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



Shock-and-kill

By Charles-Edouard!

On unnecessary and deleterious medication... Deleterious or not, unnecessary overmedication is ... useless! Genvoya® contains a powerful metabolism inhibitor: Cobicistat. Virologically inactive, it is not harmless.

The great subject of the moment is a questioning of the dogma of provirus integration, following the discovery of replicating but not integrated viruses (E. Thierry, ..., Delelis)
This is really THE topic of the moment, so let's continue our entry: it's exciting!

What is Shock-and-Kill?

The video on the right describes Shock-and-Kill: it is a bit simplistic and the visualization is sometimes distorted. Let's start with this approach anyway: the proviral DNA is integrated into the genome of 'memory' CD4 cells: it enters latency. John Le Carré would have spoken of a dormant cell.

The problem is that the dormancy isnever explained, nor the mechanism envisaged to bring it out of dormancy: a test tube manipulation, with a hyper-dangerous molecule! In practice, in clinical trials, the failures follow one another and are too similar.

The patient, credulous, is fooled: we entertain the gallery. And we take advantage of this to suggest that an early treatment would be favorable to a low reservoir, which would be favorable to a possible Shock-and-Kill... This fable going in the direction of the early treatment, therefore of the treatment-plus, therefore of the consumption-plus, finds good souls, stipendiated, to repeat with envy this tomorrow-we'll-rase-gratis, therefore, quickly, enter the treatment, illico-presto, without forgetting to pay the bill.

A well-concealed DNA

Popular imagery imagines a piece of DNA in a double helix, ready for use, transcription and expression: a devil in a box, but without the box... Just look at the picture above, the DNA is well unfolded...

In our previous post, we had seen, that in fact, the provirus is 'protected' by a methylation gangue, and, moreover, wrapped around the histone. This shaping is modulated by a histone deacetylase. The idea is therefore to inhibit this enzyme to give the green light to transcription.

I mix up methylation and histone: It doesn't matter... A detailed explanation by Margolis can be found here... In practice we try cocktails and it doesn't work...

Valproic acid (Depakine): authorized and dangerous molecule

Drug against epilepsy, strongly advised against women of childbearing age, because of its serious teratogenic effects on the embryo and the fetus and neurodevelopmental disorders induced in the future child and adult. Discovered by chance in a laboratory in Grenoble, it was the first to be effective against epilepsy, a serious disease with no cure: it was therefore authorized.

Opening the gangue where DNA is normally encapsulated is not harmless. The most visible consequence: abnormal babies, with a distinctive face (known as pear-shaped), which will have been deliberately hidden. Babies born under Depakine : the extent of the scandal becomes clearerThe risk of congenital malformations in 40% of pregnancies.

An untargeted strategy, marginal effectiveness

The can opener does not target its action on boxes identified by what is inside: the gangues are opened at random, including those that would be better left as they are... We open, we open and we make the genes (not only the provirus) express themselves, at random. So yes, we do observe a small induced, transient rise of the CV. But then... And then?

Then we do some tests, like SEARCH 019, already discussed here Always no effect on the Eclipsealways unchanged.

What future for the Shock-and-Kill?

The latest trial is the BCN02-Romi. The pharmacological gain is only a few weeks (and still... It is not sure), where the average of the natural Eclipse (patients treated very early) is already 3 weeks.

The only benefit will have been a few boxes (1-2?) put in reserve in the medicine cabinet. That is to say peanuts compared to ICCARRE 4/7 or 1/7.

Trials on mice are taking place... The new concepts try to get rid of Valproate.

There are many other proposals with generous funding...

Abivax is tempted. Except that obtaining a reduction of 131 copies of proviral RNA (per million PBMC) does not induce any gain on the Eclipse (see here). Zero, nichts, nada...

Illusory Shock-and-Kill or well-tried ICCARRE?

What we are interested in is whether to wait for the results of an illusory Shock-and-Kill, invalidated by 13 years of unsuccessful efforts, or to benefit from a proven strategy today, which will have benefited every patient, without exception.

This is the subject of the moment and it is time to move forward because we have been distracted by Siliciano, Margolis and others...

In the news

- ICCARRE in the program of VI International Eastern Europe and Central Asia AIDS Conference 2018In Moscow, meeting the need and listening...

- For ViiV, Bictegravir (Gilead) is copying DTG, and is going to court; an out-of-court settlement, as was the case in 3TC vs F-3TC, would be detrimental to patients: the truth would remain unknown and Gilead could maintain a molecule (or a combined drug) under patent, while the original would already be free (this is how Truvada will have continued to be very expensive, while TDF/3TC is negotiated at 30 Eu./per patient and per year!)

The French genius

Clair de lune (Debussy): Alexandre Tharaud, Yoann Bourgeois - piano & dance on YouTube. It is an allegory of the 3 steps, then six, with falls and rebounds. In the serenity of a light, certainly less flamboyant than the miraculous Sun, but light all the same...

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97% of patients overmedicated, 22 million without treatment... Let's stop this scandal!