Aa
Help-tx drug tapering
Hoping someone can help (getterdone,cruel, Kalio-anyone?). I am trying to locate Hepatitis Researchers posts regarding tx drug tapering..I know he posted his thoughs on one of the large 100+ post threads we had going quite some time back and may have posted directly to one of getter's posts regarding this subject. Did anyone bookmark those threads or posts? Would be greatly appreciated if anyone can help....I'm still searching..thanks Pro
I hear ya! I keep thinking I forgot to take my meds and have moved them to another room as to make myself think what I have to take and not what I use to take, if that makes sense, last shot coming up. Have had some set backs but overall am feeling better and the two shall become one, once again and yeah, the energizer bunny is starting to thump with both feet and am glad spring is just around the corner for the day is near when I’ll stand atop the mountain and disarm my mantel as a sean form “Survivor”, as each article is peeled off in the remembrance of the battles fought and the mighty sword of battle may finally be laid to rest, fore only then will the helmet, weapons’, armor belt, forearm shields, breast plate, and finally the shin covers, of the burdens of my journey will be lifted but not forgotten.
Geterdone looks around? Hum… your ok. LOL!
jasper
Geterdone looks around? Hum… your ok. LOL!
jasper
72 week sentence - you got that right. Who would think we would beg to finish it?: Please don't make me stop!
If I had my druthers I would taper off the tx drugs, after my 72 week sentence is completed. But the fact is, you need the additional tx drugs to do it, plenty of riba left laying around, but no peg. So we will see what transpires. I hate to push to hard because I've been very fortunate in that my doc's office has already supplied me with a ton of additional drugs for me to complete my 72 weeks. So they not only would have to approve, but also supply..If I had access to the peg, I honestly don't think getting approval would be a big deal, and the additional 6 weeks of tapered tx would not be a big deal either...So we play it by ear.
Wassup, most of my blood results also come with what is indicated as normal ranges. But here is 2 links explaining the cbc blood tests and results that might help you (the Janis site also has a great section on Viral load test results as well):
http://www.janis7hepc.com/labs2.htm
Here is more general blood test info
http://www.labtestsonline.org/understanding/analytes/cbc/test.html#what
Wassup, most of my blood results also come with what is indicated as normal ranges. But here is 2 links explaining the cbc blood tests and results that might help you (the Janis site also has a great section on Viral load test results as well):
http://www.janis7hepc.com/labs2.htm
Here is more general blood test info
http://www.labtestsonline.org/understanding/analytes/cbc/test.html#what
Your approach to your tx is indeed quite proactive. Although much of what you said makes sense to me. I'm certainly not up on all the jargon. The up and comming acronym list that MedHelp is going to make available to us will help. It may have been you, (who posted), or you may know where to find, the Normal ranges of stuff on our blood tests. Not that this would mean a great deal to those of us who are considerably less knowledgable than you are. Could you please direct me and a few other newbees to this info. Thank you bunches, Ant B
im in the same spot as you, less than two weeks left, my recent shot was 25% for this week with one riba a day. it is truly strange to not have to take any riba at night. i have already started bouncing back tremendously on attitude and energy and feeling pretty normal. how bout you? i am so exited about feeling normal and
diong things again i can barely get to sleep!!!!! what a weird problem eh?
the warriors are coming home baby!!!!!!
diong things again i can barely get to sleep!!!!! what a weird problem eh?
the warriors are coming home baby!!!!!!
Agree with cruelworld, your taper will take a little longer but what the heck, after 72 at 120/1600 what is an extra 8 weeks. I don’t think it is unreasonable after such a long duration and a high dosage. Good Luck!
jasper
jasper
im doing a 6 week taperoff. im on my 4th week.
since we have been on such strong medicine for so long
i consider anything less than 6 weeks taper off too short.
would you want to try and lose 100 lbs in 3 weeks?
at least give it 6 weeks and more is better, a smoother transition.
since we have been on such strong medicine for so long
i consider anything less than 6 weeks taper off too short.
would you want to try and lose 100 lbs in 3 weeks?
at least give it 6 weeks and more is better, a smoother transition.
i didnt get to read all that but ill give you my short understanding of it.
1. shock versus smooth transition. sometimes you want the shock bltzkrieg effect
like at the beginning of treatment. i dont think you benefit from that approach at the end.
a shock is always harder on your body. this destabilizes your body when it needs to be able to fight.
