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?

[St. George]

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?

[Hepatitis Researcher]

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.

[cruelworld]

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.

[jmjm530]

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

[Hepatitis Researcher]

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.

[Anna142]

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

[mremeet]

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.

[St. George]

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.

[burned74]

"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?

[mremeet]

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!

[orleans]

You were considering Alinia. Why the change of heart? jm

[jmjm530]

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

[St. George]

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.

[willing]

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.

[St. George]

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.

[jmjm530]

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

[jmjm530]

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.  

[jmjm530]

"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

[St. George]

wow, 4 weeks.  I think I will probably do the 4 week pre-game schedule.

[willing]

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.

[jmjm530]

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

[willing]

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!

[jmjm530]

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.

[willing]

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.

[jmjm530]

Willing: HgB decline seems a reasonable proxy for concentration, but I've never seen that documented.
-----------------------------------
Not handy, but I've seen maybe 3-4 papers on this, including a report by Lindahl I got from a medical library,  not available on the net, as far as I could tell. All but one found a relationship between anemia and/or RVR and SVR. One didn't but that may have been because different studies used different riba doses. I don't disagree that two weeks "priming" wouldn't be enough, but again if you wanted to build in "tweak" time, then you might go further out. BTW for anyone new on this - and I'll only speak for myself here -- these are by no means treatment recommendations, simply discussion of what is a complex and under-studied topic. And probably the reason understudied, is because riba has constantly presented clinicians with their major problem during treatment which is anemia. For that reason, my guess is that few will be receptive to getting too agressive with ribavirin, esp in light of the promising progress being made with other strategies, such as usig PI's like Telaprevir. Personally, however, I always felt that interferon was the "baddie" of the two. Probably less problems for clinicians during treatment, but maybe more problems for the patient after they say "goodbye" to their doctors when treatment is over.

-- Jim

[jmjm530]

Let me amend that to say that riba has presented both clinicians AND patients perhaps the most problems during treatment, however I still think that many of the post tx issues some of us experience are because of interferon exposure.

[FlGuy]

My pre-dosing of riba for a week was followed by double-dosing peg for the first 4 weeks.  As jim points out, I was undetectable after week 2.  Not sure to which, or both, I would ascribe the early UND.  My guess is both.

[mremeet]

willing - The riba serum concentrations may not be the only thing that needs time to come up to speed. HR has spoken many times on a possible, or even likely, effect of riba in that it provokes some type of immune response in the patient that works concomitantly with the direct and referred effects of IFN. I don't recall exactly offhand how that response was characterized by him, but I believe it had something to do with making it more difficult for the virus to hide from the T cells. It effectively spray painted them fluorescent orange so they could be seen and zapped, instead of sneaking around in their lipid over coats. Anyway, I suspect it takes the body time to immunologically react to the effects of ribavirin (similar to IFN), if in fact this theoretical mode of efficacy is correct.

George you DO know that the riba has to be ingested with fat right? There's a huge difference in riba absorption depending on whether or not the riba is digested in the presence of fat. If that 1600mg/day you were taking was ingested without a good amount of fat each and every time, pharmacologically it was only the equivalent of taking roughly half that amount!

FLguy you were the one I was trying to think of, going UND in 2 weeks on SOC. If you were geno 1 and didn't start out with a very low VL, that is amazing (and rare too). That's VX950-like is what it is. What were your stats again?

[FlGuy]

Geno 3 relapser.  Ist tx was Pegintron and 800 (not weight based) riba for 24 weeks.  Got to und before 12 weeks, relpased post tx.  2nd tx was 1200 Riba (weight based) and Pegasys, with the pre-dosed riba and the double peg and total of 46 weeks.  Start of tx 2   v.l. was 4 million.  Early cirrhosis, not overweight,  56 y/o.  The early und was primary goal.  The liverhead said 'und by  week 4 go 48, if not und by 4 go 72'.  So, I was driven to the need for a very early response.  3 month pcr results expected tomorrow so not sure how the cake baked in this recipe turned out yet.  But, was und at 3 weeks post tx.

[gauf]

Wow, Our stats are identical except I was overweight on tx and failed the second round. Even VL is a match!  Praying for a Christmas SVR for you.

[TnHepGuy_]

How about an approach of pre-dosing the Alinia (say, in the 2-4 week range/per the Egyptian study) and then adding the riba one to two weeks prior to the final addition of the Infergen?

