New Approaches Towards HIV Cure to be Tested in Protocol Zero

[dico]

New Approaches Towards HIV Cure to be Tested in Protocol Zero
Lessons learned from the failure of strategies to purge the HIV reservoir and cure HIV infection open the door to test radically different approaches.

Online PR News – 04-July-2014 – Toulon, Var, France – With the advent of combined anti-retroviral therapy HIV infection has become a chronic disease. However, if AIDS is no longer the penalty in correctly treated patients, the number of HIV-infected people increases regularly due to the decrease in mortality and the fact that the pandemic is not yet under control. Life-long anti-retroviral therapy brings the issue of cost in the context of a financial crisis with most patients living in poor-resources countries.
It is therefore mandatory to discover a HIV cure in order to stop anti-retrovirals in these patients.
The complexity of HIV persistence in an infected host is related to the existence of HIV reservoirs in different kinds of cells where the virus is latently integrated in the genome. It might also be linked to the bad diffusion of some anti-retrovirals in tissue compartments, in particular in the lymphoid organs.
“We are launching clinical trials testing revolutionnary approaches to cure HIV.”
In 2007, the report of the Berlin patient who was apparently cured from HIV has spurred the global interest for gene therapy in order to eradicate HIV. However, this case was not reproduced and the use of Zinc Finger Nucleases failed to get rid of HIV.
Anecdotal cases of HIV remission have been reported after initiating anti-retroviral therapy very early at the time of acute infection. However, this functional cure concerns a minority of patients and diagnosis of HIV at the acute phase needs strong surveillance of populations that is difficult to implement.
In the past 5 years, cure research concentrated on strategies to activate dormant proviruses in order to deplete the reservoirs. A wide range of potent HIV activators has been selected in the laboratory and a couple of them, like vorinostat, panobinostat and disulfiram, reached clinical trials. Unfortunately results showed that they were not potent enough to reactivate all latent proviruses and, furthermore, cells with reactivated HIV were not eliminated by Cytotoxic T Lymphocytes (CTL), which are deficient in patients.
Consequently, new approaches towards HIV cure have to be tested.
During an international meeting on HIV last May, Professor Mark Wainberg from Montreal declared that "a revolutionary concept is at hand to obtain encouraging results." This concept is exactly the contrary of what has been done until now: silencing, and not activating, HIV.
In the past, old world primates were infected by ancestral retroviruses which are now included in the human genome and remain silent. According to Doctor Alain Lafeuillade from France, the same could be obtained in HIV-infected patients by using drugs able to sabotage the natural history of HIV. In perspective is the use for a defined period of time of Dolutegravir, a new integrase inhibitor, as monotherapy in patients naïve of therapy. When this drug selects viral resistance (and monotherapy is the ideal situation for this) it is associated with a dramatic decrease in viral fitness, meaning that we have got a crippled HIV.
Three pilot studies are in preparation to test this revolutionary approach in different populations. They are called “Project Zero” and will be started next September. Doctor Lafeuillade and Professor Wainberg are confident to obtain breaking news for the 7th International Workshop on HIV Persistence, Reservoirs and Eradication Strategies they will organize in Miami, Fl, on December 8-11, 2015.

About the Community of Researchers for HIV Cure: it is a group of basic and clinical scientists involved in the study of HIV persistence and the set up of new therapies.

[dico]

What do you thanks about that ??

It looks really scary.

[leatherman]

btw the link to this article is
http://www.onlineprnews.com/news/497341-1404486128-new-approaches-towards-hiv-cure-to-be-tested-in-protocol-zero.html

interesting. several different drugs can develop a resistance that make HIV less viable. For example epivir (lamivudine) resistance (the M184V/I mutation in the reverse transcriptase gene) produces a less fit HIV virus that is unable to replicate properly. After a period of time, the epivir-resistance HIV actually dies off, allowing a patient to once again use epivir if necessary.

This reads like they are hoping to create this situation on a large scale so that the HIV in a person is crippled and dies off. However, any HIV that doesn't develop the resistance will be able to continue replicating and that's probably going to be a high hurdle for this treatment method. Not too mention the problems of resistance, increasing viral load, potential side effects of HIV, etc for the patient during this method.

[Jmarksto]

Thank you both for the posts. 


The video of Mark Wainberg is well worth watching -- he is pretty emphatic that Dolutegravir is a very different drug than we have seen, and believes that it should be standard first line therapy.  He also points out that this approach is counter to the thinking of other virologists.


What strikes me is how quickly they are going from the lab to clinical trials.

