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Author Topic: Dr. Savarino et al's functional monkey cure  (Read 1601 times)

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Offline Tadeys

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Dr. Savarino et al's functional monkey cure
« on: December 12, 2013, 08:56:55 PM »
The following was presented during the 6th International workshop on HIV persistance in Miami last week....but this version is in Italian. Anybody care to give us a clue as to what it says?


http://www.hivforum.info/forum/viewtopic.php?f=24&t=2786

Offline Cosmicdancer

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  • Posts: 154
Re: Dr. Savarino et al's functional monkey cure
« Reply #1 on: December 12, 2013, 11:18:42 PM »
I dumped the text into an Italian to English translator, and here's the text... not a great translation, but hopefully you get the gist.

Researchers Andrea Sabherwal and his collaborator Iart Shytaj led a workshop in Miami called “Pharmacologically Induced Functional Cure-like Condition in Chronically Infected Macaques SIVmac251 is Associated with Immune Reconstitution and Broad Anti-Gag Immune Responses Increasing over Time” – it was a deepening of one already published last summer on the control that some macaques with chronic infection with SIV managed to keep on viremie after being treated with H-iART (tenofovir, emtricitabine, raltegravir, darunavir/r and maraviroc) auranofin BSO (butionina sulfossimina).  I took advantage of the kindness of Dr. Sabherwal to ask him to send me the slides and answer a couple of questions about the future prospects of his research.  First what I am able to draw from the slides, then questions.   Since the control of viremie is observed is associated with an increased immune response anti-Gag and occurred in the presence of CD8, deepening was analysis of the long-term evolution of the parameters is of viro-immunological macaques who responded to therapy "complete", both those who were treated only with H-iART, or with the addition of only auranofin.  Before being subjected to the treatment, all the monkeys showed immune response anti-Gag or low or even undetectable, while up to one year after the end of a single treatment cycle deluxe version levels of anti-Gag responses continued to grow over time. Cellular immunity directed against the Gag just seems to give a major contribution to the control of viremia.

Nothing like you've seen in macaques that have not received the BSO, or where this was administered separately from auranofin.  The macaque monkey that departed from the higher viral set point before the therapy remained in observation for a period of longer follow-up (one year) and presented a new set point (5 months) much lower than (log of 1.4 SIV RNA/mL of blood, with a decrease of 4.7 log compared to before therapy) – and this is consistent with the continuing decrease in the viral set point and the continuous increase of CD4, increase in anti-Gag-specific responses.

However, open questions remain, affecting substantially 1. A better definition of the mechanisms of action of this therapy, because what we have seen so far is that the ART auronofin decreases the size of the reservoir of CD4; that leads some auranofin a selective destruction of CD4 memory (both Tcm and Tem) and that the ART auranofin BSO improves immune cell responses-mediated anti-Gag (and this goes in parallel with the reduction of viremie); and finally that they observed correlations between the viremie control and neutralizing antibody titers.  2. a possible critical issue which had already been highlighted in the article last summer on Retrovirology is one that concerns the number of CD4 after treatment, because it is true that among the slides dedicated to mechanisms of action there is one that shows us how Macaque 4890 viral DNA and CD4 count is decreased and increased, respectively, during the period of follow up, but it is also true that in one out of three of the "functionally cured" macaques, CD4 remained very low and that in the article Sabi feared that this might be, on the model of some elite controller, a price – even if not too expensive-to be paid in order to keep the virus count under control. 

(slide)

3. we must still assess the long-term follow-up of viral DNA – and here you play the ability to control the virus and perhaps even get rid of it. The final question that Sabi arises is whether IN a SITUATION where the RESERVOIR DECREASES and immunity IMPROVES IT is POSSIBLE that the IMMUNE SYSTEM is ABLE to control The infection, EVEN SO FAR AS to ERADICATE IT.

(slide)

The total number of monkeys in the study, as well as those who have benefited from the comprehensive therapy, is still quite low.

