Absolutely Fascinating Study: Controlled Interruption of Treatment

[jmjm530]

The author of this study, Dr. G Lake-Bakaar, practices in the same group as the esteemed  Dr. Ira Jacobson. And while not presented as an approach designed to reach SVR, one only has to read between the lines to understand this is where he hopes the concept is headed, and indeed he did get one SVR out of the group. Perhaps with some tweaking, or the addition of something -- Alinia, Vaccine, PI, etc -- he can get the cycling to produce consistent SVRs. The beauty is that in theory one would only have to treat as many cycles as necessary, since new cycles are not started until viral breakthrough. This in effect could potentially minimize tx exposure to only that which is necessary not to mention the relief a "rest" mid treatment might bring. Obviously, not ready for prime time yet, and all study participants are professionally trained patients, so do not try at home ! G Lake-Bakaar has been tweaking this concept for a number of years and I have commented upon it in the past but haven't seen anything published for some time. It's definitely outside the box and that kind of thinking can only be good for all of us.
--------------------

Cyclical Treatment Interruption in Patients Taking Interferon-based Therapy for Chronic Hepatitis C

By Liz Highleyman

Periodic interruption of disease treatment may be an attractive option for a variety of reasons, including reducing drug side effects and costs. With antiviral therapy, some researchers have proposed that stopping treatment allows viral reproduction to resume and thereby repeatedly exposes the immune system to the invader, hopefully promoting a stronger immune response.

In the February 6, 2009 Journal of Clinical Virology, Gerond Lake-Bakaar of Weill Cornell University Medical College described a study of structured treatment interruption in patients with chronic hepatitis C.

"We have hypothesized that prolonged viral suppression partially reverses immune tolerance in chronic hepatitis C virus infection," Lake-Bakaar wrote as background. "Brief periods of treatment interruption can then simulate 'auto-vaccination' and evoke powerful secondary host immune responses."

The present study attempted to determine the effect of controlled interruption of therapy in patients who previously experienced relapse when treated with pegylated interferon plus ribavirin. After HCV had been maintained at an undetectable level for 2-8 weeks on treatment, pegylated interferon and ribavirin were briefly interrupted, with therapy restarting as soon as detectable viremia returned (cycle 1). After viral load was suppressed for at least a further 4 weeks, therapy was briefly interrupted again (cycle 2).

Results

    All 4 patients experienced relapse of HCV viremia within 2-4 weeks after the first treatment interruption in cycle 1.

    In Patient 1, time-to-relapse increased 7-fold with the second treatment interruption, followed by sustained virological response (SVR) with a third cycle of treatment interruption.

    In Patient 2, time-to-relapse increased 3-fold after cycle 2 and subsequent cycles.

    In this patient, serum ALT and bilirubin levels rose significantly during treatment interruption cycles 2 and 3, but returned to baseline levels when treatment was resumed; serum bilirubin rose to 12.3 mg/dl after the patient missed 2 doses of pegylated interferon during cycle 4.

    In Patients 3 and 4, time-to-relapse was unchanged after 3 consecutive treatment interruption cycles, but HCV viral load remained more than 1 log below baseline for up to 18 months in both.

Based on these findings, Lake-Bakaar concluded, "These observations suggest that controlled treatment interruption exerts significant control of chronic hepatitis C viremia."

Structured treatment interruption for hepatitis C patients should be researched more thoroughly before it is adopted, given the unexpected outcomes of interruption of antiretroviral therapy for HIV.

While some early studies suggested that HIV treatment interruption might stimulate the immune response, later findings -- including results from the large SMART trial -- indicated that treatment interruption was a hazardous strategy, leading not only to a higher risk of AIDS-related opportunistic infections and death, but also a greater likelihood of serious non-AIDS heart, liver, and kidney disease, perhaps related to systemic inflammation triggered by ongoing HIV replication.

At this time, it is unknown whether ongoing HCV replication might have a similar effect, or whether starting and stopping treatment might have a detrimental impact on liver disease progression.

2/10/09

Reference
G Lake-Bakaar. The effect of controlled therapy interruption in chronic HCV infection: Enhanced host immune response? A hypothesis. Journal of Clinical Virology 44(2): 149-151. February 6, 2009. (Abstract).



http://www.hivandhepatitis.com/hep_c/news/2009/021009_a.html

[willing]

I dug up the paper I was referring to above:
http://www.ncbi.nlm.nih.gov/pubmed/19104424
which I believe was earlier  posted  by mike.

