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Author Topic: HIV-1 replication affected by raltegravir intensification of HAART-suppressed su  (Read 4719 times)

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Offline loop78

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Quote
HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects

Highly active antiretroviral therapy (HAART) results in potent and durable suppression of HIV-1 viremia. However, HIV-1 replication resumes if therapy is interrupted1, 2. Although it is generally believed that active replication has been halted in individuals on HAART, immune activation and inflammation continue at abnormal levels3, suggesting continued, low-level viral replication. To assess whether active replication might be driving immune activation in HAART, we examined the impact of treatment intensification with the integrase inhibitor raltegravir on viral complementary DNA and immune activation parameters. In the presence of raltegravir, linear HIV-1 cDNA is prevented from integrating into chromatin and is subsequently converted to episomal cDNAs4, 5. Raltegravir intensification of a three-drug suppressive HAART regimen resulted in a specific and transient increase in episomal DNAs in a large percentage of HAART-suppressed subjects. Furthermore, in subjects with these episomal DNAs, immune activation was higher at baseline and was subsequently normalized after raltegravir intensification. These results suggest that, despite suppressive HAART, active replication persists in some infected individuals and drives immune activation. The ability of raltegravir intensification to perturb the reservoir that supports active replication has implications for therapeutic strategies aimed at achieving viral eradication.

Source: Nature Medicine Journal

Press Release in Spanish

I'm a bit puzzled by this study, because it seems to challenge the current paradigm about HAART, i.e. that undetectable = no viral replication and that residual viremia it's just the virus coming out from the reservoirs. It also seems to contradict the evidence of the lack of signs of viral evolution in HAART suppressed people...

It would be interesting to know on what kind of regimen the people from that study were before raltegravir intensification, as the effects reported seem more posible to me in a PI based regimen than in a NNRTI based one.

Offline veritas

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loop78,

I don't believe that the current paradigm is that undetectable viral load = no viral replication. What HAART does is supress viral replication to a very low level. If viral replication was eliminated completely, one would be non-infectious with a viral load that was undetectable. I believe there are documented cases whereby transmission has occured between an HIV+person(with ud viral load) and  HIV- person.
Remember that about 98% of your virus is not freeflowing in the blood and the virus is readily detectable in semen, tissue, and other body compartments. When the virus breaks out of these hidden sites, viral replication intensifies again activating your immune system (inflamation).

Ral seems to further perturb these reservoirs, causing the virus to break-out. This is  good because it is the first step on the road to viral eradification as the study suggests. The virus becomes vulnerable to HAART.

v

Offline loop78

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Maybe you're right, veritas. It seems clear we have yet much to learn about this disease.

It was from something that Fauci said in an interview that I thought that replication in HAART suppressed people was just virus coming from the reservoirs:

Quote
Do they stop replication, or are our tests unable to detect replication below 50 copies/mL?

No. The tests can detect down to a single molecule of HIV RNA. What happens in patients who are doing well on current treatment -- and I'm not talking about raltegravir; I'm just talking about standard HAART [highly active antiretroviral therapy] -- is that the level of viremia is between 1 and 50 copies/mL. If you add another drug, it does not go any lower. What that means is that most of that viremia is not susceptible to further inhibition. In other words, we have already reached the maximum potential of HAART. You cannot do any better. The reason is that that virus, in the plasma, is coming from a stable reservoir. It's a cell that was infected before HAART started.

And this excerpt from Siciliano:

Quote
So what this means is that what HAART actually does is to reduce the level of viremia to a new plateau that is just a little bit below the limit of detection of current, clinical assays. Now the explanation that is usually given for this residual viremia is that it reflects ongoing cycles of viral replication that are occurring, but just at a lower level due to the presence of the drugs.

Now this is a very disturbing scenario because ongoing replication in the presence of the drugs will inevitably lead to the evolution of resistance and treatment failure. Fortunately, there is an alternative hypothesis. We believe that in the optimal situation, HAART actually stops all ongoing viral replication and that the residual viremia that patients experience is simply a reflection of the release of the virus from stable reservoirs, cells that were infected prior to the initiation of therapy, for example, those long lived memory T cells that I mentioned. And you might imagine that every day some of those cells become activated and they begin to produce virus, and that virus cannot go on and infect other cells because of the suppressive effects of the drugs. However, it can be detected as HIV RNA in the plasma. (...)

