Aa
Hepatitis Researcher, Pre-Dosing Ribavirin
I am starting treatment with Infergen in 2 weeks and am planning on pre-dosing riba(1,600 daily) leading up to the start date. Do you feel this may give me an edge or would it be better to just add the extra riba to the daily intake once I start the Infergen?
I'm also currently taking a plant sterol/sterolin mixture and mushroom extract( active hexose correlated compound) both of which have clinical results proving they boosts t-cells ,NK cells, and interferon levels(th1 arm) and would like to know what your feelings were about me remaining on these substances throughout my upcoming treatment?
MEDICAL PROFESSIONAL
The predosing of riba holds good theoretical merit, since the effective concentrations are not reached quickly with riba and also because "riba resistance" is not a likely quality that HCV could easily obtain.
have you or your doctor actually made some predictions for your odds of success
on this upcoming round? i would really like to know what your doc thinks this number is.
not trying to sound negative but its my understanding
that overall odds drop with each successive failed round. especially a failed 72.
from what ive seen around here, retreating with soc is a tough business.
as much as i think you should wait, i do wish you the best and hope the aggressive
attack plan works.
on this upcoming round? i would really like to know what your doc thinks this number is.
not trying to sound negative but its my understanding
that overall odds drop with each successive failed round. especially a failed 72.
from what ive seen around here, retreating with soc is a tough business.
as much as i think you should wait, i do wish you the best and hope the aggressive
attack plan works.
Have you had previous experience with 1600 mg/day of ribavirin?
If not, you might start sooner and titer up more gradually to make sure that you can handle the dose.
Keep in mind that it can take 1-3 weeks for a change in ribavirin dose to be reflected in your hemoglobin.
Also, and again based on your previous treatment experience, consider Procrit (epo) coincidental with the riba pre-dosing for same reasons.
Remember, high doses only work if they don't drive you off the medicine, or possibly treatment altogether. 1600 isn't all that high, but it is above SOC.
At week 1 of treatment, I upped my dose from 1200 to 2000mg/day. (Weighed around 175 at the time). I titered up over a five day period not understanding that ribavirin takes awhile to show its effect. Big mistake. I ended up in the ER and had to go off ribavirin completely for several days.
All the best luck with your new round of treatment. I do like the idea of pre-dosing ribavirin, just remember that higher doses of riba can often be like walking a razor's edge.
All the best,
-- Jim
If not, you might start sooner and titer up more gradually to make sure that you can handle the dose.
Keep in mind that it can take 1-3 weeks for a change in ribavirin dose to be reflected in your hemoglobin.
Also, and again based on your previous treatment experience, consider Procrit (epo) coincidental with the riba pre-dosing for same reasons.
Remember, high doses only work if they don't drive you off the medicine, or possibly treatment altogether. 1600 isn't all that high, but it is above SOC.
At week 1 of treatment, I upped my dose from 1200 to 2000mg/day. (Weighed around 175 at the time). I titered up over a five day period not understanding that ribavirin takes awhile to show its effect. Big mistake. I ended up in the ER and had to go off ribavirin completely for several days.
All the best luck with your new round of treatment. I do like the idea of pre-dosing ribavirin, just remember that higher doses of riba can often be like walking a razor's edge.
All the best,
-- Jim
MEDICAL PROFESSIONAL
George
"plant sterol/sterolin mixture and mushroom extract( active hexose correlated compound) both of which have clinical results proving they boosts t-cells ,NK cells, and interferon levels(th1 arm)"
Those are unspecific stimulators of innate immunity.It is unclear if the increased intensity of this part of the HCV specific immune pathways is stimulating or exhausting to the overall efficacy.
The results of the well prepared cpg 10101 trials by Coley pharmaceuticals (Coleypharma), using
(CPG 10101-
"Actilon") that was maximally stimulating the Th-1 response and internal IFN production)
were somewhat disappointing ( but not without some effect) and the trials have been stopped.
That was quite a surprise because this was beyond doubt an effective way to stimulate the TH1 pathway and the Nk and overall the innate immune response.
I plan on doing the same thing. Are you going to pre-dose for 1 or 2 weeks? Can anyone comment on how long to pre-dose? Hasen't Roche done a study on this? It seems that if it would work, they would have done a study and it would be posted somewhere. Hey, getting the patient to purchase an extra 2 weeks or 4 weeks dose of Ribavarin would be more revenue for them. Seems that the Pharma Companies are driving a lot by revenue, so it would make sense.