They followed 131 patients of whom 45 had pre-transplant IFN exposure.The overall finding was that patients who had txd prior to transplant had a poorer post-transplant prognosis:

"When patients with rejection were censored, patients who had received IFN before transplant had more frequent HCV recurrence, HCV disease-free survival and a trend toward overall decrease in patient survival. It appears from our data that IFN use before OLT should be evaluated as a possible factor in HCV poor outcomes after liver transplantation."

The same finding was also reported in one of the references they cite:
http://www.ncbi.nlm.nih.gov/pubmed/17256784

Not sure this data sheds  direct light on the approach suggested above, but it does indicate that viral exposure to ifn does not necessarily have an effect that weakens the virus and strengthens  the host.

[Andiamo1]

Yes, rest periods would surely feel good!  My wife and my friends would second that - LOL.
Eric

[jmjm530]

Thats probably why you only see 4 patients :) Anyway, I'm glad the doc put it out there, but like you suggest he may have to go the rest of the way alone or perhaps a like-minded medical soul will try something similar with their patients. I don't want to completely undermine the ethics question here, but for someone who had a difficult time with treatment sfx the first time around, and who might not re-treat for that reason -- this approach does offer some mitigating benefits by offereing "rest periods" (time off the drugs). Boy, I could have used a few rest periods when I was treating. Boy!!!

-- Jim

[Andiamo1]

Unfortunately, this type of study will be an orphan when it comes to funding.  The companies producing the SOC drugs have no incentive to fund it: they already have FDA approval and the result of this study might reduce their revenue.

I think the study would be as expensive as any of the PI studies currently underway.  It would require a control group and a study group of size x, where x is large enough to smooth the variables (race, age, length of time infected...).


Eric

[jmjm530]

I agree that this very small study (I'd probably call it more of a "work in progress") has a long ways to go before it proves anything, but apparently the author felt he had enough to get the info out among his peers. Indeed, that may have been part of his intent to spur further interest in this concept so it might be further researched and developed. I simply found the concept fascinating and found it refershing that someone is exploring avenues somewhat outside what everyone else seems to be doing.

Willing, we will have to disagree a bit about interferon resistance. I do think  in fact one treatment wears out the virus and the following treatment finishes the job -- but if not certainly does not impede. I've seen no evidence to the contrary. As to the week 4 test, I'll just take some of your comments tongue in cheek here, as I'm certain you would test minimally at week 4. Of course, I'd probably be suggesting the 24-hour test then which will give us room for debate :)

-- Jim

[Andiamo1]

I think the study is very interesting and thank you for posting it.

Willing did raise an interesting point: there are two very complex variables; the virus and its mutability on one side and our immune system on the other.  The question then becomes which one gains the most by this treatment.  While it is possible that the virus does not gain anything, it is not known at this point.

Given the enormous variability of responses to treatment, future studies will have to be large and complex in order to sort out all the variables.

Fascinating - thanks again for posting.

[willing]

no disagreement actually - it does seem a very interesting approach. One of the most interesting points about it is that the author had to be quite confident he was not doing his patients disservice by subjecting their virus to selection for ifn-resistance.  Since we just celebrated Darwin's 200th, it's worth remembering selective pressure is real - you wouldn't want to try this protocol with an antibiotic.

Whether viral inability to develop ifn-resistance has or has not been firmly established is unclear to me. Certainly successful re-tx by relapsers doesn't support that claim; re-tx dosing/duration  almost never  follows the original  protocol and thus can't be compared with it.

The idea seems worth investigating  though, like re-infection and vaccine candidates it might be a tad safer to try it in chimps first eg
http://www.ncbi.nlm.nih.gov/pubmed/11391537
particularly since this 'structured interruption' approach has been shown not to work in hiv.

Also, collecting  better data would help establish his claim. Finding that a geno 2 SVRed on 8wk tx or time-to-relapse diminished in patients 1 and 2 (but not 3 and 4) isn't quite proof beyond a reasonable doubt. For an example of careful tracking of  immune response  CD4/CD8 profiles, in this case  comparing  who did/did-not go chronic after needle-stick exposures see eg
http://www.ncbi.nlm.nih.gov/pubmed/11714747

It being Valentine's and all I wasn't going to bring up VL tests, but since you mention it, it appears that *finally* there is a clinical decision predicated on results of a pre-w12 VL. That Jacobson'09 review of dosing/duration makes a clear recommendation for testing G2/3s at W4 and not abbreviating  24w tx if not RVR. Give it another few years and maybe even 1s will finally get a reason (other than curiosity ) to test early..