And what is particularly interesting is that in this patient, almost all of the viruses in the plasma are identical to one another representing a single virus species that has been captured in the plasma in multiple, independent blood samples over a three year period. And we have seen this same sort of phenomena in about half of the patients studied, where the residual viremia is dominated by a small number of viral clones. And these clones do not show evolution over time, and most interestingly, we cannot find these clones in resting CD4 positive T cells, suggesting that they are coming from another source.

Offline mewithu

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Interesting, are we making our selves worse then by this regimen.
1997 is when I found out, being deathly ill. I had to go to the hospital due to extreme headache and fever. I fell coma like,  two months later weighing 95 pounds and in extreme pain and awoke to knowledge of Pancreatis, Cryptococcal Meningitis, Thrush,Severe Diarea,  Wasting, PCP pneumonia. No eating, only through tpn. Very sick, I was lucky I had good insurance with the company I worked for. I was in the hospital for three months that time. 
(2010 Now doing OK cd4=210  VL= < 75)
I have become resistant to many nukes and non nukes, Now on Reyataz, , Combivir. Working well for me not too many side effects.  I have the wasting syndrome, Fatigue  . Hard to deal with but believe it or not I have been through worse. Three Pulmonary Embolism's in my life. 2012 520 t's <20 V load

Offline veritas

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mewithu,

Your quote:  "Interesting, are we making our selves worse then by this regimen".

Absolutely not !  You want to get rid of as much virus as you can and by activating resting cells you are making them vulnerable to HAART eliminating them from your body. In theory, if you activate all the reservoirs while on a strong HAART regimen, you can eradicate HIV from your body. Less virus is better.

v

Offline Hellraiser

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I was under the impression that HAART slows the disease's ability to replicate to a point where our body can actually handle it.  Whereas without the drugs some people's systems are just overwhelmed by not only the amount of virus in their system but all the debris that begins to buildup as a result of Tcells being destroyed as well as junk that the virus just sheds in the process.

Offline veritas

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Hellraiser,

Your quote: "I was under the impression that HAART slows the disease's ability to replicate to a point where our body can actually handle it."

If that were true, then all we would have to do is get our vl to undetectable and then we could drop HAART.
Not so. The virus attacks our immune system, the very mechanism that is supposed to kill it. Only LTNP's have that special something (appropriate antibodies) that seem to keep the virus under control and yet even they have ongoing viral replication and inflamation since in most cases their vl is not ud. Your immune system can do a wonderful job at getting rid of "debris", but for most, can't stop hiv viral replication.

v

Offline Hellraiser

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Not necessarily.  If your body can handle some amount of the virus. say 50 cells a day or something, and under HAART the virus only produces 20 instead of the 1000 a day it would without HAART.  Get what I'm saying?  I have no idea if I read this or if I'm just rationalizing how I think your body reacts to the medication.  Your body isn't completely helpless against the disease it's just overwhelmed by it.

Offline veritas

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Hellraiser,

Without the appropriate antibodies, those that can attach to the constants on the virus like the proteins gp41 and gp120 or the exposed phospholipids, your immune system can't handle the virus due to viral mutation. For most of us, we cannot produce the appropriate antibodies to do the job. I believe what you are referring to is wild-type virus upon initial infection which our immune systems can seem to handle for a time until the virus overwhelms the cd4s produced  by the body by using them as replicating machines. The virus replicates faster than the body can make cd4s without HAART.

v

Offline Inchlingblue

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As loop78 has mentioned, according to Siciliano (and others) residual viremia is not due to active replication but rather virus entering the plasma from pre-existing viral reservoirs.