(slide)

The conclusion of Sabi is that the results obtained from the use of "complete" can be interpreted as the establishment of a condition that can be defined by "functional cure", with a gradual improvement in the control of viremia during the follow-up period after treatment and with a period of remission of the disease after the end of treatment that is proving to be quite long.   In one of the slides you speak of "the healing potential of this type of treatment and we list three main points: 1. high scalability: the treatment lasts three months and all drugs can be taken by mouth (except the BSO, which must be infused); 2. Good safety profile: auranofin is used for years to treat rheumatoid arthritis and the BSO has been well tolerated in phase I clinical trials; the combination of the two drugs was well tolerated in mice and, along with the ART, have been well tolerated in monkeys; 3. Hospitalization required limited: they do not serve nor highly skilled health professionals, nor particularly expensive infrastructure.

As I said before, I took advantage of the availability of Dr. Sabherwal to ask him a few questions about the future of this research. And here are his answers.    ● When last July is released the article on Retrovirology, in the press release that accompanied it said you were planning the start of clinical trials for early 2014. Then in recent months, the letter to the Minister of health written by the President of the Association "Human Rights Desk," John D'agata, and the short exchange that followed they did think that there is still something that is blocking the start of clinical phase. Is this so? It is scientific, reasons of lack of funding or what else?

Unfortunately, I regret much to point out that in little Italy is explained by eminently scientific motivations. If the reasons for the lack of interest shown so far by the Ministry of health were just so I would like to ask, why the Ministry does not listen to my own group, which, for bibliographic indexes such as impact factor (a score assigned to the type of publications) is among the first in Italy in the field of HIV/AIDS, and perhaps the first if you standardize impact factor to the number of staff devoted to research. As an example, the results of clinical trials on "vaccines" Pediatric Tat and were published in the journal PLOS One, which has an impact factor of 3.7, much less than the maximum impact specialist magazines in the field of HIV/AIDS, which are AIDS, Retrovirology and PLOS Pathogens. There is a lack of General support, which not only affects the Ministry. For example, Iart Shytaj, the first author of three of our most important scientific articles, it was not considered worthy of receiving a scholarship in a public competition launched by ANLAIDS. Inter alia Iart was, for the second time, selected by an International Commission to speak at the Conference HIV Persistence during Therapy (held this year in Miami), among the world's leading experts, presenting a relationship in which we will discuss here.

Despite the distortions of some minor and some printing titlists, I never promised a cure for AIDS, but I felt that the results on monkeys deserved greater attention by various Italian institutions. Maybe to be considered you must shoot big promise miracles as have others, but I won't do it. For now, even in the light of the final results of the "Boston patients" and failure of clinical trial on vorinostat, announced by Timothy Heinrich and David Margolis at the Conference in Miami, the cure for AIDS at chronic stage does not yet exist, though, perhaps for the first time, there are promising strategies to start betting.

● I very interested to know something about how the trial will be set: • how many patients do you recruit?  • What are the conditions of inclusion and exclusion?  • The risk reported in article on Retrovirology that CD4 increase not much as a result of treatment with H-iART/auranofin/BSO may constitute a reason for excluding some patients? • What will be the end point of experimentation? • What are the deadlines?

a)   our original Protocol was to raise between 10 and 20 patients in a study "open label".
b)   patients should be under antiretroviral therapy with permanently suppressed viral load (the threshold should be the standard of 50 copies/ml). The kind of ART in which the patient is submitted shall not constitute probably reason for exclusion. At this early stage will be excluded patients with drug resistance mutations to antiretroviral drugs, those with renal disease and those with systemic lupus erythematosus (which may have adverse reactions to the use of auranofin).
c)   c) when the first phase of the clinical trial requires the suspension of therapy, will be given a short course of ART to the rebound of the virus (following the rationale of Shytaj et al. PLOS Pathogens 2012), in order to try to prevent the reconstitution of the viral reservoir is a possible decline in CD4. In any case, the data presented in Miami by Dr. Shytaj show that CD4 decline is temporary and that, combined with the drop in viral load and CD4, viral DNA can be traced back to normal (albeit slowly). Therefore the exclusion threshold based on CD4 levels won't be particularly stringent (probably around 500/microlitre of blood).
d)   end point are primarily testing the safety and tolerability of therapy. Secondly, the effects of treatment on provirale DNA levels in three months after initiation of therapy and, in third instance (but only if the necessary resources), the eventual verification of an effect on levels of viral set point after suspension of therapy after the addition of BSO.

