Aa
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..."
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..."
Kewl - 'end of treatment plan'..... It's nice to see you planning your re-entry into the atmosphere!!!
I have just this minute e-mailed my specialist asking for him to look at a possible extension over and above 24 weeks (3a early cirrhosis, 1 x relapse), and/or tapering at the end of tx. If he isn't agreeable to a tx extension, I'd love him to, at least, give me an extra month or so with the view to taper, and will let you know his thoughts. I'm hoping there may have been discussions on 'relapsers' at the San Fransisco conference.
Have you discussed with your specialist??
I have just this minute e-mailed my specialist asking for him to look at a possible extension over and above 24 weeks (3a early cirrhosis, 1 x relapse), and/or tapering at the end of tx. If he isn't agreeable to a tx extension, I'd love him to, at least, give me an extra month or so with the view to taper, and will let you know his thoughts. I'm hoping there may have been discussions on 'relapsers' at the San Fransisco conference.
Have you discussed with your specialist??
"He also recommended adding Lactoferrin "at this time" to help the immune system come "back online".
What time is that I started to take lactoferrin a month ago and are planing to continue with that until at least 3months post.
I have 4 more shots taking the 45th on thursday.
Also benn thinking of tappering down 180 next then 135 then 100 then 50 what do you think of that, or is Hr only recomending that if I take four more shots after 48w
what you think major Tom.
ca
What time is that I started to take lactoferrin a month ago and are planing to continue with that until at least 3months post.
I have 4 more shots taking the 45th on thursday.
Also benn thinking of tappering down 180 next then 135 then 100 then 50 what do you think of that, or is Hr only recomending that if I take four more shots after 48w
what you think major Tom.
ca
One of the ideas that came into my mind a while back concerning EOT is that being the drugs are pulled from us - even if slowly tapered,,,,,our White Cells, lymphocytes and whatever are very low and if there are left over virons or any type of infection that we may have, unknown to us - tooth, ear whatever,,,our white cells/Tcells etc will be trying to fight that and that in turn will give any left over virons time to replicate,,,,,,,,,SO what I was thinking of doing was asking my Hepatologist IF giving me a shot or 2 of Neupogen EOT so that my body will have an extra army to fight left over virons etc......I can NOT understand why they don't do the Neupogen at the EOT for EVERYONE,,,,not only for reasons of dangerously low white cells/fear of infection,,,,BUT to help build up DEFENCE against the left over virons.....
Maybe I am off base, and maybe thats why its not done. Because as I said, the only reason I have heard of people getting Neup was during the tx IF the whites went under a certain amount to try to prevent infection,,,,,,I think give an EOT shot of Neupogen even if you aren't dangerously low - just to bring in a defensive army.....IF that makes sense - dunno, but I will ask my doc next visit.
Maybe I am off base, and maybe thats why its not done. Because as I said, the only reason I have heard of people getting Neup was during the tx IF the whites went under a certain amount to try to prevent infection,,,,,,I think give an EOT shot of Neupogen even if you aren't dangerously low - just to bring in a defensive army.....IF that makes sense - dunno, but I will ask my doc next visit.
I can't understand why anyone would want to stand on the virus' side and reduce SOC by tapering off before EOT. Sure, if you want, taper off by adding shots after doing the full course, but to reduce the full course by tapering before EOT is beyond my comprehension. We need every full week of SOC we can get to get the best shot possible at defeating this virus.
Our immune system couldn't get rid of the virus before tx. Too low doses of the drugs don't get rid of it. What makes you think the immune system can get rid of the virus by tapering? Either it is gone at the end of SOC or it is still there. That is my firm belief.
Our immune system couldn't get rid of the virus before tx. Too low doses of the drugs don't get rid of it. What makes you think the immune system can get rid of the virus by tapering? Either it is gone at the end of SOC or it is still there. That is my firm belief.
so has anyone thought or heard of the chinese herb that has natural interferon in it , i cant think of the name right now oh astrugula (sp?) it has natural interferon and you cant take it prior to tex cause it makes you get used to interferon and the shot , at first is supposed to shock your body ad the virus, hence your ud by 4 weeks, if lucky, what is after tx we went on the astrugala and kept the interferon going? again just wondering
There are pro and cons side to the whole tapering issue however - I would only even consider it if I got additional weeks and did not take them out of SOC. I agree with Zazza on that one. We need every full course week we can get - and since this idea while it makes great sense really isn't proven.......it sounds chancey to me.
As far as taking an chinese herb to "keep the interferon going". No no and no again. You do not know what that drug really is going to do the end of treatment response. Since there are no studies to prove it won't hurt anything - it's completely not worth it.
Your body at some time has to take over and manage it's own immune system. Guessing on such complicated body functions.....when scientists have been studying for years.....not worth it. NO way. You could end up undoing whatever 'training' has already been done by treatment in one shot.
As far as taking an chinese herb to "keep the interferon going". No no and no again. You do not know what that drug really is going to do the end of treatment response. Since there are no studies to prove it won't hurt anything - it's completely not worth it.
Your body at some time has to take over and manage it's own immune system. Guessing on such complicated body functions.....when scientists have been studying for years.....not worth it. NO way. You could end up undoing whatever 'training' has already been done by treatment in one shot.
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.
"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.
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
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
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.
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
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
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
--------
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
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
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
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
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
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
And no i am not insuating anything. You over read it.
I actually like the way Shiffman treats.
CS
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
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
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
jasper
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.
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.
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
and have no studys to back his theory with.
you a funny man
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
------------
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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