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144210 tn?1273088782

Houston, this is 13...

I am beginning to think about my end of treatment plan and looking for thoughts on the subject. HR has discussed the tapering topic in the past.....

by HR
     "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."

He also recommended adding Lactoferrin at this time to help the immune system come "back online". Has anyone tried this?  And any opinions on other immune enhancing supplements?  Thanks.
---------------------------

"Houston, we need to go over those re-entry procedures so there are no foul ups, so here is what you are going to do, give us whatever you got so we can look em over.  We are all a bit tired up here... and the earths getting awfully big in the window...."

"13... this is Houston, we are going to get those procedures to you just as soon as we possibly can. Ken Mattingly is in the simulator as we speak..."

"Roger that Houston... Kens working on it..."
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Avatar universal
LOL! I was not around in the experimental stages of the forum but HR presented some very compelling facts and reasoning as to why one might benefit from the tapering at the end and being in the final stages of treatment myself at the time and had the same thoughts of how to get off the train with less post sx made sense to me. I would not over encourage others to do the same because the means may not be available to them to do so but as I have said it worked for me and that is all that matters to me at least.

jasper
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Avatar universal
*Probably* no harm other than more drugs, but I was just making a general statement. That said, the exact thought did enter my ribadized mind when I was deciding whether or not to taper, as the subject had come up here well before HR appeared on the forum. BTW "Amazing" was not part of my quote -- as it appears --  but I'm glad that you found my thoughts so, well, "amazing". LOL.

-- Jim
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Avatar universal
But if RVR or close (like I was) the thought might enter my mind that what sounds good on paper can sometimes backfire, especially if not tested. In other words, if I felt my odds were 80-90% SVR with conventional treatment, then why risk fooling around with it? Amazing!

It would seem that no harm would be done when dosing down rather than dosing up into unknown territory on my own but then again hind sight is as they say is 20/20 : )

geterdone
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Avatar universal
I'm considering tapering myself. 52 year old male, 170 pounds, Genotype 1. Didn't clear until about week 20. I've got 4 more weeks left of 72. I'm on Pegasys, ribavirin 1600mg, Alinia 500mg twice a day, AD's, Procrit.

The elimination 1/2 life of Pegasys, according to this post, is 80 hours. The time to go from steady state to near complete elimination is about 5 half-lives for all drugs, assuming usual kinetics, no matter how long or short the half-life. That means the average time to elimination for Pegasys would be 5 x 80 hours = 400 hours, which is 16 days.

Is that long enough to allow the body to resume normal production of interferon? I don't know, but it's hard for me to conceive of any problems with a month-long taper AFTER finishing my whole 72 weeks. That's my plan.

Jeff
Facta non Verba
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Avatar universal
Assuming your facts and math are correct then I haven't made a great case -- vis a vie HR's theories -- that tapering is unecessary, nor for that matter have I seen anyone make a great case that tapering is necessary :)  As CA suggests, all we have are theories with no study data, as opposed to for example RVR data where we know RVR translates into SVR, and btw that seems to work in very high percentages without a taper.

Would I personally taper? Perhaps if I failed treatment previously or was a late responder, I might try something out of the box to hopefully give me an edge. But if RVR or close (like I was) the thought might enter my mind that what sounds good on paper can sometimes backfire, especially if not tested. In other words, if I felt my odds were 80-90% SVR with conventional treatment, then why risk fooling around with it?

As to why no HPLC testing here, probably lots of reasons including focus/finances on the sexier PI's with riba being what everyone wants to move away from. Still, lots of lost SVRs IMO while many still treat SOC. And yes, that would be an interesting study -- 48 weeks SOC with one cohort on full-dose and the second co-hort on a tapered dose between weeks 24-48.



