POZ Community Forums
Main Forums => Pre-HAART Long-Term Survivors => Topic started by: farb on September 10, 2008, 07:48:25 pm
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I am a LTS/slow progressor (21 years) who didn't go on meds until year 9. I started with a cd4 averaging around 400 on a combination of azt, ddc and viracept. The results were positive (upping my average cd4 to around 600) but not spectacular. Somewhere around year 16, I began Trizivir and experienced a phenomenal response. My cd4s peaked at 1300 for the first 2 years and now hold at an average around 1100 with an undetectable viral load. (At that same time, my hiv doc was pushing Trizivir because of its compliance benefits.) I've always suspected that I may have a partial CCR-5-delta-32 mutation (after watching my partner's immune system totally collapse while mine stayed relatively steady--unfortunately he passed in 1997).
I questioned one of the local hiv docs (whom I only see once a year because of my improved status (with monitoring and labs by my GP every 4 months, and referrals back to the specialist when necessary), about a possible link between improved immune response, CCR-5-delta-32 and Trizivir. He kind of scratched his head, then did a quick mental calculation and estimated that approximately 10 out of his 55 or so patients are currently on Trizivir and continue with similar results as mine. Hmmmm.... it seemed obvious to me that somewhere there must be a link between response and treatment and genetic makeup. Although he didn't screen me for the mutation, I fit the profile (European descent of black plague prone areas)--and given the percentage of his patients that continue to show a similar response, it would seem that demographically we lucky few may fit into the estimated 15% who possess some sort of mutation. (I'm well aware of the cardiovascular risks associated with Trizivir, but given my response, I'm willing to take the risk.)
My BIG question is why isn't genetic screening more a part of diagnosis and treatment? It would seem to me that people could live longer, healthier lives if they were paired with the right medicine or combinations thereof right from the get-go! I've read a few articles on the POZ website which seem to indicate that a few scientists may be dipping their toes into these murky waters via laboratory tests, but are there any clinical studies going on out there with this purpose in mind??? And if not so, shouldn't there be? I am woefully unaware of how to raise a stink if this isn't happening already. Maybe I'm overreacting, but I can't help but think about other people like me who are watching (or have watched) the same things happen to their loved one as happened to mine... and that he might still be alive if his treatment wasn't based on guesswork.
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why isn't genetic screening more a part of diagnosis and treatment?
Good question (and very smart post), "farb"! Why almost nothing has passed from the research to the common clinical practice in the last dozen years (even Therapeutic Drug Monitoring is not ordinarily used)?
1996:
- HIV-RNA (with 500 copies/ml cutoff)
- Lymphocyte subpopulations
2008:
- HIV-RNA (with about 50 copies/ml cutoff)
- Lymphocyte subpopulations
- Resistance tests (with many limitations)
- Abacavir hypersensitivity test (quite recently)
- Trofile HIV tropism test (even more recently, thanks to Maraviroc)
No other significant change, if I remember rightly.
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The problem with things like CCR5 mutations (or, for that matter, any of the many other factors which are linked, with varying degrees of strength, to being a LTNP) is that none of them is consistently linked with slow / non-progression. They can screen you, but it still doesn't tell them how you will progress or respond to treatment.
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none of them is consistently linked with slow / non-progression
Right! So, why do they keep wasting time and resources with this kind of research, which has already proved to be clinically useless?
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leit, are you a long term survivor or even on meds?
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Right! So, why do they keep wasting time and resources with this kind of research, which has already proved to be clinically useless?
It hasn't proved clinically useless though. Entry (fusion) inhibitors are a direct result of the CCR5 receptor mutation research. The fact that we don't yet know everything there is to know certainly doesn't mean that we aren't continuing to learn from it. This is exactly this sort of research that is likely to deliver even more new treatment options and perhaps even effective preventative therapies.
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I was recently tested for the CCR5 receptor. It could make the difference whether or not the fusion inhibitors are an open class for me.
Leit, are you an LTS and/or on meds?
It's a question worth repeating.
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Entry (fusion) inhibitors are a direct result of the CCR5 receptor mutation research.
Sorry, but CCR5 co-receptor antagonists (Maraviroc, so far) are the clinical (relatively poor) fruit of CCR5 *existence*, not mutation!
Fusion inhibitors (Fuzeon, so far), then, have nothing to do with CCR5 (nor CXCR4).
This is exactly this sort of research that is likely to deliver even more new treatment options and perhaps even effective preventative therapies.
ALL genetic research on LTNP/viremic controllers/elite controllers yielded a lot of partial results = NOTHING!
The world needs A CURE asap, not stupid Geneva CERN "God particle" catcher-machines!
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I was recently tested for the CCR5 receptor. It could make the difference whether or not the fusion inhibitors are an open class for me.
Not the fusion inhibitors, but the CCR5 co-receptor antagonists (Maraviroc, so far)!
Leit, are you an LTS and/or on meds?
Yes/yes (already told, BTW).
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Hi,
My BIG question is why isn't genetic screening more a part of diagnosis and treatment?
Perhaps because right now there are no useful genetic markers that tell us anything.
But I sure wish there were.
My bf and I both had neg and poz tests in 2006, so we were infected that year. We have the same genotype and are pretty sure we passed the bug to each other, though it's not 100% sure who got it first - I believe I got it first, based on our respective sexual histories, but it's not really important WRT the genetic factors.