Also, as has been suggested, have you considered having a riba-saturation test done early on in tx to see where things stand? If you're results were only relatively low, for example, you could try and boost the riba a bit to reach an acceptable level.


As you already know, you're out in uncharted turf when doing this. You don't know what has been causing the tx failures (inf-resistance, low riba absorption, etc.) but in each re-tx you try, your remaining pharmaceutical options diminish - along with the odds of SVR. So, you need to be "creative" with the remaining arsenal - and pre-dosing sounds like a relatively safe bet/attempt.


TnHepGuy

[jmjm530]

As long as you seem to be open to additions to SOC (other than PI's), another option is double-dosing the Peg until UND, as suggested, and as discussed on the clinical care options web site.

Another is  phlebotomy (blood letting) depending on your iron levels/stores. Some recent studies on that.

And lastly, is your weight. If you're overweight, getting down to "fighting weight" would give you more chances.

But again, at the end of the day, the important thing is how your body reacts to whatever intevention(s) you choose. The best way to find out would be by weekly viral load tests from week one, and ideally using a lab that would return results within a week.

That way you can track what is happening and tweak things if necessary. It will also give you a realistic appraisal of whether or not you should really finish up what can be a very grueling course of 72 weeks of Infergen. If it turns out that the virus simply isn;t reacting to all this, then you can always stop and cut your losses. And again, if you RVR, then 72 weeks might not be even necessary.

Another key ingredient in all this would be a liver specialist on board who is willing to work with you on your plan and provide support, helper drugs, etc, if and when necessary.

BTW since you got close to 2000 mg/day of ribavirin last time treating, you should know that a recent study by Lindahl shows that riba is saturable. That means that only so much can be absorbed at any one time. For that reason, if you end up getting over 2000 mg/day,. you probably want to break up the doses and therefore dose three times a day, as opposed to the usual two doses.

-- Jim

[cruelworld]

almost everyone around here still seems to ignore the fact that soc just didnt work for you and the chances of it working this time around are slim. i challenge you to get a real estimate of success percentage from 4 top hep docs.  again, i challenge you to get a real estimate of success percentage from 4 top hep docs. dont skip this vital step. my guess is they will say from 5% to 20%. what drives you to this desperation?  why would it be so bad to wait a few years for fda release? the new drugs are your only realistic way out. this is not just my contrary opinion, this is recognized by the medical community. many studies say that retreating in your case is a bad idea. and we see these results all around us on this forum. if you fail three or four rounds, you are in the hepatitis black hole until new drugs arrive. whats so bad about taking a rest?  maybe a year ago you would feel like you had no other choices but today
your salvation is in the wings and soon to be here. whats the rush to another
torture session with stone age drugs? statistically, it is a bad bet.
is another failed treatment really going to help you? you dont need to buy more time,
you have some. do another biopsy, ill bet you are down to stage one by now. maybe even stage 0. at some point this "treatment bandwagon" becomes a losing proposition and you have arrived at that point. yes, its true that no one knows what
the future holds but your chances with soc are all but meaningless. i think many hep doctors will agree with this. this is the first time ive seen you post a message with
this realistic concern. is it really worth it to totally destroy your life? up until now you have been barrelling towards more soc with blinders on your eyes.
all of life is a gamble,  please look at the odds before betting your life savings.
you really do have other options. and good ones at that.

i guess if youve got your heart set on it, i would try 4 weeks. if you dont rvr,
forget it. even then i think it is a bad idea. rvr's fail too.

i see far to many people on the "soc treatment bandwagon" and in my opinion they shouldnt be.
im a borderline case in this department but the scales barely tip enough for me to
see this first round of 72 all the way through. if i fail,  soc will not be part of my future as a dragon slayer.
dont trust your judgement any longer, find several other top hep docs who specialize  in retreating tough cases who will give you a real estimated chance for success. i think your decision will be all but obvious at that point.
the old days of ridiculous carnage are all but gone, rejoice man!
youve got better options.

[jmjm530]

Cruel: almost everyone around here still seems to ignore the fact that soc just didnt work for you and the chances of it working this time around are slim. i challenge you to get a real estimate of success percentage from 4 top hep docs...guess if youve got your heart set on it, i would try 4 weeks. if you dont rvr,forget it. even then i think it is a bad idea. rvr's fail too.
-------------------------
Not me, my friend. In fact, if you've been following my posts to St. George over the last month, I've been saying exactly the same thing, and have urged him a number of times to seek expert opinions, including getting some estimated odds on SVR with the proposed regimen.

