HAART holds back hypothesis-driven clinical studies aimed at viral eradication

[leit]

What are the structural barriers to performing work on HIV eradication?

There are many theoretical barriers which make it unlikely that HIV will ever be "cured". However, no one has argued that such an outcome is impossible. Given the unquestioned patient and societal benefit that would be associated with an effective cure, work in this area is clearly desirable. Why then have there been very few hypothesis-driven clinical studies aimed at viral eradication?

Regulatory hurdles. As outlined above, several groups have attempted to accelerate the clearance of HIV from an infected person. Some of these interventions have involved complex and costly interventions (e.g., gene therapy) while others have had high potential for harm to the study volunteer. The number of these studies seems to be waning. Although this decline may reflect growing pessimism over the potential for a cure, it is likely that the increasing regulatory barriers to performing clinical research may have resulted in such a harsh environment that few groups have the time and resources to perform the necessary clinical trials. The number of groups involved in overseeing clinical trials continues to grow; since each group has its own agenda and regulatory needs, it can take years for a clinical researcher to gain the appropriate approvals to begin a study.

The growing perception that treatment is highly effective in preventing disease should make it even harder to perform high risk/high gain studies in vivo. For an agent to be tried in vivo, the FDA and other groups will understandably want to see clear evidence that the drug is safe and well tolerated. This might preclude the use of a number HDAC inhibitors, since these drugs often have significant toxicity (most are being developed for the treatment of cancer). This may also preclude attempts at using immune activating drugs. The "cytokine storm" and its associated morbidity that was observed in a recent phase I study of TGN1412 (a potent anti-CD28 monoclonal antibody) raises a number of legitimate concerns for using pro-inflammatory drugs in otherwise healthy subjects. Since eradication studies generally require patients to have fully suppressed virus, and since such patients generally have a good prognosis, the risk/benefit ratio for potential study volunteer may make it difficult to justify anything but the safest interventions.

[...]

Source: aids2031 Working Paper No.7 - HIV Eradication: Is it feasible? - by Stephen G. Deeks, MD, University of California, San Francisco (the whole document is an excellent review, IMHO)

[hahaha]

I think if the barrier is THAT high in USA.  The only way is to do those clinical study outside the country.  Maybe Asia, south America or Africa will have a less stringent regulations compared to USA?  If it is so, we probably will only find a "cure" in those country instead because USA will never allow (or allow it too late) this happen.

[leit]

The only way is to do those clinical study outside the country.  Maybe Asia, south America or Africa

Would then those trials be valid for FDA and EMEA, too?

[freewillie99]

The only way is to do those clinical study outside the country.  Maybe Asia, south America or Africa will have a less stringent regulations compared to USA? 

That's an interesting point, hahaha.  It's crossed my mind more than once that countries like China or Korea, who are also technologically advanced but have far fewer tort issues (ie fewer greedy lawyers), and are less burdened with over regulation than we are here in the US, might have the upper hand in this regard.

[bocker3]

That's an interesting point, hahaha.  It's crossed my mind more than once that countries like China or Korea, who are also technologically advanced but have far fewer tort issues (ie fewer greedy lawyers), and are less burdened with over regulation than we are here in the US, might have the upper hand in this regard.

I'm not sure it all about lawsuits.  The basic premise of this thread is, I believe, the heart of the matter.  There is effective treatment (for most, but not all), so it would be somewhat unethical to put someone at risk for an unproven treatment when there are proven options available (with known risks).  I don't see having groups insuring the safety of study participants as a bad thing. 
I guess I also don't see that going to countries with less of an eye for patient safety as a "good thing", although, I know that it is likely to happen.
It is a conundrum, I admit -- I would love to see a cure, but I would not put myself into a "high risk/high gain" study while I had more proven options available to me.  So, if I wouldn't do it myself, I wouldn't advocate doing it to others (again, for folks with no options, it is a different story -- if I ever run out of options, I'll be first in line).
Mike

[Miss Philicia]

IThere is effective treatment (for most, but not all), so it would be somewhat unethical to put someone at risk for an unproven treatment when there are proven options available (with known risks). 

Exactly.

But better yet, why not have some of the members of this thread that ARE on HAART volunteer to stop and volunteer, instead of proposing that we get some naive saps from the jungle?