[jmjm530]

Willy,

Thanks for your balanced and open outlook, but keep in mind that the doc did get one SVR out of four so it wasn't just a viral reduction. As to the ethics, one can question many trials because by their very definition they are trials. One can even question recommendations to treat when some doctors I believe are paid a fee for getting someone on treatment. The best solution to the ethics issue is to become as educated as you can so you don't have to worry about the imperfect mind in the white coat, and believe me they are imperfect. I remember being pitched a trial by one liver specialist only to have him back down -- quite quickly I must add -- when I asked the right questions in terms of what might be best for me. Since he had that info before the pitch, it might have been nicer/more ethical had he not mentioned the trial, but he has slots to fill and no doubt is being paid for the trial as well, not to mention departmental pressure, responsiblities, etc.

-- Jim

[Willy50]

Thank you for posting the study Jim; it certainly is fascinating and brings up a host of questions.  Good questions for scientists but answers may not be at hand immediately, particularly for dudes like me.  I don't claim to grasp it anymore than a dog understands how the food gets in the can.

..but....

I don't think that one can fully assess success based on viral load reduction..... or whether the lower viral load stays at that low count.  I'm not sure that this could mean the virus is "tamed" in any way.  It probably could be as infectious or damaging in spite of the lower count.  I think viral load is often used as a rough gauge in predicting the speed of response but it seems as though I have seen people with high viral loads drop quickly.... and the reverse; low viral loads that refuse to budge much from baseline with SOC.  So far as damage..... we know that viral load is not much of a tool for assessing that.  I'm always wary when I see the anthropomorphic terms like "tamed" being used with a virus, or how our immune response can become "educated" (another metaphor read long ago).  I think we use these terms to explain (to dogs like me) how the food "gets in the can" but that they may be woefully inadequate.

I DO think that it is an interesting study.  It may provide a deeper or suggest a deeper and more complex understanding of our viral response.  I'm not sure that doing a study this way is more irresponsible than treating numerous times.

Although I first posted a response that may seem *alarmist* I think that we have to be careful to not compare such studies to HIV; either the virus or in the treatments.  Both are quite different.  You can't do such things with HIV patients because they may get sick rather quickly and be unable to fight infections.  With HCV patients we tend to revert back to rather slow and longer term damage.  I believe that the resistance issues are more prevalent with HIV as well.

As many people as have treated....and numerous times if this virus was something that was going to mutate into something radical and nasty it probably would have done it long before this study came up.

Still..... I brought up some reservations, not so much to provide a view.... but to ask a question so we can better understand how these things work or don't work.  I assume that it is that same reason that Jim posted the study.

I do think that there are some ethical issues that to pop up on this board from time to time;

Under treatment during SOC (under dosing, premature termination, lack of appropriate use of PCR's, or appropriate use of rescue drugs for (*a slippery slope*) patients.
(or the reverse)....
Indiscriminate treatment of people who either could wait or who stand a very small chance of success.

Counseling the drawbacks of the above so far as they concern Protease Inhibitors; do people on trials know that a failure with current PI's may mean that this means of "cure" may be dramatically reduced if retreating?  (I'm not sure just how much this has been proven yet other than in petrie dishes)

For me there are some unsettling questions around trials;  in acquiring data which could help larger groups where are the boundaries of where the care for the patient transcends the goal of the "better good".  I have hoped that there might be a better parachute for those who fail in trials.  

Anyway.... I digress a tad from the original topic.  Thanks for the thread andf feedback all....

Merryb; thanks for scaring me.  ; )  I'm glad that you waited till after Valentines day was half over.  hahahahah

Willy  (the living, breathing and volitile container of what could be the next big thing in infectious viruses)  

Happy (post)Valentines day.....

[jmjm530]

Just to add a little, if you read the study carefully you will note that in order to enter "cycle 2" the patient had to respond to the interferon. In other words, a non-responder is limited to only one cycle which could be determined at a number of points, as early as week 2 or 4, or even 1. So that leaves only responders who "relapse" and while I don't know if Mike posted a study or not, the common wisdom is that once a responder, always a responder and therefore nothing to suggest that any "inf resistant" virons would flourish. In fact, it seems quite the opposite as many here have successfully treated after a relapse. Almost as if one treatment primed or trained the immune system so the next treatment could take over. This doc seems to be trying to create a microcosm of this action all in one treatment. Quite genious IMO if it works, which I think it might if something else was added liked Alinia or perhaps one of the vaccines under development. As the the ethics of this experiment, keep in mind only 4 people have been invovled and my guess is that they were chosen carefully with full disclosure. Perhaps, for example, they had a lot of difficulty with sfx the first treatment and therefore the "rest" periods in this approach may have been a reasonable trade off for an unproven theory.