2. antibiotics approach, this rule says that if you arent getting full dose the whole time
the medicine is not strong enough to kill the enemy so you have to take every full dose until you are done. and then quit cold turkey. or the enemy learns to defeat the medicine. our long hard hep c treatment doesnt fit into this formula in my opinion. except for the fact that you do need full dose for the allotted time period. then a taper off for purposes of smooth transition.
3. smooth transition, common sense tells you this is better. without a doubt
our immune systems are altered during treatment. give it a smooth transition back to normal operation. this is the most critical time of the whole treatment, this is when the
leftover virus tries to come back. maybe that 40% dose in the taperoff helps to
kill the last hurrah that your virus makes. this could be the difference between
svr and relapse. furthermore, i cant imagine in my wildest dreams any downside to the
taperoff. once you quit full dose, most of your fate is already decided but the taperoff
should give you an extra few percent with little cost.
1. shock versus smooth transition. sometimes you want the shock bltzkrieg effect
like at the beginning of treatment. i dont think you benefit from that approach at the end.
a shock is always harder on your body. this destabilizes your body when it needs to be able to fight.
2. antibiotics approach, this rule says that if you arent getting full dose the whole time
the medicine is not strong enough to kill the enemy so you have to take every full dose until you are done. and then quit cold turkey. or the enemy learns to defeat the medicine. our long hard hep c treatment doesnt fit into this formula in my opinion. except for the fact that you do need full dose for the allotted time period. then a taper off for purposes of smooth transition.
3. smooth transition, common sense tells you this is better. without a doubt
our immune systems are altered during treatment. give it a smooth transition back to normal operation. this is the most critical time of the whole treatment, this is when the
leftover virus tries to come back. maybe that 40% dose in the taperoff helps to
kill the last hurrah that your virus makes. this could be the difference between
svr and relapse. furthermore, i cant imagine in my wildest dreams any downside to the
taperoff. once you quit full dose, most of your fate is already decided but the taperoff
should give you an extra few percent with little cost.
......................................................(an abstract study)
Hepatology. 1996 Jul;24(1):21-6.
Improved sustained response following treatment of chronic hepatitis C by gradual
reduction in the interferon dose.
Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS.
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with
a high rate of relapse. IFN is thought to exert its effect against HCV via direct
viral inhibition and immune stimulation. We have hypothesized that relapse
following termination of therapy results from the sudden withdrawal of this
immune modulatory effect and that gradual reduction in the IFN dose may decrease
the incidence of relapse. One hundred six patients with chronic HCV were enrolled
into this 24-month controlled, randomized prospective trial. All were treated
with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who
achieved biochemical response were randomized to either stop or taper IFN
gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all
three times a week). 0.5 mU twice weekly and then once weekly. Liver histology
was assessed by Knodell index and HCV RNA was measured by a quantitative
polymerase chain reaction (PCR) assay. Of the 92 patients who completed the
initial 6 months of IFN treatment, 47 (51%) achieved biochemical response.
Twenty-one of these patients were randomized to stop IFN treatment and 25 to
taper (1 drop-out). At randomization patients were well matched with respect to
age, sex, race, serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN
treatment compared with only 60% who tapered IFN (P= .04).
Virological relapse
occurred in 90% of patients who stopped and only 48% of persons who tapered IFN
therapy.
At completion of the 24-month study patients who achieved long-term
sustained biochemical response had a significantly lower mean Knodell score (3.5
vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85%
vs. 18%) compared with relapsers.
We conclude that gradual reduction in IFN dose
is associated with a SIGNIFICANT HIGHER RATE OF SUSTAINED RESPONSE and clearance
of HCV RNA from serum compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology supporting the
premise that response to IFN therapy can prevent progression to cirrhosis."
...................................................
Hepatology. 1996 Jul;24(1):21-6.
Improved sustained response following treatment of chronic hepatitis C by gradual
reduction in the interferon dose.
Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS.
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with
a high rate of relapse. IFN is thought to exert its effect against HCV via direct
viral inhibition and immune stimulation. We have hypothesized that relapse
following termination of therapy results from the sudden withdrawal of this
immune modulatory effect and that gradual reduction in the IFN dose may decrease
the incidence of relapse. One hundred six patients with chronic HCV were enrolled
into this 24-month controlled, randomized prospective trial. All were treated
with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who
achieved biochemical response were randomized to either stop or taper IFN
gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all
three times a week). 0.5 mU twice weekly and then once weekly. Liver histology
was assessed by Knodell index and HCV RNA was measured by a quantitative
polymerase chain reaction (PCR) assay. Of the 92 patients who completed the
initial 6 months of IFN treatment, 47 (51%) achieved biochemical response.
