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