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Author Topic: Treatment Intensification Doesn't Work - DUH!@  (Read 2488 times)

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Offline Inchlingblue

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Treatment Intensification Doesn't Work - DUH!@
« on: March 03, 2011, 10:33:44 PM »
I have to vent here. With precious few research dollars out there why do some studies continue to be funded for things that have already been shown not to work in previous studies? It boggles the mind.

CROI: Five-Drug HIV Therapy No Better than Standard

BOSTON -- In a disappointing result, intensified antiretroviral therapy for acute and early HIV had no effect, a researcher said here.

After 48 weeks of treatment, patients getting five drugs and those getting the standard three had equivalent levels of HIV RNA particles in their blood, according to Martin Markowitz, MD, of the Aaron Diamond AIDS Research Center in New York City.

There was also no difference in a range of measurements of the immune system, Markowitz reported at the Conference on Retroviruses and Opportunistic Infections.

"I was disappointed," Markowitz told a late-breaker session, "because I had hoped we could go further with antiretroviral therapy than we have."

Continued . . .

All due respect, Dr. Markowitz but have you been following HIV research in the past few years?



Am I missing something here? Tim? Anyone? Maybe this particular study was only those with "acute" or "early" infection? It's still ridiculous. Stop it already with the intensification studies involving HAART.

Offline Assurbanipal

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Re: Treatment Intensification Doesn't Work - DUH!@
« Reply #1 on: March 04, 2011, 09:35:49 PM »
1) Is the point of recent studies really that intensification does not work?  Seems to me it works particularly well if one is partially resistant to meds.  And, as in this study, it can drive viral load down faster.  Instead the interesting point of the recent studies is that intensification will not drive viral load levels down beyond a certain point in chronically infected people, implying that at a certain point replication stops and the amount of HIV measured in the blood is due to release from reservoirs.

There is a lot of interesting work to be done as to why that level differs for different people, whether/how it varies over time and whether that means anything for treatment.

2) Science works off replicable findings.  You only know they are replicable if someone funds studies that replicate them.  This may sound pedantic, but there are a number of real world instances in the recent past where studies based on fraud or manipulated or misunderstood data made it into top level peer-reviewed journals.  Also, one needs a data set of sufficient size as well. There's a lot of work being done in the research community to do a better job of getting funding for and a process to replicate results of important studies.

3) It is interesting to have studies that bridge the gap between PEP and chronic infection.  At some point there is a cross over -- this study of acute infection shows it is very early and that even if you treat with drugs that prevent HIV integrating into the cell DNA it is too late to substantially affect subsequent measures of infection.

« Last Edit: March 05, 2011, 01:56:30 PM by Assurbanipal »
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%
2014 VL UD - 48
2015 VL 130 Moved to Triumeq

Offline Tim Horn

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Re: Treatment Intensification Doesn't Work - DUH!@
« Reply #2 on: March 05, 2011, 11:46:20 PM »
I think what's important about the data presented by Marty Markowitz is that they sort of complete the "maximal suppression" picture. Other studies have looked at intensification in the true sense of the word -- adding Selzentry and Isentress to a standard antiretroviral regimen, several months after the standard antiretroviral regimen was started.

What Markowitz's group did hasn't really been tried before -- starting five drugs targeting several different points in HIV's life cycle (entry, reverse transcription, integration and maturity) at the same time -- in the acute/early phase of HIV infection, potentially before the virus has had a chance to ravage the immune tissue in the gut and established infection in long-lived memory CD4 cells.

It didn't work, at least not the parameters Markowitz reported at CROI. As Assurbanipal said, viral load did drop faster in those taking a five-drug regimen compared with a three-drug regimen, but this didn't make any difference with respect to single copy viral load results after 48 weeks of treatment.

