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Author Topic: A 5-drugs ART regimen induces long-term viral suppression in macaques  (Read 4896 times)

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Offline Skydrake

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Researches at the Istituto Superiore della Sanità in Rome, Italy, were able to achieve a long-term viral suppression and restriction of the viral reservoir in a Simian AIDS Model. The rebound following suspension improved the spontaneous containment of viral load following suspension of the second therapeutic cycle, thus leading to a persistent suppression of viremia in the absence of ART.

Eleven macaques were treated with a multidrug combination consisting emtricitabine, tenofovir, raltegravir,ritonavir-boosted darunavir and maraviroc, initially in order to study the effect of auranofin, which recently proved able to restrict the viral reservoir in vivo.
Dr. Savarino, leading the searching group, explains "in conclusion, we show, for the first time, complete suppression of viral load by highly intensified ART and a likely associated restriction of the viral reservoir in the macaque AIDS model, making it a useful platform for testing potential cures for AIDS"

Results available on PLOS Pathogens:
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002774
« Last Edit: June 23, 2012, 05:28:40 AM by Skydrake »

Offline LM

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That's an approach that has been suggested as a possible solution, since they had never tried an intensified ART, especially with something that could possibly bring the virus out of reservoirs. It sounds promising, I hope they get the funding to continue with it.

Offline Skydrake

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According to Savarino in this comunicate:
http://www.iss.it/pres/comu/cont.php?id=1265&lang=1&tipo=1
They are at the beginning, but all drugs are already  approved for common ARTs, so next studies and approvations can be very fast, and they are looking for external funding because the ISS can't provide it.
I remember that the ISS of Rome is conducting several studies about HIV vaccines (TAT vaccines of drs. Ensoli) and recently the budget has been drammatically cut by the Italian government.

Offline Skydrake

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Four-class, five-drug regimen given to monkeys shows signs of producing long-term viral load reductions off treatment

Gus Cairns
Published: 29 June 2012


An animal study (Shytaj) in which standard antiretroviral therapy (ART) was intensified by adding in drugs from other classes has shown signs that it may be possible, using antiretroviral drugs (ARVs) alone, to produce a permanent reduction in the pool of chronically infected ‘reservoir’ cells that are the source of the HIV that reappears when ART is stopped. Reducing the size of this reservoir is seen by many researchers as a crucial component of a possible cure for HIV infection.

The finding, by a team at the Istituto Superiore di Sanità in Rome, was unexpected: they had been testing whether a new monkey immunodeficiency virus called SIVmac251 more accurately mimicked both the pathogenicity and ARV susceptibility of human HIV than previously used laboratory viruses. The investigators hypothesise that the entry-inhibitor drug maraviroc (Celsentri), which blocks ongoing cellular infection by HIV, may be an essential part of this more profound viral suppression.

Their study was part of a series of studies which, in 2011, produced a prominent decline in the number of chronically infected reservoir cells by combining the five-drug ARV therapy with a gold-containing anti-inflammatory drug called auranofin (Lewis).

Methods

The current study was designed to look at the viral decay dynamics (rate of viral load decline) in rhesus macaques given an ARV regimen which was intensified by stages. Eleven monkeys were used in a series of experiments.

One of the features of this study is that the monkeys concerned had all been infected with SIVmac251 for 18 months before therapy was initiated, and several monkeys were already showing signs of CD4 cell loss, with counts in the 400-500 cells/mm3 range. In many previous monkey studies, therapy was started soon after the animals were infected.   

Initially, four monkeys were put on an escalating ART regimen. This started with tenofovir, FTC and raltegravir; a month later, boosted darunavir was added, and then six weeks after that, maraviroc. After this pilot phase, eight more monkeys were added: two on the four-drug regimen with darunavir; four on the full five-drug regimen with maraviroc; and two that were treated with boosted maraviroc alone for two weeks, followed by the other four drugs.

Two monkeys were then further selected for structured treatment interruption (STI) experiments. One of these was one of the four animals given escalating ART. This monkey’s regimen was then additionally intensified for three months with auranofin, after which it was taken off all drugs for a month, given two months back on the five-drug regimen without auranofin, and then taken off all therapy permanently. The other had previously been in the auranofin study, which included a similar escalating-ART regimen but with auranofin. It was then taken off ART for a month, given two months on the five-drug regimen, taken off again for four months, given a final two months of therapy, then taken off permanently.