Almost 2 years later, my CD4 and VL numbers are still close to what they were at my initial HIV+ diagnosis. But my bf's numbers were not good from the start - around 300 CD4, 13%, VL 4000 was his initial number when testing poz - already AIDS, 6 months from his last neg test. 4 months later his VL went up to 30k, and his CD4 down quickly into the low 200s, and he had to start HAART. We have the same HIV doc now and he says the huge difference in progression speed between the two of us is probably attributable to genetic differences.
Unfortunately, there is no telling specifically what those genetic factors are. My bf is asian so he can't have any CCR5 delta32 mutation. I did the CCR5 test (from hivgene.com) and I don't have any mutation either. There are probably many other genetic factors yet to be discovered that affect the speed of HIV progression to AIDS. We just don't know what they are. And until we know more, we will have no idea how that knowledge could be helpful in treatment and diagnosis. I would certainly welcome more research in that area.
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nevermind
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Sorry, but CCR5 co-receptor antagonists (Maraviroc, so far) are the clinical (relatively poor) fruit of CCR5 *existence*, not mutation!
And just how do you really think that the researchers grew to understand these facts about genes and proteins? Looking into a crystal ball?
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Are you sure this isnt the Research thread?
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Peter (Staley) referred me to this thread and asked if I had any comment.
Here's goes...it's, erm. looooooong. :)
I have added reading material throughout for nerdy types.
On the question why isn't genetic screening more a part of diagnosis and treatment? to a degree it is, the HLA-B*5701 for abacavir sensitivity is basically a genetic test. Furthermore, some labs which do pharmokinetic (TDM) tests/research are now looking a genetic associations and drug metabolism (eg University of Liverpool pharmogenomic research unit has produced key papers on this topic eg African descent and metabolism of efavirenz and incorporates some screening into its combined TDM/resistance profiling).
Genetic and immunological (which is mainly genetic) make-up do influence disease progression. There's a wealth of material on this. But there has never been a big study to draw all the small lessons learned together. Partly because the current paradigm for HIV treatment does not consider intervention/management before combo in detail: treatment = combo at CD4 count of X, nothing before.
Plus how genetic factors relate to response to combo is not at all clear.
Hence no test/decision aid for the clinic/doctor.
A useful result for further research in this area would be mainly around what to do BEFORE combo/another treatment. This would add to the treatment paradigm, and therefore has a case for being researched. It seems possible to develop simple tests that would tell you who is gonna last and who is gonna crash. I would not be surprised to see more papers/studies looking at this in the next few years.
The extrapolation of this data to HOW TO DO combo for different individuals is unlikely to add much to the treatment paradigm, therefore unlikely to be developed -- except in terms of simple gene expression/haplotype which predicts hypersensitivity to particular drugs or drug classes.
But the science is horribly complicated, so, erm, deckchair and whisky perhaps in the meantime.
This is a neat report on some genetic factors that seem to affect disease progression:
Genetic factors affecting HIV infection and progression rates: immunological factors relating to entry inhibitors
http://www.i-base.info/htb/v6/htb6-7/Genetic.html
But, consider this review:
Optimizing Long-term HIV Treatment Strategies Through a Greater Understanding of Disease Pathogenesis
http://www.medscape.com/viewarticle/413059
Half-way down there's a big section on genetics/immunologics.
The review rather optimistically states:
"The availability of genetic testing in the clinic is rapidly approaching. In theory, understanding the genetic determinants of the steady-state level of viremia may provide important insights into the critical questions facing clinicians: when to start, when to switch, and when to stop combination antiretroviral therapy."
That was 2001.
Why hasn't this been developed? Good question...
Advocates have not really been pressing for research in this area, possibly because they have been pressing for better combo studies and hep C stuff. Perhaps now is a good time to select a new target.
In the UK we have just approved a study looking at anti-inflammatory treatment way before CD4 drops, part of which will look at how immune response differs between individuals.
A first step...
CCR5 is important not just for HIV binding but as an immune signal. It may affect disease progression, especially the delta mutation. There are tons of papers on this so I am not going to post any links. Let’s just say, the CCR5, delta- and other gene/immune property research is not concluded...
In passing CCR5-32 seems to have an impact on disease progression in hepatitis C:
The CCR5-32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source
http://gut.bmj.com/cgi/content/abstract/54/8/1157.
- matt
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I see a lot of "mays" and "coulds" in this thread, which may be one reason genetic testing and evaluation isn't more common.
The answer can be explained in two words; "Its expensive."
If there isn't a demonstrated benefit to the testing, insurance companies and, for that matter, government agencies are not going to pay for such testing.
I can still remember when viral loads were still considered experimental and many insurance companies refused to cover them until they were deemed standard of care.
HUGS,
Mark
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Are you sure this isnt the Research thread?
It's become one, yes.
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In the UK we have just approved a study looking at anti-inflammatory treatment way before CD4 drops, part of which will look at how immune response differs between individuals.
Great news! Could you please provide some details (which drug will be used, for instance)? Thanks!
P.S. I'm quite sure you already know this; anyway... http://www.medscape.com/viewarticle/575812
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the research thread would be great for this
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For trial details see here:
http://forums.poz.com/index.php?topic=23090.0
- matt