Chomont, et al. have found:

The second reservoir is harbored by TTM cells and is the main reservoir in individuals with low CD4+ counts, the majority of whom are characterized by persistent immune activation....we observed that plasma IL-7 concentrations inversely correlated with the decrease of the reservoir size over time. these results indicate that IL-7 is responsible for the persistence of latently HIV-infected CD4+ T cells by promoting homeostatic proliferation of memory CD4+ T cells, resulting in the quantitative and qualitative stability of the HIV reservoir....

"Homeostatic proliferation" is the replication of some of the CD4 cells that harbor HIV, this is not the same as active viral replication but it may contribute to the persistent immune activation.

There have been raltegravir intensification studies in the past (in which they take people on a successful 3-drug HAART regimen and they add raltegravir to see if the reservoirs are activated) that have found no impact on latent reservoirs but the one that's the subject of this thread apparently has found that raltegravir can activate (or as they state it "perturb") reservoirs.

I'm not sure if the conclusion drawn by these researchers regarding ongoing viral replication is accurate. They're saying that because immune activation was normalized after raltegravir intensification, that suggests active replication persists in some infected individuals, despite HAART. It might be too soon to draw that conclusion, especially in light of what Chomont, above, has found vis a vis homeostatic proliferation being the cause of persistent immune activation. As an aside: I find it concerning that many researchers don't seem to be aware of previous research/data, many of them seem to be working in their own vacuums.

I think whether or not active replication persists in some individuals despite HAART, the fact that this study shows raltegravir can perturb some reservoirs represents good news and as the abstract states, "has implications for therapeutic strategies aimed at achieving viral eradication."

LINKS:

http://www.thebody.com/content/toparts/art50467.html#commentAdd

http://www.natap.org/2009/HIV/062609_01.htm


The Spanish press release states that they're undergoing five additional studies examining intensification strategies that could possibly lead to reservoir eradication.
« Last Edit: March 15, 2010, 12:44:47 PM by Inchlingblue »

Offline veritas

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Inch,

Viral replication is constantly going on in the gut  even with HAART:

http://www.natap.org/2009/CROI/croi_134.htm

v

Offline Inchlingblue

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Inch,

Viral replication is constantly going on in the gut  even with HAART:

http://www.natap.org/2009/CROI/croi_134.htm

v

What I don't get is that these two seemingly contradictory pieces of research (from Siciliano and from Degray) were both presented at the same conference, CROI 2009. Did nobody question this? Is there something we're missing?

As with Siciliano, Chomont's research, which I cite above, also did not find active viral replication in the presence of HAART.
« Last Edit: March 15, 2010, 05:00:50 PM by Inchlingblue »

Offline veritas

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Inch,

I believe they were looking at different reservoirs. Degray et  al. were looking at cd4s situated between gut and tissue near the gut in the link I provided. Chomont et al.were looking at the TCM reservoirs. This virus is a lot more complicated then we realise.

The aforementioned is another reason that I believe that any therapeutic that is going to be successful must go after that portion of the virus that is constant everywhere.

v

Offline Inchlingblue

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Inch,

I believe they were looking at different reservoirs. Degray et  al. were looking at cd4s situated between gut and tissue near the gut in the link I provided. Chomont et al.were looking at the TCM reservoirs. This virus is a lot more complicated then we realise.

The aforementioned is another reason that I believe that any therapeutic that is going to be successful must go after that portion of the virus that is constant everywhere.

v


Siciliano states in no uncertain terms, We will never reduce viremia any further using antiretroviral drugs, because this little bit of free virus that's in the plasma is not coming from new cycles of replication. It's actually coming from cells that were infected prior to therapy. And so, if we want to get rid of the virus, we have to deal with these stable reservoirs.

It's disconcerting that there seems to be a disconnect with what is being reported by respected researchers.

Offline Assurbanipal

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Siciliano's study was on all of 15 patients.

And even he says:

"Now we cannot exclude a small contribution from ongoing replication, but it is clear at this point that the major problem is the release of virus from stable reservoirs. So before I turn to how we find and eliminate those reservoirs, I would like to present some new research into the basic pharmacology of HIV drugs that helps us understand how it is that HAART can actually stop all ongoing viral replication. "

(see link posted above by Inchling)

The study loop cites talks about a "large percentage" showing an effect of intensification.  Not everyone.