Anna
Anna
You haven't mentioned your weight. 1600 may be reasonable for some people, but may be inappropriate for others (especially very petite women). Also be forewarned that riba not only causes anemia, it can really do a number on your skin. I HAD to drop down from 1200 to 800mg not because of anemia (although I had that too), but because of rash/itch problems. Since you're on infergen perhaps you've already tangled with these drugs and I'm preaching to the choir, but if not be forewarned about the skin issues. Good luck.
I did 1,800 mg' s for the last six months of my previous 72 week failed attempt, so 1600 for a couple of weeks will not pose a difficulty. I am 6ft and 195 lbs.
"At week 1 of treatment, I upped my dose from 1200 to 2000mg/day. (Weighed around 175 at the time). I titered up over a five day period not understanding that ribavirin takes awhile to show its effect. Big mistake. I ended up in the ER and had to go off ribavirin completely for several days."
Sorry, Jim I must be a little dense. Are you saying that, if you had it to do again, you would titer up to 2000 over a longer period, say 2 or 3 weeks, and then keep it at that level for a few weeks before starting peg, all the while taking epo?
Sorry, Jim I must be a little dense. Are you saying that, if you had it to do again, you would titer up to 2000 over a longer period, say 2 or 3 weeks, and then keep it at that level for a few weeks before starting peg, all the while taking epo?
Wow dude you took 1800mg/daily for the last 6 months of a 72 week tx? WOW, you are one tuff customer is all I gotta say. No friggin' way in humanity could I have pulled that one off. Have you considered waiting for one of the newer drugs (teleprevir, boceprevir etc)? Or maybe try enrolling in the phase 3 telaprevir trial? It sounds like you gave your last tx attempt an incredibly heroic effort. Not sure I'd put my faith in IFN and riba alone after that again. Also, how about alinia? If you're going through treatment come hell or high water again soon, I'd definitely look into the alinia too. Hoping the best for you either way...and again, you are one tough bird!
Burned,
Short answer is "No".
First, I never pre-dosed ribavirin when I treated because I never heard of the concept back then. My quote, above, was given as a cautionary tale related to my little experiment with high-dose ribavirin that I started at week 1 of treatment.
It's also importantl how we define "if I had to do it again". Because if I had to do it again, with the knowledge I have today, and with the availability of today's drugs, I'd probably either try and get in a Telaprevir trial instead of doing high-dose ribavirin -- or perhaps I'd just be watching and waiting, because later in treatment I found out that my liver damage was a stage less than I had previously thought (had the slides re-read).
That said, if someone wants/has to treat with SOC now, pre-dosing ribavirn seems like a good idea, although as stated no studies appear to exist. Adding "epo" the equation, would be a safeguard against anemia -- as with SOC -- but epo also has its risk/reward equation, so the addition of epo prophalactively would have to be considered carefully based on a number of factors, including let's say a person's riba/hemoglobin profile in let's say a previous treatment.
Very high dose ribavirin, on the other hand (per the Lindahl pilot study) is a different concept and would require a different commitment, a different risk/reward profile and the cooperation and supervision of a medical team both knowledgeable and up to the task. That's assuming that the current data on that original pilot study -- and follow ups-- is at least as good as it seemed then back then Hard to say since no data published in the last two years.
------------------------------
George,
I'll make this very general cause don't remember all your stats -- so please take what's relevant and throw out the rest.
If you previously did 1800 mg/day of ribavirin a day for 72 weeks, maybe either the ribavirin isn't the problem at all, i.e. pre-dosing isn't the answer -- or, you're not absorbing the riba very well, a crude measure of which would have been your hemoglobin response during treatment.
Anyway, taking the pre-dosing out of the equation, it seems that the only thing you're doing different this time is swapping 72 weeks of Infergen for 72 weeks of SOC. Have you looked into any study data, or spoken to your liver specialist, as to how much better your chances of SVR might be with the new approach? I think that would be important. Lastly, have you considered Telaprevir which would add an entirely new element into the mix and hopefully kick you into SVR land?
-- Jim
Short answer is "No".
First, I never pre-dosed ribavirin when I treated because I never heard of the concept back then. My quote, above, was given as a cautionary tale related to my little experiment with high-dose ribavirin that I started at week 1 of treatment.
It's also importantl how we define "if I had to do it again". Because if I had to do it again, with the knowledge I have today, and with the availability of today's drugs, I'd probably either try and get in a Telaprevir trial instead of doing high-dose ribavirin -- or perhaps I'd just be watching and waiting, because later in treatment I found out that my liver damage was a stage less than I had previously thought (had the slides re-read).