But George appears to have his mind set on re-treating again using what's available as opposed to something new like a PI. So...under those conditions, at least what I'm trying to do is give him some add-ons to think about like pre-dosing the riba. And I def agree, as already stated, that he's got to take a good and sober look at viral response should he go ahead now. Personally, I'd test weekly from week 1.

Just to be clear, I agree with about everything you've said, except the part about people ignoring what you're saying :)

-- Jim

-- Jim

[cruelworld]

make a list of all the people around here that you respect.
ask them specifically what they would do if they were in your shoes.
would they retreat or wait.
the answers should be interesting.

[cruelworld]

sorry if ive insulted anyone and hope no offence is taken. i know that you are
a proponent of waiting, in fact youve played a big part in helping me to see
the diminishing returns of repeated soc. this may be rude but i hope we can
talk help st george out of his date with what he considers "the only option".

[jmjm530]

Cruel: this may be rude
------------------------------
Hopefully, George accepts all the opinions he's been given in a postive light and if he doesn't, well, he can tell some of us to "shut up" -- that's his right -- and it won't be the first time someone told me to shut up :)

Yes, we seem to be on the same page, and from early-on, I was afraid that the strong treatment "soup" George was putting together might not be in his best interests -- at least until he's had a chance to reacess his current liver damage (biopsy or fibroscan) and consult with at least two more top liver specialists.

George, if you at all are interested -- and if not, certainly understand at this point -- you might want to refresh everyone with your stats, including:

Age, weight, height, race, date of last biopsy and result, any relevant conditions such as fatty liver, diabetes, etc;

Also, dates of previous treatments, what drugs were used, doses and length of treatment, etc -- and viral response for each of the previous treatments, minimally including the week you had a two-log drop and then became UND in each treatment.

-- Jim  

[lanier]

well now I understand if your dosing ribavarin in the amounts you claim.  You have no clue what is coming.  You are making choices that are impossible to even contemplate, read these other posts.  taking taht dose pre treatment and from the gate.  
You were so rude to me, from absolutely nowhere,and now I see some of the reason why.  you really have one big pile of eggs in this basket you have taken on.  Life is what you make it and life is what you put into it, all subjective statements that really apply.  

what do you weigh? over 350 ?  thank goodness JIMJIM advised you to keep your viral loads and pathology close at hand.

[St. George]

ha ha 350 lbs.  What a rapier wit.

[lanier]

well it would be better if you did, at least as the ribo is changing you shole blood chemistry as it is absorbed intoyou lipo cells maybe you would be better off.  what do you think will happen with that doe? do you think your erythrocytes stop being produced?  they last what about 2 weeks, and tranfers lots of good and bad stuff in and out of the body via the interstial fluid.  also there is the marrow and t-cells and so many other issues I can not even begin to process how it would not just put you flat out.  I'll have to get my ribo bottle out, I a regular weight and in no time after starting my platelets were down to below 100, I was dosing 2x.  it just seems so frightening.  but I am new here maybe hundreds of you guys have dosed this "drug" in this fashion, for me, I cannot understand how.  you must be in perfect health and  less than 40?  chronic less than 15 and low viral load, less than 1million?  

[lanier]

I'm all 4 re-treating, but not with whats available now.  even though you think I am an idiot who attacked your hero, I really, really hope you take good care with this ribo overload.  and I am sorry I hit the wrong buttons on my laptop, i have not cut my finger nails, or my dreadlocks (smile now)  and my 3 teeth need brushing too.  but alas I have not ribo inside my mangy body.

L Lanier

[willing]

tn : hey - great to see you!

mremeet : whatever the mechansim by which riba exterts its effect, and there are 4 per that recent mutagen article (inhibition of viral RNAP, competitive inhbition of IMPDH, immunomodulary and the ever-popular HCV mutagenic effect) they would kick in at the therapeutic dose. I can see a "priming-the-pump" argument, that one doesn't reach the therapeutic dose for the first one or two weeks. However it seems you are suggesting something else entirely, that one's system somehow needs to "warm-up" to riba's effect, and as far as I know there's no support for such an effect. If such an effect existed, wouldn't it simply affect the optimal total drug duration?