Twenty-one of these patients were randomized to stop IFN treatment and 25 to
taper (1 drop-out). At randomization patients were well matched with respect to
age, sex, race, serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN
treatment compared with only 60% who tapered IFN (P= .04).
Virological relapse
occurred in 90% of patients who stopped and only 48% of persons who tapered IFN
therapy.
At completion of the 24-month study patients who achieved long-term
sustained biochemical response had a significantly lower mean Knodell score (3.5
vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85%
vs. 18%) compared with relapsers.
We conclude that gradual reduction in IFN dose
is associated with a SIGNIFICANT HIGHER RATE OF SUSTAINED RESPONSE and clearance
of HCV RNA from serum compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology supporting the
premise that response to IFN therapy can prevent progression to cirrhosis."
...................................................
thanks: I am sending some snippit quotes from you and george as well as hr's(keeping HR's annominity in tacked-his opinions presented speak for themselves..)
, plus the shiffman abstract along in my final headsup email..my doc is on vacation next week, but am hoping for a response prior to my appointment(1 week post tx) and prior to tx end. My NP (who is fantastic, already replied to my preliminary warning shot on Sunday(g))...Now I'm just shooting a little larger caliber in my final subject warning email (LOL)
this is what I listed as reference to begin the discussions,
"I agree that these are the biggest hurdles to overcome when deciding to taper. IFN is expensive and anything that exceeds "SOC" is typically frowned upon. This is sad, because the concept that abrupt stopping high dose IFN will lead to a temporary state of immunodepression and therefore vulnerability for relapse is fairly easy to accept. I have explained earlier, why this mode of stopping was not part of the registration trials, it was a matter of practicality. Extra protocols of patient training and compliance assurance, possibly additional testing requirements would have been imposed by the FDA on the trial performers, not to mention the extra time."
........................................
"Here is one more specific EXAMPLE how the Tcell effect depends on the presence of some Interferon: The presentation of the viral epitopes is performed - as described in detail in an earlier post- by the cellular proteasome and the class I MHC molecules that bind the peptide and bring it to the surface for recognition by the "cognate" Tcell receptors of the "cognate" Tcell patrolling the liver.
IFN has a strong influence on the intensity of expression - the number of proteins produced per cell - of the MHC class I proteins. Less IFN - less MHC, less presentations- less recognition - less killing of remnant virus infected cells, less general intrahepatic antiviral milieu by the gammaIFN secretion of these Tcells....
If you abruptly stop the enormous whipping up of the hepatocyte MHC production it will likely go into lower than normal mode for a while being so used to the whip...thus temporarily HCV remnants become invisible to the Tcell system."
......................................
Question by poster:
What would an example of a tapering schedule schedule look like ifor someone who had done 48 weeks of 15 mcg daily Infergen? 1/2 dose 1/3 or 1/4 and for how long? All strictly hypothetical.
Response:
"Each week one half of the previous dose would get you down in a "geometrical" fashion, as opposed to a linear one. 16mcg 8 4 2 1 1/2 1/4 Stop.
From patients reporting the "feel" of tapering down, each reduction feels quite good. As a matter of fact, some who stopped abruptly reported negative side effects from the counterswings of the system used to all that IFN. The point is, that tapering is not a useless extension of tx sides, but rather a gentle readjustment of the complex immune regulatory pathways directly or indirectly depending on IFN."
........................................
Question by poster
"When I complete my 48 weeks in the first week of February, I will have completed the SOC as prescribed by the doctor. BUT, rather than stopping abruptly as prescribed by SOC at the end of treatment, I will in the 49 week (Friday night) reduce the Interferon 180 by a quarter (3/4 injection) and drop the riba from 600mg evening dose to 400mg and continue the 400mg morning dose regime until the 50th week in which I will cut the Interferon to a (half dose injection) and reduce the riba from 400mg to 200mg (Friday night) and 200mg Saturday morning and follow through the rest of the week with that regime. In week 51 (Friday night) I will reduce the Interferon by another quarter dose and drop the riba to 100mg in evening and 100mg in am and continue that regime for the rest of the week. In week 52 (Friday night) I will take my last quarter shot of Interferon and no riba because of its half life which will decrease over the final week and beyond
response:
"This is a good tapering schedule IMO, except I would add one more 1/8 of IFN in the week 53. You must realize, that even 1/4 IFN is still a large amount of IFN. I have seen how people reacted to even 1/20 ! of Pegasys - still with quite noticeable IFN symptoms. Nothing wrong with sliding it out like stopping a car filled with delicately placed eggs......It does not cost, it does not hurt and it might do a lot of good....