That said, if someone wants/has to treat with SOC now, pre-dosing ribavirn seems like a good idea, although as stated no studies appear to exist. Adding "epo" the equation, would be a safeguard against anemia -- as with SOC -- but epo also has its risk/reward equation, so the addition of epo prophalactively would have to be considered carefully based on a number of factors, including let's say a person's riba/hemoglobin profile in let's say a previous treatment.
Very high dose ribavirin, on the other hand (per the Lindahl pilot study) is a different concept and would require a different commitment, a different risk/reward profile and the cooperation and supervision of a medical team both knowledgeable and up to the task. That's assuming that the current data on that original pilot study -- and follow ups-- is at least as good as it seemed then back then Hard to say since no data published in the last two years.
------------------------------
George,
I'll make this very general cause don't remember all your stats -- so please take what's relevant and throw out the rest.
If you previously did 1800 mg/day of ribavirin a day for 72 weeks, maybe either the ribavirin isn't the problem at all, i.e. pre-dosing isn't the answer -- or, you're not absorbing the riba very well, a crude measure of which would have been your hemoglobin response during treatment.
Anyway, taking the pre-dosing out of the equation, it seems that the only thing you're doing different this time is swapping 72 weeks of Infergen for 72 weeks of SOC. Have you looked into any study data, or spoken to your liver specialist, as to how much better your chances of SVR might be with the new approach? I think that would be important. Lastly, have you considered Telaprevir which would add an entirely new element into the mix and hopefully kick you into SVR land?
-- Jim
I am going to add Alinia to the mix hoping it will work on 1A's as well as it has with type E in Egypt. I am starting to second guess this 4th treatment experience because I'm so tired of being disappointed about failing the previous three. I would love to get into the Telaprevir study but they aren't even accepting patients yet and who knows if I would be in the non-placebo arm of the study anyway. To put it midly I'm burned out on the whole process and this last 72+ weeker really changed me mentally and physically. I feel pretty helpless and beaten regarding this disease.
have to admit I'm baffled by this. As best I can tell:
1) riba concentration under usual dosing quickly reaches a steady-state concentration and remains stable thereafter (eg see Fig 1 in PMID 17494069)
2) riba has been documented to have insignificant mono tx effect. The reason for its synergistic combo effect remains elusive; of the various proposed mechanisms, none has found conclusive support (see discussion in that same study).
3) As a putative HCV mutagen it *might* make sense to continue riba dosing post tx to expose remaining HCV virions which have mutated away from any recognizable CTL epitopes, as detailed in HR's nice post in the "vaccine" thread, but I believe that remains entirely speculative at this point.
So what support is there for the notion of pre-dosing? I don't mean to seem critical of a tx decision, just not sure I understand its rationale.
1) riba concentration under usual dosing quickly reaches a steady-state concentration and remains stable thereafter (eg see Fig 1 in PMID 17494069)
2) riba has been documented to have insignificant mono tx effect. The reason for its synergistic combo effect remains elusive; of the various proposed mechanisms, none has found conclusive support (see discussion in that same study).
3) As a putative HCV mutagen it *might* make sense to continue riba dosing post tx to expose remaining HCV virions which have mutated away from any recognizable CTL epitopes, as detailed in HR's nice post in the "vaccine" thread, but I believe that remains entirely speculative at this point.
So what support is there for the notion of pre-dosing? I don't mean to seem critical of a tx decision, just not sure I understand its rationale.
The reason for pre-dosing is that Riba takes a few weeks to reach meaningful concentrations in the bloodstream (cumulative effect) and therefore when the Interferon I won't have to wait for that 2-3 week lag period with the Riba.
As I see it, the rationale, is not as you say because of it's "mono tx effect" because there doesn't appear to be any. The rationale therefore is to have the serum riba level up to speed coincidental with the first couple of injections, where all of the heavy work is done.
Not sure what they mean by "quickly reaches a steady state" but most here take their first riba pill the morning of their first injection. Serum riba levels do not build that fast to "steady state". Keep in mind there's a 1-3 week lag in hemoglobin response to a ribavirin change, which should tell us something.
As to "support" -- no studies that I've been able to find on this, although there was a poster here about a year ago who suggested here husband was in such a study. It's quite possible that she just described the study incorrectly. Of course it's only one case, but you are aware that FLGuy pre-dosed riba on this second go-around as was UND at week TWO. Nice, huh.
