). This same error occurs in another place in the theory of immediate return(we will come back to this). The re-analysis of the Levothyrox data confirmed the methological error. The authors very explicitly consider that the error was intentional. Le Monde wonders why Merck was overzealous in its evaluation of the new formula.

The multi-year prize goes to the HAS and the health 'authorities' who have been blamed for this sad Levothyrox affair! The mathematical breakdown is here : Why did it take more than 200 subjects to demonstrate the bioequivalence of a new formulation of levothyroxine with an old one?. Didier Concordet, Pierre-Louis Toutain & al. are ... veterinarians ... (from Toulouse). Ah???? Well??? The doctors, where were they? In the Bahamas ??? Well... We are not going to bite the hand that feeds us!

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

129

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 5

By Charles-Edouard!

Yes...It's been exactly 1000 days since 4/7 was authorized by the Morlat Report. Our practical guide dates from 2014: print it and put it under the nose of your doctors. At Homo Parisianus, 4/7 is becoming more and more common... For the 1/7, it comes slowly... Remain the province, the chicks, the disconnected of the Tout-Paris-Qui-Compte. One could have reproached Quatuor for a prejudicial waiting period: 3-4 years lost. Very formally, this is not the case: Morlat, who could have been blamed for this wait-and-see attitude, has in fact explicitly authorized 4/7, as early as 2017! Slow and proactive at the same time: Quatuor is here, in French: It's a flat-out success: we'll come back to it!

DTG-25 mg: Basic Dose (BD) and Rescue Dose

The FDA considers 3 groups: group 1: patients with no problems, group 2: multi-resistant patients, with no solution, group 3: multi-resistant patients, with options. Here, there is no need to dwell on group 3. Group 2, in the USA, is 5000 patients. Out of 1.1 million S+ patients, this is very few, even negligible. The manufacturer could very well want to concentrate its marketing choices on group 1: that would make sense. However, it would make sense...

Let's call DB (Basic Dose, in mg) the oral dose necessary to zap a wild virus (not mutated). This base dose will deliver a plasma dose roughly corresponding to the IC95 (or IC90), the 95% (or 90%, respectively) inhibitory concentration (for DTG: 64 nanograms/mL).

Let's look again at this table published by ViiV, but from the perspective of RAL (raltegravir, aka Isentress ®). There are several primary mutations in red, including one with an FM (Multiplier Factor, FC) of 85. For patients in group 1, i.e. 99.9% of the market, if you want to be sure of your chances, you have to cover the red zones, including the highest one, which invites you to choose a dose of 100 times the DB! It is no longer surprising to see Isentress HD dosed at ... 1200 mg;

For secondary mutations (table 2), it is clear that even at 100 DB, it is so red that it will not work: even at 12,000 mg... If we have resistances elsewhere, the deadlock is total.

Fast Track or... bankruptcy...

Offering a solution to group 2 is very hard, and at the cost of marginalization on the market. However... For ViiV, is an ABSOLUTE priority. Why is that? Because:
1 - it is possible, certainly the dose is high, but it is playable
2- it's urgent: ViiV is on the verge of bankruptcy: its drugs are old and will soon be genericized, ALL of them, which means a drop of 80 to 90% in turnover! Do you know many companies that are resisting to such a downturn?

Solving the problem of group 2 will save ViiV from a predicted industrial disaster: thanks to the (super) fast track, accelerated approval by the FDA. For ViiV, it is vital. On the other hand, we can observe that Gilead has been rather late to release the TAF. Big Pharma delays to perpetuate its profits, but sometimes accelerates to save its skin.

But let's look at the table of secondary mutations, for DTG this time, with 50 times the DB, that's enough! And moreover, in the clinic (SAILING trial), it will do it! For the FDA, for the DHHS (US guidelines), it's a great move! Whoever solves the problem of group 2 will not be objected to in the slightest. Translated into good French, the ASMR, delivered by the commission of transparency, will be rather nice! It is published here:


If you approach the MA with an ASMR of 5, you'll be passed over, with an ASMR of 4 you'll pass, but the economic committee will take its time. If you have an ASMR of 3 and a market price, it will go fairly quickly. This is in fact what happened, see the Efficiency Opinion (May 2014)

The naive patient... Indeed, quite naive!

So, you, patients of group 1, naively thought that the dose had been thought for you, and that by chance, by inflating a little, we solved the problem of group 2. Well, no... It is the opposite: we solve the problems of group 2, in priority, and by deflating a little, we will solve group 1(who can do more can do less), but regardless of the FM needed for group 1 (FM from 3 to 5).

INI	DTG	RAL	EVG
FM Max group 2	50	500	50000+
Dose for group 2	2 x 50 mg	unusable	unusable
FM Max group 1	3	90	500+
Dose for group 1	50 mg	1200 mg	with booster
Prior eligibility for group 1 (only)
7/7 Therapy	YES	YES	YES with booster
Bitherapy 7/7	YES	YES ?	NO
Monotherapie 7/7	YES	NO	NO
Eligible 4/7	YES	YES (?)	YES (?)
Eligible 3/7	YES	NO	NO
Eligible 2/7	YES	NO	NO
Eligible 1/7	YES (?)	NO	NO
Eligible half dose	YES	NO	NO

And this is how they will get a MA with a price of 600 Eu. for 25 DB (50 mg). In practice, this will make 1200 Eu. for the rescue treatment: the 50 mg at 600 Euros is the market price for the first line and, at 2 x 600, in the market price for the second. Nothing and nobody will find fault with this.

That is... 12 Euros per DB/month

You, patients of group 1, without the slightest risk to switch to group 2, you only need 5 DB (counting very large). But here's the thing, ViiV, they are not stupid: they are not going to propose a drug at 5 DB but at 25 DB... Of course, in vivo, one can obtain different results. And they are remarkably discordant: Mono-DTG which works very well here, in humans (and we'll watch what Morlat says about it), and, surprise, very badly in monkeys (Mesplède article). Whatever, what concerns us is us...

We'll see next time why and how ViiV is going to optimize its income a super max, at your expense. To get a head start, try to imagine the extraordinary loss of income for ViiV, if they had chosen 10 mg

In the news

- Stromae is better! A time forced to an artistic retreat after almost ending his life during a depressive episode triggered by a drug intolerance'I made a reaction to Lariam, an antimalarial, super super serious, he added in late 2017. I had a psychic decompensation. It's really not nice.' Really??? Does drug-induced depression exist? We don't even need Lariam, EFV, RPV, DTG are more than enough... Not to mention the interactions between drugs...

- Chlamydia: a vaccine is being developed. For an immunizing disease (you get over it, and then you don't get it anymore) such as measles or Ebola, it is well conceived. For non-immunizing diseases (HCV, HIV, Tuberculosis), it is already much less obvious! That the BCG is useless, they did not shout it from the rooftops! As for HIV, don't expect too much from the ANRS in this matter (given the mishmash of personal conflicts on the subject). On the other hand, finding an invariant, such as TAT OY, is already more encouraging: this is the BIOSANTECH approach. We will see...

The French genius

One can hold one's breath, but one comes out under high blood pressure! Film noir under a blazing sun, a dry hell under a torrent of sweat... No need for a big budget to make a cult film, a film that the Americans will remake. Well... Unless they remake QUATUOR, they'll let us have the exclusivity of the extraordinary economic gain, a real gold mine for us alone. That's just fine!

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