It needs to be understood that when stopping IFN, a new form of antiviral defense against possible HCV remnants needs to take hold and establish itself - the adaptive Tcell response, that up to this point was greatly aided by the direct effect of IFN on the hepatocytes and the local intrahepatic immune cells. With this IFN aid gone all the burden is on the Tcell response, that will typically get stronger if more remnant viruses are seen ( if they can be seen now, because new epitopes are now present) - with incredible sensitivity, but it takes time to come to full swing and it can furthermore, at this very critical moment, be paralyzed by the prominent absence of innate signals needed to get adaptive Tcell responses going after IFN is abruptly missing from the equation."
continued (more than 8000 charecters)
, plus the shiffman abstract along in my final headsup email..my doc is on vacation next week, but am hoping for a response prior to my appointment(1 week post tx) and prior to tx end. My NP (who is fantastic, already replied to my preliminary warning shot on Sunday(g))...Now I'm just shooting a little larger caliber in my final subject warning email (LOL)
this is what I listed as reference to begin the discussions,
"I agree that these are the biggest hurdles to overcome when deciding to taper. IFN is expensive and anything that exceeds "SOC" is typically frowned upon. This is sad, because the concept that abrupt stopping high dose IFN will lead to a temporary state of immunodepression and therefore vulnerability for relapse is fairly easy to accept. I have explained earlier, why this mode of stopping was not part of the registration trials, it was a matter of practicality. Extra protocols of patient training and compliance assurance, possibly additional testing requirements would have been imposed by the FDA on the trial performers, not to mention the extra time."
........................................
"Here is one more specific EXAMPLE how the Tcell effect depends on the presence of some Interferon: The presentation of the viral epitopes is performed - as described in detail in an earlier post- by the cellular proteasome and the class I MHC molecules that bind the peptide and bring it to the surface for recognition by the "cognate" Tcell receptors of the "cognate" Tcell patrolling the liver.
IFN has a strong influence on the intensity of expression - the number of proteins produced per cell - of the MHC class I proteins. Less IFN - less MHC, less presentations- less recognition - less killing of remnant virus infected cells, less general intrahepatic antiviral milieu by the gammaIFN secretion of these Tcells....
If you abruptly stop the enormous whipping up of the hepatocyte MHC production it will likely go into lower than normal mode for a while being so used to the whip...thus temporarily HCV remnants become invisible to the Tcell system."
......................................
Question by poster:
What would an example of a tapering schedule schedule look like ifor someone who had done 48 weeks of 15 mcg daily Infergen? 1/2 dose 1/3 or 1/4 and for how long? All strictly hypothetical.
Response:
"Each week one half of the previous dose would get you down in a "geometrical" fashion, as opposed to a linear one. 16mcg 8 4 2 1 1/2 1/4 Stop.
From patients reporting the "feel" of tapering down, each reduction feels quite good. As a matter of fact, some who stopped abruptly reported negative side effects from the counterswings of the system used to all that IFN. The point is, that tapering is not a useless extension of tx sides, but rather a gentle readjustment of the complex immune regulatory pathways directly or indirectly depending on IFN."
........................................
Question by poster
"When I complete my 48 weeks in the first week of February, I will have completed the SOC as prescribed by the doctor. BUT, rather than stopping abruptly as prescribed by SOC at the end of treatment, I will in the 49 week (Friday night) reduce the Interferon 180 by a quarter (3/4 injection) and drop the riba from 600mg evening dose to 400mg and continue the 400mg morning dose regime until the 50th week in which I will cut the Interferon to a (half dose injection) and reduce the riba from 400mg to 200mg (Friday night) and 200mg Saturday morning and follow through the rest of the week with that regime. In week 51 (Friday night) I will reduce the Interferon by another quarter dose and drop the riba to 100mg in evening and 100mg in am and continue that regime for the rest of the week. In week 52 (Friday night) I will take my last quarter shot of Interferon and no riba because of its half life which will decrease over the final week and beyond
response:
"This is a good tapering schedule IMO, except I would add one more 1/8 of IFN in the week 53. You must realize, that even 1/4 IFN is still a large amount of IFN. I have seen how people reacted to even 1/20 ! of Pegasys - still with quite noticeable IFN symptoms. Nothing wrong with sliding it out like stopping a car filled with delicately placed eggs......It does not cost, it does not hurt and it might do a lot of good....