-- Jim
Not sure what they mean by "quickly reaches a steady state" but most here take their first riba pill the morning of their first injection. Serum riba levels do not build that fast to "steady state". Keep in mind there's a 1-3 week lag in hemoglobin response to a ribavirin change, which should tell us something.
As to "support" -- no studies that I've been able to find on this, although there was a poster here about a year ago who suggested here husband was in such a study. It's quite possible that she just described the study incorrectly. Of course it's only one case, but you are aware that FLGuy pre-dosed riba on this second go-around as was UND at week TWO. Nice, huh.
-- Jim
Just to tighten up my last post up a little. If you do not pre-dose ribavirin, in effect you are on mono-therapy (interferon only) for your first injection (where most of the virons are often killed)and probably are not on a full-level of combo therapy (Peg and Riba) until around week 2. If you pre-dose, the riba is there in your serum to work with the first injection. And for all our speculation, we still do not know exactly how riba works other than it does work.
"Our study reconfirmed that serum ribavirin concentrations take at least 4 weeks to reach a steady state...."
-------------------
http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1365-2125.2003.01780.x
-------------------
http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1365-2125.2003.01780.x
OK, I can understand some priming-the-pump effect, but please take a look at that Fig. 1. Blood serum concentration is expressed in log ng/ml. By day 5, for the 11 patients shown, concentration looks pretty close to the 3 ng/ml (log units) steady state value. And thanks for the clarifiication.
I don't know if 4 weeks, 1 week (like FlGuy - I think?) or five days is the magic number. I've used the 2-4 and 1-3 week numbers in the past because that's what I was told by some researchers as the time it takes for a change in ribavirin to be fully reflected in Hemoglobin. If I were to pre-dose riba today, I'd probably spend more time on the charts and studies before coming up with a precise number -- and maybe that five day number would make the most sense. Don't know. One advantage, however, of starting out a bit further out, is that it offers an opportunity to dose tweak (up or down with interim CBCs) if that is part of your strategy.
George, I certainly admire your courage, but again, it would be great if you could add a really big (and proven) gun to your mix like Telaprevir. Not sure what the liver damage situation is and if you can wait a little, because I believe there is a new set of trials starting soon.
That said, if you do take your planned approach -- I would definitely monitor viral load WEEKLY from week 1 and weigh my decision whether or not to complete your treatment on your viral response. If you don't seem to be responding well to the new regimen, I don't see a reason to subject yourself to another 72 weeks. On the other hand, if the added munition gives you an RVR, maybe you don't even need 72 weeks. Boy, these are difficult decisions, and I wish you the very best.
-- Jim
George, I certainly admire your courage, but again, it would be great if you could add a really big (and proven) gun to your mix like Telaprevir. Not sure what the liver damage situation is and if you can wait a little, because I believe there is a new set of trials starting soon.
That said, if you do take your planned approach -- I would definitely monitor viral load WEEKLY from week 1 and weigh my decision whether or not to complete your treatment on your viral response. If you don't seem to be responding well to the new regimen, I don't see a reason to subject yourself to another 72 weeks. On the other hand, if the added munition gives you an RVR, maybe you don't even need 72 weeks. Boy, these are difficult decisions, and I wish you the very best.
-- Jim
also note the riba dosages in the Japanese study Jim cited: they start on 400mg/day then go up to 800mg on day 3 whereas in the French study patients received 1000/1200 depending on weight (75kg) from the start. In both sudies, it looks like the steady state concentration flattens around 3 micro grams/ml but part of the reason the Japanese patients took so much longer to get there may be their reduced dosage.
However, the Japanese finding that there was a significant difference between concentrations in those that did and didn't get to SVR seems pretty compelling:
"The steady-state assessment between weeks 4 or 8 and 24 indicated that SVR patients constantly maintained higher values than other patients at each time point. Specifically, the concentrations at weeks 4 and 8 were significantly higher in SVR patients than in others (P < 0.05, each)."
Not sure you need to start 4 weeks in advance, but overall it seems a good strategy. Good luck!
However, the Japanese finding that there was a significant difference between concentrations in those that did and didn't get to SVR seems pretty compelling:
"The steady-state assessment between weeks 4 or 8 and 24 indicated that SVR patients constantly maintained higher values than other patients at each time point. Specifically, the concentrations at weeks 4 and 8 were significantly higher in SVR patients than in others (P < 0.05, each)."
Not sure you need to start 4 weeks in advance, but overall it seems a good strategy. Good luck!