-- Jim
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Avatar universal
It is an individual decision whether to taper off the interferon and ribavirin at the end of treatment, as you well know. Do what is best for you as you have done so far, the bottom line is what is it going to hurt if the meds are available to you to do so and if not, dig a little deeper on the supplement Lactoferrin as mentioned. The choice is yours and yours alone. I only know of two here on this board who have “actually” tapered off the meds with HR’s input and those who haven’t only read the limited text about it. There is a cost associated with the taper extension of treatment and a case had been made long ago by the medical community and the insurance companies not to peruse further research and the funding to do so. Good Luck in what ever you decide

jasper
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Avatar universal
Bad Maths
After two weeks 1:32 of the drug etc

Should be 1:16th of the drug. then 1:64 after 3 weeks

CS
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Avatar universal
"Jim - I think you're you're confusing half-life elimination with elimination."
Sorry Jim but aint they the same thing.

The elimination Half life of a drug is how long it takes to eliminate half the drug.
In pegasys’s case this is 80 hours on average so after one week you would have 1 quarter of the drug left in your system, if you were Mr/MS Average.

After two weeks 1:32 of the drug etc.

Aside from this being quite a deal quicker than the model HR suggests, It also depends on whether you are eliminating the drug faster or slower than the average.

So yes I can see how this natural taper can let some people down. It happens too fast.

You're comparing a 12-year old study that would be easy to implement (tapering) with a recent finding that would be very difficult to implement (if not impossible) in this country because HPLC testing for serum ribavirin is not available in clinical settings.

Not really. I was trying to show that an idea can be sound even if it hasn’t been thoroughly investigated. In any case If enough Drs wanted HPLC testing it would be available in the US or any other country for that matter.
1 or 2 studies that showed it improved response rates and it would be in use everywhere.

The study may even suggest that lower-doses of interferon should be investigated for months 6-12 instead of full-dose.

Have to agree with you there and makes you wonder why it hasn’t.
I know I would like to see the results of such a study

CS
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Avatar universal
Maybe this is for the same reason that he does not advocate dosing Riba according to serum concentration. Instead prefers dosing by weight still.
------------
You're comparing a 12-year old study that would be easy to implement (tapering) with a recent finding that would be very difficult to implement (if not impossible) in this country because HPLC testing for serum ribavirin is not available in clinical settings. Also, my guess is that Shiffman is quite flexible on riba dosing (other than weight) if he's in sync with some his collegues that I've consulted with. As to your half-life models, I'm no expert, but I think you're confusing half-life elimination with elimination. The taper, as Dr. Dieterich suggests seems to be built in and lasts to some degree or another for several weeks. My main point was that this is the critical period of taper per what I understood to be HR's thesis that there is an immune drop somewhere after the interferon is stopped. So, in effect, the natural taper covers this hypothetical period as I see it. That does not mean I'm not open to tapering as an add on, but I haven't yet seen a good case for it.

-- Jim
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Avatar universal
And who would I put my biggest believe in a doc who has been treating this HCV from the beggining or a researcher whos makes his living in coming  up with wild theories,
and have no studys to back his theory with.

you a funny man
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388154 tn?1306361691
To cocksparrow ,jm gauf and other interested, yes to my self also. LOL
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388154 tn?1306361691
Thanks for clearyfing, forgive me for jumping conclusions.

But you got to admitt when well-renowned doc as Schiffman who has been paricipating in a study 12 years ago ( the study was probaly performed 14 years ago) that seems to be very relevant for many whether to become SVR or not.
Still 12 years later doesn´t mention anything further about it, makes me wonder.
And who would I put my biggest believe in a doc who has been treating this HCV from the beggining or a researcher whos makes his living in coming  up with wild theories,
and have no studys to back his theory with.

Dont forget Dr D who is also a well-renowned HCV treater and also have the same motivation as you and me to find the optimal cure being a relapser and all, don´t believe in it either.

Don´t get me wrong on this one, its guys that HR that makes the differens when their wild theories gets proven right, but until proven its still just a theory, and let me tell you we are many who got paranoid with the thought of  an abrubt finish and even consider tapering down within the standard time ( although that is not the direct adwise from HR on the contrary maybe) specially if extending is not an option simply because our treating docs wont aprove to extending.