It needs to be understood that when stopping IFN, a new form of antiviral defense against possible HCV remnants needs to take hold and establish itself - the adaptive Tcell response, that up to this point was greatly aided by the direct effect of IFN on the hepatocytes and the local intrahepatic immune cells. With this IFN aid gone all the burden is on the Tcell response, that will typically get stronger if more remnant viruses are seen ( if they can be seen now, because new epitopes are now present) - with incredible sensitivity, but it takes time to come to full swing and it can furthermore, at this very critical moment, be paralyzed by the prominent absence of innate signals needed to get adaptive Tcell responses going after IFN is abruptly missing from the equation."
continued (more than 8000 charecters)
this is after studying the Pharmacokinetics of each drug, Interferon, Ribavirin, Procrit, and the duration time to c-max in serum level and plotting it out from the (Cmax) and the duration of each to clear they system in a step down matrix. Below is how I am doing my last 4 weeks of treatment.
BTW results from week 48 PCR Quantasure Plus test results I still remain at <10 UND - AST 21 ALT 17.
jasper
Done - Shot 50
135 INF - Friday
Riba 600 mg 1 am 2 pm Saturday through Monday / Tuesday Dropped to 400mg through Thursday.
Procrit .50ml 2x week Tuesday and Thursday
Done - Shot 51
90ml INF - Friday
Riba 400 daily 1 am 1 pm, Friday through Tuesday / Wednesday dropped to 200mg through Thursday.
Procrit .25 2x week Tuesday and Thursday
Doing - Shot 52
35ml INF - Friday
Riba 200 daily 1 in pm Friday through Thursday.
Procrit .25 once a week, Tuesday
Shot 53
1/8 INF Friday - LAST SHOT
No Riba
No Procrit
BTW results from week 48 PCR Quantasure Plus test results I still remain at <10 UND - AST 21 ALT 17.
jasper
Done - Shot 50
135 INF - Friday
Riba 600 mg 1 am 2 pm Saturday through Monday / Tuesday Dropped to 400mg through Thursday.
Procrit .50ml 2x week Tuesday and Thursday
Done - Shot 51
90ml INF - Friday
Riba 400 daily 1 am 1 pm, Friday through Tuesday / Wednesday dropped to 200mg through Thursday.
Procrit .25 2x week Tuesday and Thursday
Doing - Shot 52
35ml INF - Friday
Riba 200 daily 1 in pm Friday through Thursday.
Procrit .25 once a week, Tuesday
Shot 53
1/8 INF Friday - LAST SHOT
No Riba
No Procrit
I generally try and stray away from advice giving around here (seems to get me in trouble(g))...But something I have done throughout treatment, that I feel has been really helpful to me when dealing with my doc or np etc. and also helps me to avoid getting that feeling of tongue tiedness, medical intimidation, is to send them a headsup email prior to my appointments..Kinda of a next step up strategy from having a list when attending appointments...I send them a "warning" email of the direction I'm planning on steering our monthly appointments (once we quickly zip through the blood tests,chest and belly thumping,blood pressure, wieghing in etc.)...I figure I'm paying for an hour of their time, so I'm damn well going to use it for question and answering. So it is only fair to prepare them, supply them my questions, links to what I feel is relevant info or copy and pasted source material.It gives them time to gather together their response to my questions...keeps everyone on the same page so to speak....and if they aren't prepared, thay have no excuse imo and will suffer the rath of a high dose riba patient (vbg)
thanks jasper, that was one of the threads I found, as well as another you had started..
as you can tell, I'm getting closer myself to have "gottendone" (lol)..But I have decided to make my medical team work for their money, by posing a few challenging end of treatment questions.................;^) proactive (a cage rattler)
as you can tell, I'm getting closer myself to have "gottendone" (lol)..But I have decided to make my medical team work for their money, by posing a few challenging end of treatment questions.................;^) proactive (a cage rattler)
Here is the link I think your looking for.
http://www.medhelp.org/posts/show/393732?post_id=post_2325287
jasper
http://www.medhelp.org/posts/show/393732?post_id=post_2325287
jasper
and lastly
"Let us not forget that the real situation with respect to epitopes is never black and white, but there are numerous shades of "epitope quality" and, very importantly, epitope QUANTITY available for presentation/recognition. There are many dynamic equations going on simultaneously, with a net overall effect.