[freewillie99]

instead of proposing that we get some naive saps from the jungle?

Who's proposing that we enlist "naive saps from the jungle" to test dangerous treatments?  I'm simply suggesting that when you have a mountain of ever growing bureaucracy to navigate and tens to hundreds of millions of dollars to come up with to run a treatment through phases 1-3, someone who has less of a hurdle to clear perhaps has an advantage.

[georgep77]

Who's proposing that we enlist "naive saps from the jungle" to test dangerous treatments?  I'm simply suggesting that when you have a mountain of ever growing bureaucracy to navigate and tens to hundreds of millions of dollars to come up with to run a treatment through phases 1-3, someone who has less of a hurdle to clear perhaps has an advantage.

Agree with you freewillie99....by the way miss philicia, im a sap from the jungle, but not naive

[sharkdiver]

freewillie

are you poz?

[sharkdiver]

georgep

are you poz?

[leit]

why not have some of the members of this thread that ARE on HAART volunteer to stop and volunteer

The usual, trivial remark. Ideas and trials are missing, not volunteers!

[georgep77]

georgep

are you poz?

Yes sharkdiver.....im poz since 2008   

[leit]

Sorry to have to post this but, though not encouraging, it's an excellent review (perhaps still incomplete, unfortunately) of the medium/long term effects of HIV + "highly effective treatment" (a.k.a. HAART), and relevant "good prognosis".
That considered, I think it's time to move ahead, and in a hurry.

[bocker3]

The usual, trivial remark. Ideas and trials are missing, not volunteers!

It's actually not trivial at all.  The point of this thread seems to be that we can't have the high risk/high value studies on people in the US because of regulatory hurdles i.e. you can't withhold proven treatments to test a potential "breakthrough" without their knowledge and/or approval of some regulatory bodies.  Other posters were commenting on how it might be possible to do this in other "less regulated" countries.
What seems to be being trivialized is the possibility of hurting folks for scientific advancement -- when there are other, proven, options available.  We wouldn't want to withhold treatment from someone with syphilis just to see how the disease progresses now would we..... oh, wait -- that did happen!  Perhaps that has something to do with all the regulatory oversight.
Mike

[MitchMiller]

Along the same lines... remember the SMART studies... that took subjects off their regimens to see what would happen if TCells dropped to a certain level before restarting meds... would the subjects develop resistance leaving fewer options for future treatments?  would their immune system recover to the level it was before stopping meds?

Seems to me volunteers are always subject to a certain amount of risk when entering a study... even using existing treatments.   I was in the Epzicom study and was lucky enough not to end up in the Viread ARM (vs the Sustiva ARM).   Many of the subjects in the Viread ARM ended up resistant to Viread before GSK pulled the plug on that ARM.  The risk was thought to be minimal, but reality proved otherwise.

Personally, I'd like to see at least one of the TAT inhibitors go forward, especially given the recent article on the detrimental effects of TAT in the brain.

[hahaha]

I'm not sure it all about lawsuits.  The basic premise of this thread is, I believe, the heart of the matter.  There is effective treatment (for most, but not all), so it would be somewhat unethical to put someone at risk for an unproven treatment when there are proven options available (with known risks).  I don't see having groups insuring the safety of study participants as a bad thing. 
I guess I also don't see that going to countries with less of an eye for patient safety as a "good thing", although, I know that it is likely to happen.
It is a conundrum, I admit -- I would love to see a cure, but I would not put myself into a "high risk/high gain" study while I had more proven options available to me.  So, if I wouldn't do it myself, I wouldn't advocate doing it to others (again, for folks with no options, it is a different story -- if I ever run out of options, I'll be first in line).
Mike

Picture this,Mr. Bocker3,  a china HIV farmer who earns less than USD 70 per month, and he had three children and a wife to feed.  ( I mean it, it is NOT exaggerated).  He can not even survive for next meal. And you talk about the "risk of life" at that moment?   

Let us just face it, this world is NOT EQUAL.   Somebody will die because of hunger, and there priority is "MONEY", "FOOD" NOT "judgement of the risk".   If they are willing to exchange the risk for the next meal, which one stands for better moral?   