His group may, however, find something when they begin looking at what happens in the gut after 60 to 72 weeks of treatment -- it could be that five-drug therapy did a better job at protecting gut-associated lymphoid tissue than three-drug therapy. They'll also be looking at the amount of residual virus being produced by resting memory CD4s in the blood after 96 weeks of treatment.

They might find an important difference -- or they might not. But this study definitely needed to be conducted, if only to confirm what others have only been able to suggest.

Offline coolstone25

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Re: Treatment Intensification Doesn't Work - DUH!@
« Reply #3 on: March 06, 2011, 07:11:10 AM »
Noteworthy was that all three virological failures happened in the 5 drug arm at 48 weeks. (!!!)

Also, the time of cross over between PEP and chronic infection suggests that very early in the infection, there is an establishment of reservoir and integration of proviral DNA in long term memory CD4s and haematopoetic stem cells, so the provirus is already integrated and once that happens, there's nothing that can be done(I dont know why you(assurbanipal) suggested, that no integrase inhibitors could help(its obvious once the provirus is integrated!). No wonder PEP fails sometimes once the provirus is already in an ill-fated long term memory CD4 cell DNA or bone marrow stem cell DNA.

Unless there's any study that establishes, that HIV post-fusion/entry but pre-proviral-intergration in cells and tissues in-vivo can stop an entire systemic infection by raltegravir, clearly.

I am hoping i haven't misunderstood any crucial data. Corrections and elucidations gladly invited. :)

Offline coolstone25

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Re: Treatment Intensification Doesn't Work - DUH!@
« Reply #4 on: March 06, 2011, 07:18:05 AM »
I think if this study suggests anything at all, viral protein activated or transduced anti-hiv RNAse and HIV sequence specific excisional DNA topoisomerase recombinant enzyme encoding genes might need to be constructed to rid the stem cell reservoirs for a complete post-integration therapeutic cure... immunological network and signalling is still such a hazy subject.

Offline Inchlingblue

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Re: Treatment Intensification Doesn't Work - DUH!@
« Reply #5 on: March 06, 2011, 09:39:14 AM »
Other very respectable researchers have definitively shown that treatment intensification has no effect on residual viremia and if that alone was what Markowitz set out to prove, it's already been done.  The way the results of Markowitz's study were reported implied this was its primary endpoint. I get that one-quarter of those studied were in the acute infection stage and I suppose this made it novel (along with using five drugs from five phases of HIV's life cycle).

The quote that follows is from Robert Siciliano at Johns Hopkins, from February 2009. I don't think a researcher of his caliber would make such a definitive statement were he not convinced of it's accuracy:

Really, the definitive experiment that people in the field have been proposing for a long time is to intensify therapy -- take a patient who is doing well on treatment and add a fourth drug, and see whether this trace amount of viremia goes down any more.

We have done this in collaboration with John Coffin and others, and it turns out that it doesn't. What this means is that we have already reached the theoretical limit of antiretroviral therapy. 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.



When reading the results as reported in MedPage Today I found it frustrating because this isn't the first time I've come across a study that seems to basically repeat past studies.

Add to that, the quote from Scott Hammer, MD, chief of infectious diseases at New York-Presbyterian/Columbia University Medical Center, who did not find the results surprising since in patients with chronic infection, "study after study after study has shown you do not reduce the residual viral load" if treatment is intensified, Hammer said.

And add to that the fact that Markowitz was himself surprised, saying something that implied he wasn't aware of past studies: "I was disappointed," Markowitz told a late-breaker session, "because I had hoped we could go further with antiretroviral therapy than we have."  Why would anyone familiar with the existing research by Siciliano, Coffin and others be led to believe we could go further with ARV therapy? The opposite would have been a surprise: had his results showed intensification lowered residual viremia.

I'll give Markowitz the benefit of the doubt and hope he finds something noteworthy (maybe, as Tim says, with respect to GALT).

I would think after this the book will be closed on treatment intensification as it applies to residual viremia.
« Last Edit: March 06, 2011, 04:46:46 PM by Inchlingblue »


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