In this context considering the relevance of the intensity of nonstructural HCV protein expression and the extent to which those are being processd in proteasomes might be the crucial aspect ( Low MHC - too low presentation of an already nonabundant epitope class).
We can genrally assume that the nonstructural proteins - with quite a quantitative margin/difference even within that class have potentially less adapted epitopes/= potentially more reactive ones, because the number is small and they have not been selected against and because of higher structural/functional sequence constraints they are harder to mutate away from for the virus..
In HBV we have exaclty this situation, and it is well researched and proven : The Polymerase contains an abundance of good CTL epitopes, and the blood of acute and astonishingly some chronics contains quite reactive CTLs to those epitopes - yet no cytolytic action - no effective defense.
The reason for the insufficiency of these epitopes, that are well binding and effective ex vivo - is actually quite simple : there are very few polymerase molecules synthesized per cell and they are not typically processed into the class I pathway, so the hepatocyte surface only rarely shows even a single one of these epitopes.
So we have to keep this in mind.
Why by the way do we (or the mice in the model) still have CTLs agains these? Again, simple answer: The large amount of virion debris picked up by the peripheral dendritic cells will digest these remnants and - using class II to class I transpresentation pathways - will certainly mount a CTL response that you can find in the circulation - DOING UNFORTUNATELY NOTHING USEFUL.
Transfer experiments of these CTLs in the Chisari mouse model have confirmed that these highly active CTls working on well sticking epitopes do very little upon transfer to a recipient, while the CTLs directed towards an abundant epitope - like the eAg/core one - upon passive transfer - lead to fulinant hepatitis in the passive recipient!!
Thus the abundance AND presentation/intracellular processing of a nonabundant viral protein with potentially reactive epitopes is an extremely important variable in the understanding of the final "vigor/actual effectiveness" of a CTL/epitope pair.
I have detailed this thought,( that even Tcell vaccine developers sometimes are missing ( looking only at the "vigor" of the response as measured in the CTL assays) and not if these CTLs can actually find something where needed)
because it leads up to my current pet theory on how Nitazoxanide might actually work:
It causes misfolding of a substantial portion of viral proteins - including nonstructural ones.
This misfolding , as you know, will invariably lead to a redirection of a very substantial portion of the HCV protein processing into the proteasome - the garbage can of the cell.
Now these nonstructural epitopes appear on the hepatocyte surface in much higher numbers - and we have a new high quality CTL recognition/killing/noncytolytic local cytokine antiviral effect! "
"Let us not forget that the real situation with respect to epitopes is never black and white, but there are numerous shades of "epitope quality" and, very importantly, epitope QUANTITY available for presentation/recognition. There are many dynamic equations going on simultaneously, with a net overall effect.
In this context considering the relevance of the intensity of nonstructural HCV protein expression and the extent to which those are being processd in proteasomes might be the crucial aspect ( Low MHC - too low presentation of an already nonabundant epitope class).
We can genrally assume that the nonstructural proteins - with quite a quantitative margin/difference even within that class have potentially less adapted epitopes/= potentially more reactive ones, because the number is small and they have not been selected against and because of higher structural/functional sequence constraints they are harder to mutate away from for the virus..
In HBV we have exaclty this situation, and it is well researched and proven : The Polymerase contains an abundance of good CTL epitopes, and the blood of acute and astonishingly some chronics contains quite reactive CTLs to those epitopes - yet no cytolytic action - no effective defense.
The reason for the insufficiency of these epitopes, that are well binding and effective ex vivo - is actually quite simple : there are very few polymerase molecules synthesized per cell and they are not typically processed into the class I pathway, so the hepatocyte surface only rarely shows even a single one of these epitopes.
So we have to keep this in mind.
Why by the way do we (or the mice in the model) still have CTLs agains these? Again, simple answer: The large amount of virion debris picked up by the peripheral dendritic cells will digest these remnants and - using class II to class I transpresentation pathways - will certainly mount a CTL response that you can find in the circulation - DOING UNFORTUNATELY NOTHING USEFUL.
Transfer experiments of these CTLs in the Chisari mouse model have confirmed that these highly active CTls working on well sticking epitopes do very little upon transfer to a recipient, while the CTLs directed towards an abundant epitope - like the eAg/core one - upon passive transfer - lead to fulinant hepatitis in the passive recipient!!