[jmjm530]

What I find most striking about it is that they got past the ethics review board and tried it in humans rather than in chimp.
-------------
LOL. Why is it surprising that we don't see eye to eye once again. Do you still think the week 4 viral load test has no clinical relevance and that sensitive tests are unecessary. Happy V. Day :)

-- Jim

[willing]

thanks for posting - interesting study. What I find most striking about it is that they got past the ethics review board and tried it in humans rather than in chimp.  There would be no better way to select strains of ifn-resistant virions than to repeatedly select the subset able to withstand x weeks of tx, let that subset flourish and multiply, then repeat the process. That the host immune system gains more from this training than the virus says a lot about how difficult it is for the virus to develop ifn resistance; an encouraging thought for all us multiple txers. I believe mikesimon posted a study a while back that suggested an opposite effect, but I couldn't read it at the time and have since lost the reference. If anyone has it please post.

It's a shame they didn't collect data any CD4 data to support their hypothesis. If CTI actually helps control infection it should be possible to measure that in the breadth/depth of the CD4 response.

PS - on the topic of ethics review boards, it's interesting to compare this with PIs.  I remember an editorial by Pawlotsky that critiqued PI trials with low soc-dosage/duration as unethical exposure of patients to PI resistance.

[geterdone]

It dose not look promising as to its past record but I do wonder if there are any studies published or going on that once reaching UND be it at 4 weeks 8 or 12 that reducing the meds would still be effective during the lower killing cycle and then spike it back up to the original dosage going in to the end of the recommended treatment cycle. It would seem to me that once the major killing cycle is over there would be no reason to kill the patient by staying full force. But how would one accomplish this and what would be in the soup of ingredients?

jasper

[merryBe]

definitely every study I read going back all the way to pulsing INF alone, before riba was available, all producded the same results.....bupkis...

why beat the same dead horse all these years later would be my question.

if you'll allow me a dennis miller moment


knowing, than every bacterium and virus studied so far have adaptaive abilities, knowing some on an order of magnatude staggering to eveyr microbiologist and that especially inclused the retrovirus such as HCV/HIV...knowing that adapting produces the superstrains and is HOW germ warfare has been developing resistant strains, then why on earth would you want to give an inch to something you know will take a mile.

Most people don't know that the retrovirus has been observed mutating as often as every 20 minutes, but researchers should know better. Hit it long and hiit it hard is now the proven, and indeed the only tx that seems to be showing ever better results so why suddenly would they be looking for a way to undo that?  
What, make the patient more comfortable, and hope it doesn't turn into something MORE transmittable, MORE resistant?  When every bacterium, virus and insect becomes immune and indeed thrives in this scenario still they want to explore it?

It's kind of akin to why did the surge finally work in Iraq....because they put enough troops on the ground to finally scour out all the little buggers....and now we have 4000 women just elected to office in Iraq.   Why?  Because we blasted the bugs out with a surge. Would cutbacks have done this?  NO.

same idea here, germs adapt. You want them gone you must overwhelm them with force and give them no rest or quarter to hide in. Allow a let up, they muster and rearm, coming out stronger. It's as true on the microbe level as on the human level.

I mean, I understand that maybe what the research wants is to stop the suffering, and I'm in week 71 of tx....feeling like a cheesgrater has been taken to my soul....so I'm all in favor or reducing suffering.
But they need to consider at what COST. All the attempts to reduce dosages could be building our own immune resitance as jm suggests, but it could also be what has allowed the newer more resistant strains.....I think 1 genotype as 10 sub-types now...
it may be only a matter of time before one of these new strains breaks the blood barrier and becomes fully transmittable through mucous and saliva and ergo an airborne disease. The big fear of the CDC, homeland security and others in the know about viral mutations is the very real concern that some things formerly not pnumonic may become or be engineered that way very soon. (In the British news last week, 40 alqueda died of bubonic plauge in a cave along the border...the question was, did they die of bubonic, or pnemonic....had they bioengineered an stronger strain than the one that killed half of europe in the 1300's)  (of  course nothing was on the news here about all this).

meanwhile, keeping these little bugs we all carry under heavy artilley makes the most sese to me, and giving it enough rope to see if it will hang itself, or start doing lasso tricks is just wrong wrong wrong, not to mention risky, not to mention having produced no positive results in 10 years.

so thanks Willy, you are spot on, and thanks for letting me rant!

mb

[Tallahassee]

My starting viral load was always lower with each new treatment.
Thus, eventually, it was reduced from >20 million to 500 - 600 K.