You will learn a lot in threads like this I think, so I wanna thank you jm and gauf for your solid interest in the subject, thats the forse thats helps me learn more and often if someone is posting something that event isn´t solid facts and totally correct from the beginning, thats what force your ( my ) brain to work a little more.

ca

PS Thx for the info on the differens between pegintron and pegasys could be an interesting question for someone whos on pegintron to ask Dr D.
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Avatar universal
Worked for me, read all the pro’s and con’s back then on the topic of tapering from the various folks here with a big imprint from HR as to my reduction schedule and then went for it after completing the 48 weeks, took 4 weeks to complete but I got my SVR. Could I have reached the same outcome at the end of 48 with the abrupt stoppage, don’t know but then again I don’t have to answer that question. As part of the pre surgery physical my AST is 21 and ALT is 17 at 8 months post.

jasper
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Avatar universal
One other thing.
The point i was trying to make is that just because a Dr doesnt do something doesnt mean that a concept or theory doesnt have merit.
CS
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Avatar universal
Either way it doesnt matter he nor anyone else does it.
And no i am not insuating anything. You over read it.
I actually like the way Shiffman treats.

CS
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388154 tn?1306361691
Are you insinuating that Schiffman is incompetent.

Do you know hes really not in favor for the serumbased aproach, couldn´t it just be that the labs dont perform such tests as a standard just yet.

ca
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Avatar universal
The extracts below are interesting in regard to tapering
Review article: Pegylated interferons: chemical and clinical differences
Aliment Pharmacol Ther 2004; 20: 825–830.

PHARMACOKINETICS OF THE DIFFERENT PEG-IFNS
The differences in the basic chemistry of the PEG-IFNs are associated with significant differences in the pharmacokinetics and pharmacodynamics of the two drugs.
The 12 kDa PEG-IFNa-2b has a relatively rapid absorption (absorption half-life of 4.6 h, compared with 2.3 h for conventional IFNa-2b), a wide volume of distribution (approximately 0.99 L/kg) a peak-to-trough ratio of >10 (after multiple doses) and reduced clearance (725 mL/h compared with 6000 mL/h for the unmodified IFN).7

The 40 kDa PEG-IFNa-2a is absorbed more slowly (the absorption half-life is 50 h), has a restricted volume of distribution (8 L), a narrow peak-to-trough ratio of 1.5 (after multiple doses) indicating minimal fluctuation in serum concentration, and a markedly reduced rate of clearance (60 mL/h) when compared with non-PEG-IFN.8 Thus, PEG-IFNa-2b is quickly absorbed, circulates widely and declines to undetectable serum levels within a few days, whereas the 40 kDa
PEG-IFNa-2a is absorbed slowly, is restricted largely to the vasculature and well-perfused organs, such as the liver, and is still detectable in serum after a week. Table 2 lists the pharmacokinetic and pharmacodynamic differences between the two PEG-IFNs.

PegIntronPI
Pharmacokinetics: Following a single subcutaneous (SC) dose of PegIntron, the mean absorption half-life (t 1/2 ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The Cmax and AUC measurements of PegIntron increase in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PegIntron. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PegIntron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of PegIntron is estimated to be approximately
22.0 mL/hr•kg. Renal elimination accounts for 30% of the clearance.

Pegylation of interferon alfa-2b produces a product (PegIntron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A, PegIntron (1 mcg/kg) has approximately a seven-fold lower mean apparent clearance and a five-fold greater mean half-life permitting a reduced dosing frequency. At effective therapeutic doses, PegIntron has approximately ten-fold greater Cmax and 50-fold greater AUC than interferon alfa-2b.



Below comes from two Pegasys Product Info Sheets
Pegasys-RBV PI
Elimination: After intravenous administration, the terminal half-life of PEGASYS in healthy subjects is approximately 60 hours compared to 3 to 4 hours for standard interferon. A mean elimination half-life of 160 hours (84-353 hours) at primary elimination phase was observed in patients after subcutaneous administration of PEGASYS. The elimination half-life determined after subcutaneous administration may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of PEGASYS.


Pegasys PI
Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON-A). The mean terminal half life after sc dosing in patients with chronic hepatitis C was 80 hours (range 50 to 140 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.