Obviously nearly all of the SVRs in the world managed to reach that state even without steady-state concentrations of riba for their first couple of weeks. Nevertheless, if one is looking to extract all the benefit one can out of SOC priming the riba pump can't hurt.

All descriptions of viral kinetics emphasize the huge drop that occurs in the first phase, in the first 48-72 hours when the ifn first kick in. This wholesale slaughter of inocent virions may be even more destructive if accompanied by riba - which it usually isn't as Jim  points out.

BTW, re the TVR/SOC combo strategy you brought up the other day, if it's taken more than 10 years to simply figure out riba dosages, how long do you think it'll take to  figure out how to optimally combine tvr, r1626, ntz and soc?

stgeorge : you might want to take a look at aasld abstract 1310 for encouragement. Their results with daily infergen were some of the best re-tx SVR stats on relapsers I've ever seen:

1310. Retreatment of HCV Genotype 1 Relapse Patients to Peginterferon/Ribavirin Therapy with an extended Treatment Regimen of 72 weeks with Consensus Interferon/Ribavirin versus Peginterferon alpha/Ribavirin

S. Kaiser; B. Lutze; B. Sauter; L. Bissinger; C. Werner; H. Hass; M. Gregor

there should be a copy here if you scroll down a bit:

http://www.hcvadvocate.org/news/reports/AASLD_2007/Abstracts/Tuesday%20posters.htm

[lanier]

COPEGUS (Ribavirin, USP) can be extremely harmful and cause birth defects in an unborn baby. Female patients and the female partners of male patients should avoid getting pregnant. Ribavirin is known to cause anemia (low red blood cells), which can make heart disease worse. Also, ribavirin can harm your DNA and possibly cause cancer (see medication guide for more information and warnings).

Who should not take PEGASYS and COPEGUS?

Do not take PEGASYS alone or with COPEGUS if:

You are pregnant or your partner is pregnant
You or your partner plans to get pregnant during therapy or within 6 months after treatment ends
You are breastfeeding
You have hepatitis caused by your immune system (autoimmune hepatitis)
You have unstable or severe liver disease before or during treatment
You are allergic to alpha interferons or any of the ingredients in PEGASYS and COPEGUS
You have abnormal red blood cells (caused by conditions like sickle-cell anemia or thalassemia major)

The most serious side effects of PEGASYS and COPEGUS are:

Risks to pregnancies
Mental health problems (such as irritability, depression, anxiety, aggressiveness, trouble with drug addiction or overdose, thoughts about suicide, suicide attempts, suicide and thoughts about homicide)
Blood problems (like a drop in blood cells leading to increased risk for infections, bleeding and/or heart or circulatory problems)
Infections (which sometimes cause death)
Lung problems (like trouble breathing, pneumonia)
Eye problems (like blurred vision, loss of vision)
Autoimmune problems (such as psoriasis, thyroid problems)
Heart problems (including chest pain and, rarely, a heart attack)
Liver problems (rarely, liver function worsens). Patients with both the hepatitis C virus and HIV can have an increased chance of having liver failure during PEGASYS treatment. Change in a blood test that measures liver inflammation occurs more often in patients with hepatitis B. If you have a rise in this blood test you may need to be watched more closely with additional blood tests.

http://www.pegasys.com/

the best treatment available has the possibilities/disclaimer of affecting/destroying/damaging many other systems inside the body.

COPEGUS® (Ribavirin, USP), which you also may have heard of by its generic name, ribavirin, is a medication that is used in combination with PEGASYS to help fight the hepatitis C virus. COPEGUS is taken in the form of several tablets every day.

Although COPEGUS cannot fight hepatitis C on its own, studies have shown that it does help PEGASYS work better. The precise reason why this combination of drugs works well is not clear. What is known is that COPEGUS interferes with the reproduction of the hepatitis C virus in many ways—one way is by causing mistakes to be made when the genetic material of the virus is being copied during reproduction. For viruses to survive in your body, they need to reproduce quickly. Interrupting that process helps your body fight off the attack.

Since all medications can cause side effects, it's possible that you could experience side effects while taking PEGASYS alone or in combination with COPEGUS. If you have any questions about your treatment, be sure to speak with your healthcare professional.

