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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.



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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