Thus the abundance AND presentation/intracellular processing of a nonabundant viral protein with potentially reactive epitopes is an extremely important variable in the understanding of the final "vigor/actual effectiveness" of a CTL/epitope pair.
I have detailed this thought,( that even Tcell vaccine developers sometimes are missing ( looking only at the "vigor" of the response as measured in the CTL assays) and not if these CTLs can actually find something where needed)
because it leads up to my current pet theory on how Nitazoxanide might actually work:
It causes misfolding of a substantial portion of viral proteins - including nonstructural ones.
This misfolding , as you know, will invariably lead to a redirection of a very substantial portion of the HCV protein processing into the proteasome - the garbage can of the cell.
Now these nonstructural epitopes appear on the hepatocyte surface in much higher numbers - and we have a new high quality CTL recognition/killing/noncytolytic local cytokine antiviral effect! "
These are some snipits pulled from HR's posts on the tapering subject: anymore to add?
............................................
"I agree that these are the biggest hurdles to overcome when deciding to taper. IFN is expensive and anything that exceeds "SOC" is typically frowned upon. This is sad, because the concept that abrupt stopping high dose IFN will lead to a temporary state of immunodepression and therefore vulnerability for relapse is fairly easy to accept. I have explained earlier, why this mode of stopping was not part of the registration trials, it was a matter of practicality. Extra protocols of patient training and compliance assurance, possibly additional testing requirements would have been imposed by the FDA on the trial performers, not to mention the extra time."
...........................................
"It needs to be understood that when stopping IFN, a new form of antiviral defense against possible HCV remnants needs to take hold and establish itself - the adaptive Tcell response, that up to this point was greatly aided by the direct effect of IFN on the hepatocytes and the local intrahepatic immune cells. With this IFN aid gone all the burden is on the Tcell response, that will typically get stronger if more remnant viruses are seen ( if they can be seen now, because new epitopes are now present) - with incredible sensitivity, but it takes time to come to full swing and it can furthermore, at this very critical moment, be paralyzed by the prominent absence of innate signals needed to get adaptive Tcell responses going after IFN is abruptly missing from the equation."
........................................
"Here is one more specific EXAMPLE how the Tcell effect depends on the presence of some Interferon: The presentation of the viral epitopes is performed - as described in detail in an earlier post- by the cellular proteasome and the class I MHC molecules that bind the peptide and bring it to the surface for recognition by the "cognate" Tcell receptors of the "cognate" Tcell patrolling the liver.
IFN has a strong influence on the intensity of expression - the number of proteins produced per cell - of the MHC class I proteins. Less IFN - less MHC, less presentations- less recognition - less killing of remnant virus infected cells, less general intrahepatic antiviral milieu by the gammaIFN secretion of these Tcells....
If you abruptly stop the enormous whipping up of the hepatocyte MHC production it will likely go into lower than normal mode for a while being so used to the whip...thus temporarily HCV remnants become invisible to the Tcell system."
......................................
"If you do all the heavy lifting and want to shift it to another crew, you better transfer the burden gradually - the other party needs to come into function slowly.
Tapering IFN has indeed been compared to abrupt stopping:
Hepatology. 1996 Jul;24(1):21-6.
Improved sustained response following treatment of chronic hepatitis C by gradual
reduction in the interferon dose.
Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS.
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with
a high rate of relapse. IFN is thought to exert its effect against HCV via direct
viral inhibition and immune stimulation. We have hypothesized that relapse
following termination of therapy results from the sudden withdrawal of this
immune modulatory effect and that gradual reduction in the IFN dose may decrease
the incidence of relapse. One hundred six patients with chronic HCV were enrolled
into this 24-month controlled, randomized prospective trial. All were treated
with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who
achieved biochemical response were randomized to either stop or taper IFN
gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all
three times a week). 0.5 mU twice weekly and then once weekly. Liver histology
was assessed by Knodell index and HCV RNA was measured by a quantitative
polymerase chain reaction (PCR) assay. Of the 92 patients who completed the
initial 6 months of IFN treatment, 47 (51%) achieved biochemical response.
Twenty-one of these patients were randomized to stop IFN treatment and 25 to
taper (1 drop-out). At randomization patients were well matched with respect to
age, sex, race, serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN
treatment compared with only 60% who tapered IFN (P= .04).
Virological relapse
occurred in 90% of patients who stopped and only 48% of persons who tapered IFN
therapy.