The clinical trial will start in two foreign countries, as a "proof of concept" on the tolerability of auranofin ART and its potential impact on the reservoir. Following on from what I said before, given that, at least for now, the entire economic burden of experimentation will weigh on foreign funds, will be sampled only auranofin. It would be nice to also add BSO and suspend therapies, but what would a hospitalization that, no matter how short, would raise costs. I attend scientifically, but, having no say in the economic side, I will have to adapt to the decisions of others. It is therefore not possible at the moment, make predictions about the timing of the trial of auranofin and BSO. As for proof of concept study of auranofin, I expect (but I can't swear) that you can start in the first half of 2014 in at least one of the two countries (Brazil and USA). However I will not be the Director of studies, so I won't be able to recruit. I received during these months hundreds of messages from people living with HIV/AIDS and who want to make an improvement to their lives. Taking the opportunity of this interview, I mean Italian patients that I regret infinitely cannot give them the want information about the start of a clinical trial in Italy. Io ce l'ho messa tutta, but really the thing transcends all my control.

Are you considering the long-term follow-up of viral DNA? On what you will be working now? For example, you have to delve into the matter, you discussed in Miami, the role of cellular immunity against the Gag of SIV? If, as you have shown, anti-Gag responses stimulated by treatment with H-iART/auranofin/BSO are what allowed the good control of viremia in some macaques, there is no way to increase these answers? And promoting them in macaques that have not responded well to treatment?

This research branch is dealing with my collaborator, the above-mentioned Shytaj Iart. The project (that is not funded by ANLAIDS) also included follow-up to the viral DNA. If we succeed, we will work however on further characterization of the immune responses of macaque monkeys treated with auranofin and BSO (comparing it with that of some controls) and in General immune status analysis that accompanies the control of viremia following discontinuation of therapy (activation, proliferation marker etc.). We are also waiting for a US laboratory results of the sequencing of the virus that emerges in the various "blip" (which are then controlled by the immune system) to see if they are episodes of latent virus reactivation or if there is some reservoir of viral replication in low levels throughout the follow-up.

The idea of using what has been learnt about the immunity of these macaques to further increase these answers is interesting and we're thinking about. However, the data that we showed in Miami suggest that control of the viral load as a result of better therapy over time and so even under result recently posted by Louis Picker, it's important to continue the follow-up to see if, in the long run, the infection can be eliminated naturally by the immune responses that we have described. I would like to point out, however, that there are macaques that have not responded to combined cycle of ART/auranofin/BSO, both macaques undergoing this treatment have shown a long-term control of viral load and immune reconstitution. As the number of these Macaques are limited, the slide that precedes the conclusions show a statistical analysis indicating how to get 100% therapeutic success in  all macaques receiving auranofin and BSO (and only those, throughout the cohort) is most likely due to a real therapeutic effect and not to chance.
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
June, 2008 - undetectable, 612 cd4
January, 2009 - undetectable, 670 cd4
May, 2009 - undetectable, 593 cd4
Sept, 2009 - 83 vl, 763 cd4, 34%
Dec, 2009 - undetectable, 889 cd4, 32%
April, 2010 - undetectable, 860 cd4, 31%
October, 2010 - undetectable, 800 cd4, 38%
April, 2011 - undetectable, t-cell test not done
October, 2011 - undetectable
April, 2012 - undetectable, 850 cd4, 39%
November, 2012 - undetectable, 901 cd4, 41%
April, 2013 - undetectable, 846 cd4, 36%
October, 2013 - undetectable
May, 2014 - undetectable, 784 cd4, 48%
October, 2014 - UD, 1084 cd4, 48%

Offline Tadeys

  • Member
  • Posts: 162
Re: Dr. Savarino et al's functional monkey cure
« Reply #2 on: December 13, 2013, 10:06:48 AM »
Thank you cosmicdancer. This looks promising. Lets see how it translates into Homo Sapiens...

 


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