[komnaes]

Picture this,Mr. Bocker3,  a china HIV farmer who earns less than USD 70 per month, and he had three children and a wife to feed.  ( I mean it, it is NOT exaggerated).  He can not even survive for next meal. And you talk about the "risk of life" at that moment?   

Let us just face it, this world is NOT EQUAL.   Somebody will die because of hunger, and there priority is "MONEY", "FOOD" NOT "judgement of the risk".   If they are willing to exchange the risk for the next meal, which one stands for better moral?   

Oh yeah, indeed, and as long as this unequal-ness benefits you than it's OK. Alas it's already happening and with blessing from a lot of those regimes who couldn't give a rat ass to those poor pozzies. They're better off dead anyway and if they're already so poor that they cannot feed themselves, we might as well feed them a whole of lot of untested drugs and see how they thrive. I mean, really, they might be dead anyway tomorrow.

Too bad only YOU can see through this reality, while the rest of us worry about those small issues such as safety.

[bocker3]

Picture this,Mr. Bocker3,  a china HIV farmer who earns less than USD 70 per month, and he had three children and a wife to feed.  ( I mean it, it is NOT exaggerated).  He can not even survive for next meal. And you talk about the "risk of life" at that moment?   

Let us just face it, this world is NOT EQUAL.   Somebody will die because of hunger, and there priority is "MONEY", "FOOD" NOT "judgement of the risk".   If they are willing to exchange the risk for the next meal, which one stands for better moral?   

Preying on the needy will always fail the morality test - using the economically distressed because they are willing is obscene.

Now -- if you are talking about trying a "high risk/high value" type of study on individuals for who all other treatments have failed, then you have a case -- it's called "this or nothing" (of course, sometimes nothing could be the better option).  If there is oversight to insure that even these individuals are not being preyed upon, of course.

Mike

[Miss Philicia]

This thread is, indeed, amazing.  Amazingly sad.

[leit]

Since I started this thread, I'd like to clarify my position:
- I didn't mean to exploit anybody's difficulties in order to perform high risk/high gain studies in vivo.
- Nevertheless, I think that kind of studies is essential to move ahead - HAART is not enough.
- Though I wrote "high risk" above, risk is not always valuable beforehand. Please consider TGN1412 case: it did no harm in preclinical studies but, AT SUBCLINICAL DOSES, it made enormous damages at the very start of clinical phase I.

Bottom line: No risk = no progress, even if this doesn't mean that everything deserves to be tested in vivo, obviously.
On this point, let me recall Koronis' KP-1461 fraud: MAYBE KP-1461 was harmless, but it did absolutely nothing even in vitro (contrary to Koronis' claims!). Nevertheless, it progressed till phase IIa, when the scandal finally came to light.
So, how can we have unreserved trust in FDA's risk and gain evaluations?

[hahaha]

Oh yeah, indeed, and as long as this unequal-ness benefits you than it's OK. Alas it's already happening and with blessing from a lot of those regimes who couldn't give a rat ass to those poor pozzies. They're better off dead anyway and if they're already so poor that they cannot feed themselves, we might as well feed them a whole of lot of untested drugs and see how they thrive. I mean, really, they might be dead anyway tomorrow.

Too bad only YOU can see through this reality, while the rest of us worry about those small issues such as safety.

Of course is not me, and luckily, is not you.  I am on Haart for three years.   If my income is less than USD 70, and I do not have any medical care at all because I can not afford it and government do not support any.   Now here comes the chance that I may survive, without spending a penny on Haart.  I go to the doctor and doctor say:
"No, you can't, because it is not moral because there is risk".
Is this fair to that dying farmer?

 

[komnaes]

Of course is not me, and luckily, is not you.  I am on Haart for three years.   If my income is less than USD 70, and I do not have any medical care at all because I can not afford it and government do not support any.   Now here comes the chance that I may survive, without spending a penny on Haart.  I go to the doctor and doctor say:
"No, you can't, because it is not moral because there is risk".
Is this fair to that dying farmer?

Why should this farmer, as in your example, be given a choice that is essentially not a choice? Or, to put it another way, why the big pharmas should be allowed to take advantages of their poverty and just because their country would not give a flying fuck about them?