Results

The first observation was that the addition of maraviroc further suppressed viral replication beyond that achievable by the four-drug regimen. SIVmac251 is more difficult to control virologically than HIV is in humans (because monkey immune cells produce about 20 times more viral particles) and the tenofovir/FTC/raltegravir regimen only suppressed viral load in one monkey out of the original four and, with added darunavir/r, in three out of four. All monkeys achieved undetectability on maraviroc. Adding in maraviroc increased viral load suppression from about 1.5 logs (a fifty-fold reduction in viral load) to about 3 logs (an 800-fold reduction).

In one case, a monkey in which treatment persistently failed to suppress HIV was found to have a higher viral load in its cerebrospinal fluid (CSF) than in its blood. It finally reached undetectability (in both blood and CSF) when the ritonavir-boosting dose was doubled: ritonavir facilitates drug transport over the blood-brain barrier. This finding provides interesting support for the hypothesis that a number of cases of treatment failure are caused by unsuppressed HIV in the central nervous system.

Secondly and unexpectedly, it was found that adding in maraviroc produced a continued decline in viral DNA – a measure of the number of infected cells rather than free virus. Normally, even on fully-suppressive ART, there is a residual viral load that stays fairly constant. The investigators found that under the five-drug regimen there was a slow but continued decline in viral DNA over 200 days of five-drug therapy, indicating that the proportion of circulating lymphocytes that were HIV-infected declined from 20 per million to four per million.

Thirdly, measurements in three monkeys of the subsets of T-cells that comprise the chronically infected reservoir of cells – the central-memory and effector-memory cells – found that in two out of three cases, the proportion of these cells relative to the total T-cell population declined over a period of four months, whereas naive T-cells, a subset not thought to be part of the reservoir, did not.

Fourthly, in four monkeys that were taken off therapy, it was found that the viral load ‘set point’ – the average viral load maintained off therapy – was lower than it was before therapy, in three out of four cases by about one log (ten times lower). The only experiments in humans that have managed to produce a permanently lower set point were in people treated in very early infection.

Finally, the two monkeys subjected to treatment interruptions not only maintained much lower viral loads when taken off therapy, but intermittently had undetectable HIV. The monkey in the original study that included auranofin, which was given three treatment interruptions, initially had a viral load of two million copies/ml but after the second treatment interruption maintained one of about 800 copies/ml, varying between undetectable and a couple of peaks of about 10,000 copies/ml.

The second, which had escalating ART, then three months on five drugs and auranofin, then two treatment interruptions, had a pre-treatment viral load of about 80,000 copies/ml and a post-treatment viral load that averaged about 250 copies/ml, varying between undetectability and about 4000 copies/ml. Neither showed any signs of breakthrough to higher viral loads within a time period of about 200 days.

Andrea Savarino, one of the investigators, told Aidsmap that the team is now optimising the treatment protocol in macaques. When asked if there would in his opinion be benefit in adding maraviroc to ART regimens in humans right now, he said "Yes, and human studies point in the same direction."

Source:

http://mobile.aidsmap.com/Four-class-five-drug-regimen-given-to-monkeys-shows-signs-of-producing-long-term-viral-load-reductions-off-treatment/page/2411367


Offline younghopefulpoz

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Offline songs06

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  • Posts: 114
well i think they really found something good. but it is too early to tell anything. really good article indeed.
18.03.2012 - infected.
14.04.2012 - first positive elisa - UD western blot
30.04.2012 - western blot confirmation positive
03.05.2012 - first lab- CD4: 256   VL: 2.3 M
01.06.2012 - sec lab- CD4: 390 (end of ARS)
01.07.2012 - third lab- CD4: 388 VL: 150.000
11.07.2012 - Started Truvada + Kaletra
04.08.2012 - CD4: 401 VL: 3800
30.09.2012 - CD4: 510 VL: 709
04.01.2013 - CD4: 650 VL: UD! (aka 20)
01.04.2013 - CD4: 460 VL: UD
09.2013 - CD4: 510
02.2014 - CD4: 490

Offline wherehope

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I read some papers before saying that intensive ART treatment didn't succeed.
Is this a different method? Bless something good...

Offline Skydrake

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I read some papers before saying that intensive ART treatment didn't succeed.
Is this a different method? Bless something good...

Usually, "intensive ART treatment" indicates an high dosage treatment (with 3 drugs), instead this has 5 drugs.
Most important, it includes Maraviroc. This drug works in a completely different method (it blocks CCR5 receptors).


Offline Dr.Strangelove

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One of the talks at CROI 2012 was by Prof Sharon Lewin. She briefly mentioned that there are some rare cases where people had been on ART for a long time and when they stopped taking it their body was able to control the virus.
I don't know if this is related to this but I guess the 5 drug approach is aiming in the same direction.

 


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