[Matts]

Yes it is scary. If it goes wrong You end up with several mutations and Integrase resistance.
I had posted the following link one year ago; (HIV eradication with multiple cycles of Dolutegravir On/Off therapy in monkeys. But it was only theoretical, and I am surprised that they want to try it in humans before animal tests have even started.

http://www.retrovirology.com/content/10/1/22

[leatherman]

If it goes wrong You end up with several mutations and Integrase resistance.... I am surprised that they want to try it in humans before animal tests have even started.

totally agree! it's not like this is is 1986 or 1990 and it's worth trying anything because there aren't any options. It also sounds a little unethical to ask people to take such a risk

[wolfter]

Doesn't this potentially lead to a resistant strain that could easily reach the general population?  Obviously, I'm not much versed in the research field as I typically forget shit that I read within the hour.

greg

[Jmarksto]

The video in the link that Leatherman posted addresses the point of developing resistance -- Mark Wainberg makes two key points:


1.) In the three major trials and thousands of people in those trials, nobody has developed resistance to Dolutegravir or the drugs that were used with it.


2.) The two mutations related to Dolutegravir diminishes viral fitness to 20% of wild type HIV, and are not able to grow out of drug pressure.


He goes on to identify why Dolutegravir is so different and superior from the other meds.  He is pretty emphatic, almost like there is a connection to GSK.  He also acknowledges that other researchers question his theory --- which does raise the ethical question about jumping to a human trial so quickly.

[xman]

what is not clear is how the drug can affect the genetics of the virus inside resting cells. since the new particles exit the cell and don't enter it how is it possible to make the genome inside the resting cell resistant to the drug? does hiv reinfect a cell and in this case with the resistant genetic profile to dolutegravir?

[Matts]

a new Glasgow JIAS paper from Mark Wainberg:

"The R263K mutation in HIV integrase that is selected by dolutegravir may actually prevent clinically relevant resistance to this compound"

http://www.jiasociety.org/index.php/jias/article/view/19518

I found this (hypothetical) sentence interesting:

"The R263K mutation alone conferred an approximate 3-fold level of resistance to DTG and a 40% loss in viral replicative capacity and recombinant integrase activity. Secondary mutations selected at positions H51Y or E138K did not individually affect either enzyme activity or DTG resistance, but the combination of R263K together with H51Y or E138K increased DTG resistance to about 7-fold accompanied by a ≈75% loss in each of viral replication capacity, and both in vitro and in vivo integrase activity. Conversely, combinations of R263K together with multiple resistance mutations for RAL and/or EVG at positions 92,143, 148 and 155 resulted in even further diminished enzymatic activity that may be incompatible with viral survival."

(Dolutegravir+Raltegravir+Elvitegravir+H51Y+E138K and HIV cant survive anymore? A quite strange approach)

But I like the author's recommendation on Dolutegravir for tratment-naives:

"Conclusions: Secondary mutations to R263K following selection with DTG have all led to diminished viral and enzymatic fitness, helping to explain why resistance to DTG in previously drug-naïve subjects has never been observed. The use of DTG in first-line therapy may prevent the facile development of drug resistance and help to forestall ongoing HIV transmission."

[Matts]

Doctor Lafeuillade and Professor Wainberg are not right anymore. There is a new "Berlin Patient" The first one who got resistant to Dolutegravir (Tivicay), with the new mutations T97A and S147G.
He is on ART for 20 years and was HCV-coinfected, resistant to all classes and never achieved fully suppressed viral load.
I think that this example shows that Dolutegravir monotherapy is much too dangerous, and that an omni-drug-class resistance is still possible after many years of ART.

Maybe it is also a question mark for quarterly injections. Dolute- and Cabotegravir are not indestructible as believed.
Dualtherapies are possibly not appropriate in the long run.

full story:
http://www.jiasociety.org/index.php/jias/article/view/19749/html

My dual clinical trial of Maraviroc/Prezista/r  already failed and was shut down.

[buginme2]

Doctor Lafeuillade and Professor Wainberg are not right anymore. There is a new "Berlin Patient" The first one who got resistant to Dolutegravir (Tivicay), with the new mutations T97A and S147G.
He is on ART for 20 years and was HCV-coinfected, resistant to all classes and never achieved fully suppressed viral load.
I think that this example shows that Dolutegravir monotherapy is much too dangerous, and that an omni-drug-class resistance is still possible after many years of ART.

Maybe it is also a question mark for quarterly injections. Dolute- and Cabotegravir are not indestructible as believed.
Dualtherapies are possibly not appropriate in the long run.

full story:
http://www.jiasociety.org/index.php/jias/article/view/19749/html

My dual clinical trial of Maraviroc/Prezista/r  already failed and was shut down.

Wow, poor guy.

[buginme2]

Doctor Lafeuillade and Professor Wainberg are not right anymore.

How's that?  This person wasn't on his first line therapy.