I mean they charge massively for new meds right? They claim that they involves lots of development costs, right? So, WHY the hell not paying a bit more to make sure those tests are also adhering to the same health and safety standards in those third world country as well? Or, WHY don't they commit to also provide proper medicines and pay for their care if they're willing to sign up for a risky test?

Your reasoning remains that those with no choice because of their poverty should be treated, er, excuse me, like shit and if it's to your benefits all the better. This blocks you from just adding a few things there - better transparency, still subject to high of health and safe standards, or to promise to provide care to those willing to take the risk.

Now THAT'S a choice. Won't cost them much, will it? And it won't cost you ANYTHING, and you can't even think of these few steps to take for this poor farmer?

And if you wish to reply to this PLEASE THINK harder first before repeating the same flawed example.

[frenchpat]

On the moral and practical aspects of this thread, an interesting read:

http://www.soniashah.com/index.php


Pat

[hotpuppy]

There is one really easy way to fix this.

Stop your HAART and volunteer.  Enroll in a study.

I would be more worried about taking people out of established therapy to expirement on them.  The US has an unacceptable history of expirementing on populations that are perceived as being marginal.

Remember, the Nazis did horrible expirements in the name of "science.".  The US did awful things to people at Tuskegee in the name of "science."  In Dutch Harbor, Alaska, the US government barried 10 tons of nuclear waste.... with the intent to blow it up.  When they changed their mind they decided to leave the waste, say nothing to the natives and see what happened.  That is unacceptable.

I volunteered for a drug study.  I'd be happy to give you pointers on the process if you need them.  There are some good studies out there that need patients.  My drug study is not a normal 3 drug study.  While I am taking 3 drugs, Norvir is a boost.  I'm only taking a PI and a EI (Entry Inhibitor).  Yes, there is some risk to it, but I'll fall back to established drug combos if this fails for some reason.  In the meanwhile, I'm doing what needs to be done to help.  They need people willing to take meds, adhere to them, not do drugs and drink like a fish, etc.

In Houston, they have been trying to recruit patients for a study on diarrhea... they can't get anyone to volunteer. 

Marginalizing others is not the answer.  Including those who are poor.  They have enough headaches in life to worry about.  Hell, most people who are poor have trouble just finding a doc, let alone getting to a study doc often.  We need to be working on prevention, testing, and treatment, period.  But especially in places like Africa, China, Russia, and the more developed countries. 

The future must include everyone or we will all suffer.  That is the lesson HIV will force Humanity to master.

[hahaha]

Why should this farmer, as in your example, be given a choice that is essentially not a choice? Or, to put it another way, why the big pharmas should be allowed to take advantages of their poverty and just because their country would not give a flying fuck about them?

I mean they charge massively for new meds right? They claim that they involves lots of development costs, right? So, WHY the hell not paying a bit more to make sure those tests are also adhering to the same health and safety standards in those third world country as well? Or, WHY don't they commit to also provide proper medicines and pay for their care if they're willing to sign up for a risky test?

Your reasoning remains that those with no choice because of their poverty should be treated, er, excuse me, like shit and if it's to your benefits all the better. This blocks you from just adding a few things there - better transparency, still subject to high of health and safe standards, or to promise to provide care to those willing to take the risk.

Now THAT'S a choice. Won't cost them much, will it? And it won't cost you ANYTHING, and you can't even think of these few steps to take for this poor farmer?

And if you wish to reply to this PLEASE THINK harder first before repeating the same flawed example.

What you have said is just like "water in thousand miles away to put off the fire in front of a man's eyebrow"
That is all I can comment. 

[bocker3]

Hey HaHaHa,

No one is saying that people shouldn't be allowed to take part in trials -- we are saying that there should be safeguards in place to insure that people aren't victimized by unscrupulous entities or individuals.  Are you really advocating allowing a free for all simply because there are some poor folks "available" due to a country that doesn't care about safety?  Perhaps there is someone who study involves watching how HIV would progress if left unchecked vs. if someone got a std. treatment.  The folks in the "no treatment" arm all WOULD be able to take the treatment (i.e. no resistance, etc), but we need a control arm, so........  their gov't doesn't preclude it, so no problems then?  I mean some folks are going to benefit here? 
This is pretty much what you are proposing

Mike

[komnaes]

What you have said is just like "water in thousand miles away to put off the fire in front of a man's eyebrow"
That is all I can comment. 