So perhaps the group of undetectable patients is not uniform with respect to viral replication, but instead includes both those who are virally suppressed but with low levels of replication as well as those in whom replication has stopped?

This would also explain why some people who have gotten to undetectable have a viral load rebound -- they were undetectable, but still having some low level replication...
5/06 VL 1M+, CD4 22, 5% , pneumonia, thrush -- O2 support 2 months, 6/06 +Kaletra/Truvada
9/06 VL 3959 CD4 297 13.5% 12/06 VL <400 CD4 350 15.2% +Pravachol
2007 VL<400, 70, 50 CD4 408-729 16.0% -19.7%
2008 VL UD CD4 468 - 538 16.7% - 24.6% Osteoporosis 11/08 doubled Pravachol, +Calcium/D
02/09 VL 100 CD4 616 23.7% 03/09 VL 130 5/09 VL 100 CD4 540 28.4% +Actonel (osteoporosis) 7/09 VL 130
8/09  new regimen Isentress/Epzicom 9/09 VL UD CD4 621 32.7% 11/09 VL UD CD4 607 26.4% swap Isentress for Prezista/Norvir 12/09 (liver and muscle issues) VL 50
2010 VL UD CD4 573-680 26.1% - 30.9% 12/10 VL 20
2011 VL UD-20 CD4 568-673 24.7%-30.6%
2012 VL UD swap Prezista/Norvir for Reyataz drop statin CD4 768-828 26.7%-30.7%

Offline veritas

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A,

If you bring Degray's study into the mix (20 patients ), whereby all twenty had ongoing replication in the gut, the  hypothesis that some have no viral replication goes out the window.

Bottom line----- we don't know for sure, however, we do know that for right now if you stop HAART, your viral load rebounds and if you have a measureable viral load you have viral replication and inflamation.

We have a ways to go, unless they can find something that goes after both freeflowing and resting virus.

v

 

Offline loop78

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To add even more confussion to the mix, here is an excerpt of an interview wit J. Gallant about CROI 2010 published a week ago on thebody.com

Quote
The other type of intensification [we saw presented at CROI] was raltegravir. There was a twofold rationale for this. One was, again, looking at CD4 increases. There had been a little hint of CD4 improvement with earlier raltegravir intensification studies. That was not seen with these [studies at CROI, in which raltegravir intensification] didn't seem to make much of a difference in CD4.

The other idea was to see whether you could take people whose viral loads were under 50 copies/mL, but not under 1 -- in other words, they have some low-level viremia in that 0 to 50 range -- and further suppress it. The idea there being that maybe it's better to have a viral load of less than 1; maybe that would reduce inflammation and immune activation. But also because, from a pathogenesis standpoint, it would tell us whether or not there is ongoing replication of HIV despite therapy -- and that's a really important question.

Most of these studies have not shown any change. You take a person whose viral load is, let's say, 20, and you give him raltegravir, or other drugs. In almost all of the studies, we've seen no difference. What that probably indicates is that there really isn't viral replication going on. This low-level viremia that we see is probably not a function of replication, but a function of release of virus from reservoirs. That's good news, in the sense that we really are suppressing patients' viral replication with the therapy we have. But it perhaps also tells us that we're not going to be able to deal with eradicating reservoirs just with antivirals alone.

Offline Inchlingblue

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Loop, I think Gallant was referring to all the previous RAL intensification studies, which did not find any changes. This new study from Spain is the only one that seems to have found a change. I wonder what they did that was different? It would be interesting to get Gallant's opinion on it. I'll ask.

Offline loop78

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Yep, I know he wasn't referring to this last study in particular. But still...

I'll be waiting for his answer, inchling! :-)

Offline Inchlingblue

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Gallant has not yet responded but this article from amfAR explains the science more clearly and discusses the issue of viral activity or lack thereof in the presence of HAART.

Reducing HIV Growth to Zero
BY ROWENA JOHNSTON, PH.D., AND JEFFREY LAURENCE, M.D.