Willing: However, the Japanese finding that there was a significant difference between concentrations in those that did and didn't get to SVR seems pretty compelling:
-----------------------------
Which brings us back to the problem of determining what those concentrations really are without HPLC serum riba testing that's not readily available. Pre-dosing, in theory will give us a jump start, and hemoglobin decline measured via frequent CBCs can give us a crude estimate on riba concentrations, but just that. BTW in the Swede study, I believe the target serum riba concentration was 14.7 µmol/L using very high does between 1600-3600 mg/day or riba, depending on the response in serum. As far as I know the 14.7 number was somewhat arbitrary, and hopefully less is needed but again, not a whole lot of mature studies to go by.
-----------------------------
Which brings us back to the problem of determining what those concentrations really are without HPLC serum riba testing that's not readily available. Pre-dosing, in theory will give us a jump start, and hemoglobin decline measured via frequent CBCs can give us a crude estimate on riba concentrations, but just that. BTW in the Swede study, I believe the target serum riba concentration was 14.7 µmol/L using very high does between 1600-3600 mg/day or riba, depending on the response in serum. As far as I know the 14.7 number was somewhat arbitrary, and hopefully less is needed but again, not a whole lot of mature studies to go by.
yeah, agreed that the whole area of riba dosing seems to be handled very crudely. From the posts I've seen here, it seems drs take much more liberty with their riba dosages than with other drugs. And progress seems very very slow: though it seems obvious that mg/kg based dosing should be superior to a simple 75 Kg cutoff this was only recently confirmed as a major finding:
Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA; WIN-R Study Group.Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.Hepatology. 2007 Oct;46(4):971-81. PMID: 17894303
HgB decline seems a reasonable proxy for concentration, but I've never seen that documented. Testing for effective drug concentration is supposed to happen as part of the early phases of testing so I suppose at this stage the main impetus for such a test would be data showing that patients with similar dosages exhibit a wide range of concentrations.
BTW the 14.7 µmol/L expresses concentration as molarity whereas both the French and Japanese studies used weight (g/ml) so you'd need riba's molecular weight, which should be on the drug's data sheet, to compare.
a couple of other quotes from the French study which may be relevant :
" We have also recently shown in a prospective randomized trial involving patients infected by HCV genotype 1 that the principal effect of ribavirin is to prevent breakthroughs during and
relapses after therapy for individuals who initially respond to the pegylated IFN-–ribavirin combination (4). This suggests that ribavirin shortens the half-life of infected cells during IFN
administration, allowing their complete elimination during the standard 48-week treatment period in the majority of patients who initially respond to combination therrapy"
the shortened half-life for infected cells being consistent with HR's CTL epitope theory
and
"High ribavirin concentrations in serum were achieved within a few hours after the first oral intake, but the levels fluctuated during the first days of administration. A plateau was reached by day
14 in all cases"
suggesting that at typical 1-1.2 g/day dosing, 2 weeks of pump-priming should be enough.
Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, Becker S, Wakil AE, Pound D, Godofsky E, Strauss R, Bernstein D, Flamm S, Pauly MP, Mukhopadhyay P, Griffel LH, Brass CA; WIN-R Study Group.Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.Hepatology. 2007 Oct;46(4):971-81. PMID: 17894303
HgB decline seems a reasonable proxy for concentration, but I've never seen that documented. Testing for effective drug concentration is supposed to happen as part of the early phases of testing so I suppose at this stage the main impetus for such a test would be data showing that patients with similar dosages exhibit a wide range of concentrations.
BTW the 14.7 µmol/L expresses concentration as molarity whereas both the French and Japanese studies used weight (g/ml) so you'd need riba's molecular weight, which should be on the drug's data sheet, to compare.
a couple of other quotes from the French study which may be relevant :
" We have also recently shown in a prospective randomized trial involving patients infected by HCV genotype 1 that the principal effect of ribavirin is to prevent breakthroughs during and
relapses after therapy for individuals who initially respond to the pegylated IFN-–ribavirin combination (4). This suggests that ribavirin shortens the half-life of infected cells during IFN
administration, allowing their complete elimination during the standard 48-week treatment period in the majority of patients who initially respond to combination therrapy"
the shortened half-life for infected cells being consistent with HR's CTL epitope theory
and
"High ribavirin concentrations in serum were achieved within a few hours after the first oral intake, but the levels fluctuated during the first days of administration. A plateau was reached by day
14 in all cases"
suggesting that at typical 1-1.2 g/day dosing, 2 weeks of pump-priming should be enough.
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