You realize this just sounds selfish and stupid right? If that was all you could comment you might as well save it.

[georgep77]

Cat fight.......  Meow !!!

             

[sharkdiver]

Cat fight.......  Meow !!!

             

Seriously,
that type of comment does not help

[komnaes]

Seriously,
that type of comment does not help

I have learned from observing long time ago that those who find it fun to watch cats/dogs fighting and even egging them on usually would get their asses bitten..

[georgep77]

I have learned from observing long time ago that those who find it fun to watch cats/dogs fighting and even egging them on usually would get their asses bitten..

Wooot !!!

[hahaha]

It is a meaningless catfight, so I give up my point of view. 
Maybe I am too much into "Will and Grace" and Karen Walker and Jack McFarland is my favorite.  So whenever they start "all men are equal......" and start laughing alll over, I just feel funny.

Apologize for my "naiive ignorance" to high noble men here......

[komnaes]

It is a meaningless catfight, so I give up my point of view. 

Your attempt to trivialize others arguments by calling the whole exchange a "catfight" without answering questions will only do your disservice hahaha.

Apologize for my "naiive ignorance" to high noble men here......

Why, I thought you had the "noble" idea that those poor farmers in China could at least get something by participating in high risk medical tests that no one is sure of any actual benefits to those participants ARE STILL BETTER than nothing, right? So how dare we to insist that there should be more safeguards for big pharmas to comply before they'd be allowed to run rampant in third world countries to conduct whatever tests that would be outright banned"?

The difference between you and I, hahaha, is that, despite a very very small part, I did even before my diagnosis involved in a campaign to raise funds for HIV+ patients in China, in particularly in villages where whole population were infected by selling their blood to centers using contaminated needles repeatedly. And I know first hand what it's like there, in the real world. It was more than 10 years ago - at the beginning local officials would hide those dying folks and reporters we arranged to visit those places were beaten up.

10 years later situations there have been improved, not as much as most of us want but at least the Chinese government is doing a bit more to provide health care to those "AIDS Villages", and they are beginning to do more on public education. Your Karen Walker's world view is funny in sitcom but we don't live in a sitcom world, maybe you do - attitude and policy changes come slowly and unfortunate many suffer, but at least things are moving in the right track.

Your displace of a complete lack of empathy by labeling this exchange a catfight one'd see in a sitcom and to be laughed at is just amazing sad.

[Moffie65]

For anyone to think that the United States of America doesn't already execute whole masses of people in drug testing and food modification all over the planet; is an exercise in fantasy.  These greed driven tests and corruption of the food supply from seed, has been going on since the fifties in countries which have surpressed populations.  To believe anything else is simply walking in the dark.

[David Evans]

Let's get this thread back on track. I think the point originally raised, which is a good one, is that the successes of HAART (and most people have to admit there are some successes, despite side effects and the like) have now made it difficult to design and conduct studies of new drugs and technologies that are very much different than HAART.

Some of the obstacles are ethics. Some of the obstacles are also structural. In fact, despite the sentiments of some in these forums, researchers universally tell me that trials of new strategies have become very difficult to recruit. Not only in the U.S., either.

But the primary obstacle is that getting a drug all the way through the development process currently depends on the investment and expertise of the pharmaceutical industry, and companies have been taking a step away from AIDS research, not towards it. Activists and independent researchers all over the world are currently working and advocating to try to keep promising research going. One activist, Martin Delaney, is almost solely responsible for getting Anthony Fauci at NIAID to acknowledge that research devoted to finding a cure for HIV needs to be given devoted resources at the NIH.

With the economy the way it is, everyone is going to be competing over the next three years for a very small pot of money. Perhaps one of the best things a person can do is to send letters to your congress persons and senators asking that novel high-risk/high-gain research be supported financially and structurally by the NIH over the coming five years, and to cc: those letters to Fauci at NAIAD.

People can also support groups like Project Inform and TAG, who are working behind the scenes to keep novel research alive, while also protecting the health and wellbeing of people living with HIV all over the globe.

Respectfully,
David