COPEGUS can be extremely harmful and cause birth defects in an unborn baby. Female patients and the female partners of male patients should avoid getting pregnant. Ribavirin is known to cause anemia (low red blood cells), which can make heart disease worse. Also, ribavirin can harm your DNA and possibly cause cancer (see medication guide for more information and warnings).

maybe you guys will all call this "old news"  but it's worth revisiting, if you are considering re treating, these are just the "published" facts.  anybody remember those "sleeping pills" they gave out in the 50's to pregnant mothers and said "no worries"  and then the armless, legless babies atarted being born.  now I'm not saying we are having babies, but there are other things more personal that could happen to our homeostasis.

Lanier

[copyman]

like you said this is "old news" and even though most of us know the dangers of riba we know there is nothing else that will "cure" this disease at the present time. actually the riba scares me more then the interferon. the bad things that these tx drugs can do to you is something that we elect not to discuss that often. most likely because reading the facts just makes you feel worse so we kinda never bring it up.

[mremeet]

willingquote: “I can see a "priming-the-pump" argument, that one doesn't reach the therapeutic dose for the first one or two weeks. However it seems you are suggesting something else entirely, that one's system somehow needs to "warm-up" to riba's effect, and as far as I know there's no support for such an effect.”

Yes, I’m suggesting there may be and probably is at least some form of phase lag between the increasing riba serum levels and the (apparent) immuno-modulative effects it has on the body. Of course if the serum levels are increased very slowly, then the phase lag is probably negligible. But if the serum levels ramp up very quickly (as you’ve suggested), then I would suspect there would be a lag between riba-referred immuno-modulation and serum concentration. It does not seem reasonable to expect the body to respond near instantaneously to these referred effects (should they exist, of course). And yes, I believe you’re correct in suggesting there’s “no support for such an effect.” But using my amazing powers of deductive logic, that’s my story and I’m stickin’ to it. ;-)  Also, as an anecdotal aside, I tinkered with my riba dose constantly during my own tx. I could see and feel this postulated phase lag both in my side effect profile and in my labwork.

willingquote: “If such an effect existed, wouldn't it simply affect the optimal total drug duration?”

Not sure I understand what you’re saying here, but if it did simply affect optimal total drug dose duration (by shortening it), wouldn’t that we a worthwhile objective? And assuming you buy into the importance of RVR (within the context of SOC), and assuming (for the moment) pre-dosing riba is an effective strategy for achieving RVR, then wouldn’t it be important to have the riba-referred immuno-modulative effects fully (or largely) engaged prior to commencing IFN dosing? And since RVR (or ultra-RVR) imparts the possibility of both truncated treatment AND enhanced odds of achieving SVR, then I would think the assertion that this strategy would “simply affect the optimal drug duration” might be a bit overly simplistic.

willingquote: “Obviously nearly all of the SVRs in the world managed to reach that state even without steady-state concentrations of riba for their first couple of weeks.”

True, but a fairer question might be “how many people in the world did not achieve RVR and were subsequently denied their SVR as a consequence of not pre-dosing ribavirin?”

willingquote: “re the TVR/SOC combo strategy you brought up the other day, if it's taken more than 10 years to simply figure out riba dosages, how long do you think it'll take to  figure out how to optimally combine tvr, r1626, ntz and soc?”

Agreed, the combinatrix of the possible drugs, their dosages and when to take each drug is growing exponentially. It’ll be interesting to see how things develop as time goes on, especially in regards to the staggered PI dosing mentioned for that particular 28 week boceprevir group.

[TnHepGuy_]

Thanks for the greeting - and great to see you, too!

If you get the chance, fire me off an e-mail (if you still happen to have mine floating somewhere). My entire contact list when "poof" a couple of months ago when Micro-squish asked me to "update" Windows Live Mail. Still trying to recover from that "helpful" upgrade.