March 18, 2009—Since three-drug highly active antiretroviral therapy (HAART) became available in the mid-1990s, scientists have been debating whether intensifying anti-HIV treatment might be able to slow virus growth rates even further than HAART, or even eradicate the virus from infected patients. Although the debate remains far from settled, new data from a group of scientists, including amfAR-funded researcher Dr. Sarah Palmer, are thought provoking.


Dr. Sarah Palmer
In a research article released online in Nature Medicine, Dr. Palmer, from the Swedish Institute for Infectious Disease Control, Dr. Mario Stevenson, chair of amfAR’s Scientific Advisory Committee, and a group of scientists from Spain studied patients whose virus levels were already well controlled on standard HAART. Although these patients had virus levels deemed “undetectable” by standard medical tests, more sensitive laboratory assays revealed each patient had extremely low but measurable amounts of virus in their blood. The researchers set out to determine whether adding one more drug to the treatment regimen—a recent addition to the treatment arsenal called raltegravir—would lower even further the ability of the virus to grow.

Measuring changes in growth rates in extremely low levels of virus is a considerable challenge. To do this, the researchers took advantage of the way in which raltegravir slows virus growth: the drug does not prevent the virus from entering a cell or from converting its genetic material into DNA, but it does prevent the virus’s DNA from being integrated into the patient’s DNA.  They reasoned that if low-level viral growth was ongoing before the addition of raltegravir, then adding that drug would result in an accumulation of viral DNA inside infected cells, because the viral DNA would be unable to move on to the next step in the lifecycle, namely integrating into the cell’s DNA. Left out in the cold, this viral DNA assembles into 2-LTR circles, which Palmer and colleagues could find and measure utilizing a special test.

And find circles they did. Among 45 people who received raltegravir in addition to their standard drug regimen, 29 percent had an increase in 2-LTR circles inside infected cells. This suggests that although the patients’ virus levels had previously been extremely low, there may have been ongoing viral growth that was susceptible to further tamping down with raltegravir.

The fact that 71 percent of the subjects in this study did not show evidence of 2-LTR DNA when given raltegravir is good news. Most HIV positive individuals on HAART truly do not have active virus needing further attack. But these researchers suggest that for the one-third or so of patients who appear to have ongoing virus growth despite low levels of virus, intensifying treatment by adding raltegravir could be key to impeding the ability of the virus to grow and thereby maintain the viral reservoirs that stand in the way of HIV eradication.


LINK:

http://www.amfar.org/lab/article.aspx?id=8507&tr=y&auid=6088707

Offline loop78

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J. Gallant just posted his answer to the question Inchlingblue asked him (thanks, Inchling!), I'm posting it here for everyone:

Quote
Question:
I was reading your excellent CROI recap on thebody.com (thanks, by the way!). In part of it you discuss the various RAL intensification studies that found no significant changes in residual viremia. Apparently there is a new study out of Spain that has found a change. I wonder what they might have done that was different from previous studies. It was reported in Nature Medicine: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2111.html

Answer:
On Mar 21, 2010 Joel E. Gallant, M.D., M.P.H. replied:
The results of previous raltegravir intensification studies have mostly been negative, but you're right that this Spanish study showed an increase in episomal cDNA following intensification, which, unlike other studies, suggests that active viral replication persists in some suppressed patients. They also found normalization of immune activation, suggesting that active replication despite HAART is a cause of immune activation. Other studies, including a recent one from San Francisco, have had very different results.

I would say that the majority of studies have suggested that there is no ongoing replication on effective ART, which is why there is not benefit to intensification. However, I'm not dismissing the Spanish study. The jury is still out on this subject.

Offline veritas

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With Gallant's answer, the bottom line is they don't know yet exactly what happens when Ral is added to the mix, but it looks like it reacts differently in different populations of patients.

v

Offline Inchlingblue

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I find the article from amFAR, above, very informative. It seems that the answer to whether there is ongoing viral replication or not in the presence of HAART could be that in some people there appears to be viral replication (29% according to this study) and in others there appears not to be any viral replication (71% according to this study).

This explains why other studies have not found any ongoing viral replication, they were probably looking at people for whom there wasn't any, since those are in the majority.

 


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