All the best!

[Rockerforlife]

i know times are tough but heres a tune to help take the edge off


http://www.youtube.com/watch?v=0IRjl3SWC2U&feature=related

[Rockerforlife]

You are still a fighing warrior in my books....a hero,

[nygirl7]

I would think that undertreating the disease....and then stopping TX so that the microbe/ virii could reproduce and create more of their resistant selves would be one method.  


Well they do say this is true with the PIs and why someone like Susan was not allowed to treat again.  The concept as interesting as it is still scares the hell out of me and I wouldn't be in that trial group for nothin'.

I'm old fashioned just load me up on the poisons and watch me go.

[Rockerforlife]

I asked the study nurse that "would one be resistant to another round of tx after just relasping 3 yeras earlier with SOC ...shes say no...and that actually it helps with the new second round of tx because the liver more that likely is much better shape now...maybe this is why better VL reductions on second tx`s

[Willy50]

Thanks for the explanation.  I think that i will do some reading now instead of posting.  good policy for me since I don't know much here.....

My analogy explanation is that the virii may be come resistant to a drug such as PI's that only partially blocks/inhibits reproduction.  The ones that do not get effectively blocked may be resistant....reproduce and do an end run around the PI.

IFN stimulates immune response....which is infinately adaptive and therefore is also able to deal with variants.  The virii don't become resistant to IFN per se.  The thing that kills em is not a drug... but rather our immune response.

I still wonder if natural selection comes into play where treating with these drugs over and over on a virus which is characterized by it's ability to mutate and reproduce rapidly.  If it were the case...... one would not judge the prudence merely by noting if the treatment produced some SVR's.  If one was to create a more resistant virii in the process...... well.....that was what I was wondering about.

best,
Willy

[apache1]

Willy, here is a very crude analogy about SOC TX and PI resistance from a mutating virus.

SOC is more like submersing the viron under water and drowning it, where as PI's are more like a plug that fits in the nose and mouth of the viron not letting it breath, hence suffocating it.

We know the virus can mutate. If it mutates a really big nose and the PI plug doesn't fit anymore, well now it can breath again and it is immune to that PI that does not fit tight in its nose anymore.

But the virus will always need air, so if it is flooded under water(interferon) there is no mutating out of that. Again this is a very crude analogy.

So that is why HCV does not get resistant to inf.
Hcv and other virus do mutate into strains that no longer let the PI bind to there specialized configured slot on there hard shell, thus preventing the viron from duplicating.

Again, I am no microbiologist so this analogy is crude at best.

apache

[jmjm530]

The author himself has put forth strong reservations in the abstract, above. I still find the study both fascinating and promising but that doesn't mean I'm convinced this will work and neither is the author. That said, he did get one SVR out of four and what appeared to be a tamed virus in the other three. Maybe not so bad for a work in progress.

-- Jim

[Willy50]

Ya got to love board censors........

Son of a pregnant dog.

Willy

[Willy50]

Jim....if you say so.  : )  On the other hand this is a novel approach and so I wonder if the outcomes could differ?

I know that HIV and HCV are different and distinct but I believe that resistance to treatment is an issue with that virus; one keeps needing new and different drugs.  It is clear to me that PI's are far more prone to resistance issues than SOC..... but you are not suggesting...or is anyone suggesting it cannot/ does not happen?  The old..."if it doesn't kill you it makes you stronger" I thought did apply to this virus as well.

I didn't understand the principle as it applied towards current SOC treating HCV .  I rather thought that the chances of retreating dropped partially due to this issue; not just eliminating the fast responders from the retreating group.  Or....what then is a viral breakthrough?  I have thought that the virus in part may mutate around the SOC treatment.  Maybe that only occurs where PI's are involved?

Just because I don't grasp it doesn't mean the guy isn't on to something.  Probably the chance of success is inversely proportional to my ability to grasp the concept.  ; )

Flguy; I shouldn't even joke about such things or we may not be allowed in swimming pools this summer.  

Facinating idea Jim; I'll have to get out my "**** and Jane" viral primers and get to work....

best,
Willy