The 60 hours Half-Life is via IV administration
Its 80 Hours Half-Life with SQ administration
The mean terminal half life after sc dosing in patients with chronic hepatitis C was 80 hours (range 50 to 140 hours)
Notice the elimination range “A mean elimination half-life of 160 hours (84-353 hours)”

The mean PegIntron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection.

So with PegIntron you basiclly would not have any form of natural taper as you would basically have none left by the time you finish off the Riba.

With Pegasys you do get a natural form of Taper but not for everyone.
So tapering off at the end of Tx still appears to be a valid theory to me.

Jim- I assume Shiffman would be advocating tapering which to my knowledge he doesn't.

Maybe this is for the same reason that he does not advocate dosing Riba according to serum concentration. Instead prefers dosing by weight still.

All the Best
CS
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144210 tn?1273088782
Wherever is HR when you need him?! He suggested tapering to me last February.
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Avatar universal
CA: The study (Schiffman) you refering to is 12 years old and it was with the old interferon (not pegulated) its make me wonder why Schiffman hasn´t continued trapping down now 12 years later when treating patience, if it really was something in this trapping down theori.
--------
Not having the full-text but based on the abstract --

Not only was the interferon not Pegalayted, but no ribavirin may have been used. Also, note that the non-taper group was only treated for SIX MONTHS and I'm assuming it had it's share of genotype 1's. The "taper" group was treated TWELVE months if you take into account the six monthly taper periods.

The only thing this study seems to prove is that a longer period of interferon treatment benefited the so-called "taper" group. The study may even suggeat that lower-doses of interferon should be investigated for months 6-12 instead of full-dose. What it does not prove at face value is that tapering interferon has any benefit.

And yes, if this study had legs to carry over to modern treatment protocols, I assume Shiffman would be advocating tapering which to my knowledge he doesn't.

Link to study abstract: http://www.ncbi.nlm.nih.gov/pubmed/8707264

-- Jim
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Avatar universal
Swenglish - I like it!
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Avatar universal
Dr. Dieterich addressed the tapering issue in our Expert Forum so time back.

Essentialy, what he said is that there's no reason to taper since there's a natural taper built into both the Peg and riba, being their half life.

So in effect, what you and HR are talking about is extending the taper.

As to extending the taper, this concept does not seem to address what I believe were HR's concerns regarding what might be termed a low immune "window" right after the drugs are stopped when he proposed the virus might rebound.

It would seem to me that the during this window the natural taper would protect such a rebound from happening should that window/rebound theory be correct.

Also keep in mind that around 90% of all relapses occur within 30 days of stopping the peg -- again, a period that should be covered by the natural taper of Peg, i.e. stopping all the Peg at once.

Lastly, if you do want to taper, the taper should be at the end of the pre-determined course of treatment -- i.e. as an add-on -- as opposed to shortening the full course because of the taper.

-- Jim
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388154 tn?1306361691
Was talking some swenglish here i mean tapering when said trapping in swedisk trappa means stair so the correct translation would have been staring down like walking downstaiers a little bit of the time instead of jumping down all the stairs at once.
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388154 tn?1306361691
The study (Schiffman) you refering to is 12 years old and it was with the old interferon (not pegulated) its make me wonder why Schiffman hasn´t continued trapping down now 12 years later when treating patience, if it really was something in this trapping down theori.

And I think we should all bear in mind that HR is not and never has treaten any HCV patient. I could be missinformed here both about Schiffman and HR please anyone correct me if I´m wrong.
Gauf if you have any fresher studys articles or other information that support (prove) the trapping down aproach please write in.

ca

ps.  the fact can very well be that the people trapping down might just as well got the better SVR nr because they needed a little extra extending tx
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144210 tn?1273088782
I agree that the tapering should be done AFTER the full soc treatment timeline. here is a copy of a study on the subject...

"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. "
--------------------------------
More from HR

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 taper AFTER the end of the full standardized tx period, then you will never have to ask yourself in case you still relapse, if it was the premature tapering that caused it. Tapering in this fashion can certainly cause no propensity for relapse, rather the opposite. Then at least you have done all you could under the circumstances.


What type of tapering schedule?

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   1/8   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.
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