At completion of the 24-month study patients who achieved long-term
sustained biochemical response had a significantly lower mean Knodell score (3.5
vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85%
vs. 18%) compared with relapsers.
We conclude that gradual reduction in IFN dose
is associated with a SIGNIFICANT HIGHER RATE OF SUSTAINED RESPONSE and clearance
of HCV RNA from serum compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology supporting the
premise that response to IFN therapy can prevent progression to cirrhosis."
...................................................countined
............................................
"I agree that these are the biggest hurdles to overcome when deciding to taper. IFN is expensive and anything that exceeds "SOC" is typically frowned upon. This is sad, because the concept that abrupt stopping high dose IFN will lead to a temporary state of immunodepression and therefore vulnerability for relapse is fairly easy to accept. I have explained earlier, why this mode of stopping was not part of the registration trials, it was a matter of practicality. Extra protocols of patient training and compliance assurance, possibly additional testing requirements would have been imposed by the FDA on the trial performers, not to mention the extra time."
...........................................
"It needs to be understood that when stopping IFN, a new form of antiviral defense against possible HCV remnants needs to take hold and establish itself - the adaptive Tcell response, that up to this point was greatly aided by the direct effect of IFN on the hepatocytes and the local intrahepatic immune cells. With this IFN aid gone all the burden is on the Tcell response, that will typically get stronger if more remnant viruses are seen ( if they can be seen now, because new epitopes are now present) - with incredible sensitivity, but it takes time to come to full swing and it can furthermore, at this very critical moment, be paralyzed by the prominent absence of innate signals needed to get adaptive Tcell responses going after IFN is abruptly missing from the equation."
........................................
"Here is one more specific EXAMPLE how the Tcell effect depends on the presence of some Interferon: The presentation of the viral epitopes is performed - as described in detail in an earlier post- by the cellular proteasome and the class I MHC molecules that bind the peptide and bring it to the surface for recognition by the "cognate" Tcell receptors of the "cognate" Tcell patrolling the liver.
IFN has a strong influence on the intensity of expression - the number of proteins produced per cell - of the MHC class I proteins. Less IFN - less MHC, less presentations- less recognition - less killing of remnant virus infected cells, less general intrahepatic antiviral milieu by the gammaIFN secretion of these Tcells....
If you abruptly stop the enormous whipping up of the hepatocyte MHC production it will likely go into lower than normal mode for a while being so used to the whip...thus temporarily HCV remnants become invisible to the Tcell system."
......................................
"If you do all the heavy lifting and want to shift it to another crew, you better transfer the burden gradually - the other party needs to come into function slowly.
Tapering IFN has indeed been compared to abrupt stopping:
Hepatology. 1996 Jul;24(1):21-6.
Improved sustained response following treatment of chronic hepatitis C by gradual
reduction in the interferon dose.
Shiffman ML, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS.
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with
a high rate of relapse. IFN is thought to exert its effect against HCV via direct
viral inhibition and immune stimulation. We have hypothesized that relapse
following termination of therapy results from the sudden withdrawal of this
immune modulatory effect and that gradual reduction in the IFN dose may decrease
the incidence of relapse. One hundred six patients with chronic HCV were enrolled
into this 24-month controlled, randomized prospective trial. All were treated
with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who
achieved biochemical response were randomized to either stop or taper IFN
gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all
three times a week). 0.5 mU twice weekly and then once weekly. Liver histology
was assessed by Knodell index and HCV RNA was measured by a quantitative
polymerase chain reaction (PCR) assay. Of the 92 patients who completed the
initial 6 months of IFN treatment, 47 (51%) achieved biochemical response.
Twenty-one of these patients were randomized to stop IFN treatment and 25 to
taper (1 drop-out). At randomization patients were well matched with respect to
age, sex, race, serum alanine transaminase (ALT), and liver histology.
Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN
treatment compared with only 60% who tapered IFN (P= .04).
Virological relapse
occurred in 90% of patients who stopped and only 48% of persons who tapered IFN
therapy.
At completion of the 24-month study patients who achieved long-term
sustained biochemical response had a significantly lower mean Knodell score (3.5
vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85%
vs. 18%) compared with relapsers.
We conclude that gradual reduction in IFN dose
is associated with a SIGNIFICANT HIGHER RATE OF SUSTAINED RESPONSE and clearance
of HCV RNA from serum compared with abruptly stopping treatment. This in turn is
associated with a significant improvement in hepatic histology supporting the
premise that response to IFN therapy can prevent progression to cirrhosis."
...................................................countined
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