TnHepGuy

[willing]

tn: will do. BTW, re ntz, among the many things that remain to be shown is whether its effect on relapsers/nonresponders is significant. As far as I know, what's been released about its mechanism of action is "selectively inhibiting dephosphorylation of eukaryotic initiation factor 2α (eIF2α)". In the context of anti-viral effect, phosphorylation of that initiation factor is done by the PKR kinase in response to ifn-alpha receptor binding on the cell membrane (normally part of the "spraying the neighborhood" effect as HR described it).  One of the tools in hcv's bag of tricks is a domain on its E2 protein, the PePHD domain, that may inhibit this action allowing an infected cell to happily keep translating its mRNA in the presence of ifn. Regardless, ntz's mechansism of action seems to be closely correlated to ifn's. In fact, for the data released at aasld, SVR among the tx-experienced arm, 36%,  was much less impressive than the 93% among the tx naive.

mremeet : OK, there may well be other riba dosing strategies that work better than  co-administration per current soc but that remains open speculation in the absence  of any evidence. My point was only that there is no known reason to believe  that starting riba before ifn has a beneficial effect.  We do however know that riba serum concentration bounces around for the first two weeks and thus that most patients go through their first-phase VL decline without having reached steady state concentration.

In fact, along the lines of open speculation I think there's more support for continuing riba post-EOT. Per the CTL epitope theory,  as substantiated by that "shortens the half-life of infected cells" quote above, there may be reason to believe that continuing riba post eot may expose the relapse-inducing virions that remain  in infected cells at eot.

[mikesimon]

It's always nice to see your name here - and to read your thoughts too. Be well, Mike

[mremeet]

willingquote: “My point was only that there is no known reason to believe that starting riba before ifn has a beneficial effect.”

We may not have any scientifically proven reason (yet, anyway) to believe that pre-dosing riba will enhance anti-viral kinetics (and subsequent SVR rates), but we have a quasi-plausible theory that it just might help (including FLGuy’s anecdotal report of going UND in 2 weeks with a starting VL of 4 mil with cirrhosis). As is often the case in HCV treatment, especially for those in tough to treat scenarios, we must make decisions based on limited and imperfect evidence (as is the case for alinia right now). The way I see it, if the proposed “off-label” strategy does not introduce an unreasonable level of risk and the suspected/hoped for benefit is meaningful, then it’s reasonable to implement and include that strategy (be it IFN doubledosing, alinia, riba predosing etc). In the case of riba predosing, I think it rises to an actionable level and the risk is usually manageable (especially with pre-emptive procrit onboard). As far as the previously mentioned lag between serum levels and possibly referred immune responses, effectively all this means to me is letting the serum levels come up to strength and then letting them “season” at those levels for maybe a week before starting the IFN – with total predosing duration maybe lasting 2-3 weeks (4 on the outside) depending on how convinced I was serum levels ramped up quickly. In the event that little sub-theory turns out to be hogwash, then not much harm done, especially when the totality of a 48 wk (or more) tx is factored in. Bottom line is that if I were entertaining starting an SOC based tx anytime soon, I’d incorporate riba-priming into my treatment. Out of curiosity, what would you do?

willingquote: “We do however know that riba serum concentration bounces around for the first two weeks and thus that most patients go through their first-phase VL decline without having reached steady state concentration.”

That’s interesting to hear that it bounces around for the initial 2 weeks, I didn’t know that. I would think there would be a fairly steady increase to full strength levels over the course of a few weeks. Is it understood why this happens? And if what you say above is true concerning patients undergoing their most profound viral decline while their riba levels are fluctuating (presumably up and down?)…then might this also suggest that predosing riba and equilibriating it to steady levels (full strength) prior to the introduction of IFN might pay dividends?

willingquote: “In fact, along the lines of open speculation I think there's more support for continuing riba post-EOT. Per the CTL epitope theory, as substantiated by that "shortens the half-life of infected cells" quote above, there may be reason to believe that continuing riba post eot may expose the relapse-inducing virions that remain  in infected cells at eot.”

That’s interesting, never heard that one before (at least in the absence of extending IFN too). I know HR had discussed the theory for IFN dose tapering after EOT, mostly as a way to allow the body’s own IFN production/modulation to come online instead of simply shutting off the synthetic IFN faucet cold turkey. Also, I would think the speculated effects of riba you describe above would occur anyway for some time after EOT considering its long half-life.  One thing’s for sure, when I finally quit riba I was glad to see it go!

[Myown]

I was hoping to pre dose ( I still might) and I went for another consult - a "rock star" and asked him his opinion on pre dosing with riba and he said it was "VooDoo." So I guess that means he's not impressed:) He just doesn't buy into it at all.

He used another doctors name and said  "that's Donovan" < not real doctors name ,,,and I said "no, I haven't discussed this with him yet, I forgot, but I will the next appointment."  He thought I got the "pre dose" idea from that particular doctor. I wouldn't tell him that I heard it here. I've made that mistake before(saying I get good info from MH) and I get "the look", but I give ~the look~ right back.

Good luck with whatever you decide.

I have no choice but to tx now cause all these doctors have said that there is nothing around as far as new drugs for geno 2's - and being I am a geno 2 'relapser,' I would be waiting even longer for studies to be done he said. But I figured that, and thats why I call myself " a minority within a minority," - not too many geno 2 relapsers out there:)

Kind of stinko when I really think about it, but at least I am feeling good these days and I am thankful for that.

[jmjm530]

MO: I'm his opinion on pre dosing with riba and he said it was "VooDoo.
----------------------
LOL. I assume it's the "Rock Star" I'm familiar with? Curious though, can you tell us who "Donovan" is. I ask because very little on pre-dosing within the medical community and might be worthwhile knowing what he knows. Just mostly us here with our voodoo dolls :)

-- Jim

[Myown]

LOL I'm supposed to tell "MR SECRET" who? LOL You tell me nothing about you OR I should say, you tell US (your brethren here at MH) nothing,,,so why should I tell you?

Uhm, the rock star,,,,,,,you WOULD know him. When he said "Donovan,"
I have no idea what Donovan thinks about this - Donovan might say he doesn't believe in it either. It may have just been a guess on this doctors part that Donovan is into it. I had quite a few consults
prior to tx and with all my labs sitting in front of him, he may have thought that I got the idea of pre dosing from one of those doctors. I told him no.

He also doesn't believe in tapering off at the end. I said I would go the 48 weeks as other doctors have told me during other consults, but would it be possible to tack on extra weeks and taper. Again, he said no - he doesn't see any reason to do that.

So I have another doctor to talk to and I will weigh it all. That all any of us can do really, right?

[jmjm530]

MO: You tell me nothing about you
---------------------------------------------------
I didn't ask for your name, ssn or measurements (btw what ARE your measurements :)) . Just asking for a doctor's name that you didn't even treat with. I've mentioned a number of doctors I' haven't treated with. Anyway, thanks for clearing up Donovan, and speaking of "secrecy" how come your voice tape was removed from the other side so quickly? Great voice btw, never would have thought it came from a white girl, assuming you are.

-- Jim

[Myown]

how come your voice tape was removed from the other side so quickly? Great voice btw, never would have thought it came from a white girl, assuming you are.
-----------------------------------------------------------------------------------------------------------------------------
I had no idea SFbay was going to do that. Its fun to find out other peoples talents and I wish we could all share ours, but I really didn't want it on here, so when I saw it I asked for it to be removed. SFbay said she was so proud of me, shes so sweet, but I didn't want it on forum.

Yup I'm white. Whenever I sing before a black audience they love me. They always look at each other with jaws dropped. They don't expect it. Its alot of fun to sing in front of an audience that has never heard me before. I like to make people happy and music does just that. I love music so much. I can't even put into words how much I love music. I just love it. I'm glad you enjoyed it.

[TnHepGuy_]

Thank you, Mike.

You've been a great help to many here - myself included - for a long time now. Thanks for sticking around to share your knowledge and experience(s) with those who can use it.


TnHepGuy

[TnHepGuy_]

Makes me wonder that if Alinia's "mechanism of action" is actually so closely related to interferon's, could those re-tx'ers who don't respond when Alinia is added to the regime be experiencing a form of "Alinia resistance" - which in turn might therefore be closely related to interferon resistance (which might explain the reason for their initial tx failures to begin with)?

If true, then adding Alinia in this case (tx-failures) would be just like pushing more interferon into the mix - with no added benefit.


TnHepGuy

[GoofyDad]

willing: Nevertheless, if one is looking to extract all the benefit one can out of SOC priming the riba pump can't hurt.

As I see it, it could conceivabley hurt - just as it could help. There's no evidence that it would hurt - but let's suppose it were to trigger some type of viral wake-up call that ramped up the mutation engines in advance of the interferon induce t-cell attack.

I'm picking nits only to make the point that we don't always foresee the reactions that will occcur when we introduce changes into the mix - kinda like the Starlings imported from England - well actually not at all like that..... more like a sewage spill at a Victoria's Secret... no that's not it either.