to late responders

[cruelworld]

many here are already on higher riba doses throughout treatment, 6 to 8 a day. i dont think any liver doc will argue that it does give you better success. it has no obvious long term side effects like heavy dose interferon does. as far as i know, this accepted knowledge is not very well documented through studies.
but, the little study that jim dug up shows a 90% SVR for 1a high viral load!
(google lindahl ribavirin)
now youve got my attention, but at a cost of 12 riba a day. ive only sold my doc
on uping my dose slightly so far, it is the beginning of my ramp up. im going to shoot for 12 riba a day. each week i will add another and do blood work. i am at 6 a day now, i felt it the first day and now i dont feel it at all, i should be there in 6 weeks. the effectiveness of procrit should be the only factor that could keep me from acheiving the goal. when ive hit the max dose of procrit ,ive hit my wall, i trust from the lindahl study, that i have a good chance of surviving 12 riba a day facilitated with the horsepower of procrit. if the misery level gets to high ill try ADs or pain meds. i actually beleive that if i can pull this off my success numers will go through the roof.  50% to 70%! and i have the worst success profile possible. the deck is totally stacked against me and this can defeat my present low odds (25%). now those numbers make this misery feel worth it. i think each and every person treating out there can get better numbers with upped riba and if you want to go for it, your numbers really look good. i cant find any known long term side effects, all you have to do is live through the anemia once and its over. even though you dont think you can stand it, try it. you cant lose, just revert to lower dosage if you cant stand it. remember, the lame 5 riba a day SOC is tailored the the masses and those studies didnt use rescue drugs,(i dont  think)  i now consider it to be a low and somewhat ineffective dosage.
the problems to get this done are 1. selling my doc on it, i may have to go get a real liver doc in the next few weeks, i havent sold mine on the real high doses yet. 2. getting strong meds for the misery if its bad. i would like to hope that if procrit keeps my hemo at least at 10.5 or 11 it shouldnt be too bad.
everyone, think about this for yourself,
youre going to suffer anyway, why not up your chances?
ill update on my progress with this once a week.

[jmjm530]

Be VERY careful upping your riba.

The "Lindahl" study group was closely monitored using HPLC (high performance liquid chromatography) serum riba testing, that to my knowledge is still not readily available in this country. That, and the fact that 2 out of the 9 active participants required two blood transfusions each.

The "tricky" part, if you want to call it that, is titering up the riba in a way that will get you to a preset therapeutic level (difficult to determine without HPLC testing but in theory possible using the level of anemia as a guide) without putting you in the ER, which is where I ended up when I added riba too fast based on my impatience of "catching up" to the Lindahl study after starting a week late.

You have to keeep in mind that it may take as long as 2 weeks to feel the effects of an increase in ribavirin, so the fact that you can tolerate, say an extra 200 mg, means nothing until you wait 2 weeks and see how you are affected. In other words, you don't want to add xtra riba on Friday just because you could tolerate the xtra riba you added on Monday (my faulty logic), because all of a sudden the xtra riba can catch up to you on a delayed time basis. For this reason, higher dose ribavirin should only be attempted in a very controlled manner and under the supervision of your treatment doctor who hopefully has done some research into higher dose ribavirin and ideally has contacted the Lindahl group for more current feedback on their protocols, etc. My doctor and NP were aware of my exact ribavirin dose at all points during treatment.

All the best,

-- Jim

[SonicBandaid]

Cruelworld, thats great advice you had from jmjm530,
The general "feeling" among liver docs (supported by many studies, but not a question specifically addressed at the outset of those studies) is that the more ribavirin a patient can tolerate, the better, in terms of eventual SVR rates.  Obviously, doing this without careful monitoring, especially for small women, could be very dangerous.  As jmjm530 implies the onset of ribavirin toxcity can be precipitous, and increasing your ribavirin dose beyond 'standard' doses should only be undertaken with the knowlewdge of your Doc and with very careful, frequent monitoring of your bloods.
be well,
sonic

[jmjm530]

Specifically, what I did -- in other words what NOT to do -- was to go from 1200 mg/day to 2000 mg/day by upping my riba 200 mg every 2 days. Even worse, this was very early in treatment -- week 2 -- when my body wasn't at all used to lower hemoglobin levels.

Your idea of upping the riba 200 mg, every 7 days, is obviously more sensible, but still has the potential for overdosing since it takes around two weeks for a change in ribavirin to fully impact your hemoglobin. But again, whatever you do, make sure your doctor is on board, and insist on WEEKLY CBC's at a very minimum (I had two CBCs per week several times) during the time you're increasing the riba and until you hemoglobin stabalizes. The thing you must firmly plant in your mind is that all the xtra riba in the world will do you no good if it forces you off treatment due to unexpected side effects.

-- Jim

[jmjm530]

Our posts crossed.

Do they use HPLC in your country? I'm suprised it's not available in the U.S. given all the papers on the importance of riba dosing.

From what I've read, weight-based riba dosing seems somewhat primitive compared to basing riba dose on constantly monitored serum riba level like the Lindahl group did in the Sweedish Pilot study.

My guess is that most of the resources are now focused on the newer and sexier drugs as opposed to tweaking what already exists. I'm certainly no fan of SOC -- esp the interferon part -- but I think many SVRs have been lost in those who really needed those SVRs, because of the underdosing of ribavirin. BTW glad to see you still posting after that little commotion below.

-- Jim

[FlGuy]

Are you suggesting that you would attempt this without the sanction of the doc? You are nuts.  As Jim mentions, and as the study report, these people were closely monitored during the trail.  And, if I recall (did not recently look at it) these poor souls ran the course of tx at those riba levels.  I think you are in week 25 or so? Where did those increase possibilities (50-70%)  come from or are they wishful thinking?  Why did you decide it was the riba that is lacking, why not the peg?  If it was me, and I was a detectable slow responder, I'd look at the IFN first - at least that stuff won't kill you.  There are people here (Jim, NYgirl, Bill1954, Fishdoc and currently Spacecst) who have had various experiences and results with increased riba.  But, the doc (who has some knowledge) needs to be on board.  The risk you are facing is the possibility of too much riba which might cause you to stop the riba altogether.  Then where would you be? Then again, if going to 12 riba a day cuts down on the number of threads you open daily....maybe a plan.

[jmjm530]

You bring up an interesting point I wasn't aware of, as to the fact that "Cruel" is doing this later in treatment -- week 25 as you state.

That said, while the common wisdom in the U.S. is that increasing ribavirin late in treatment isn't helpful, I'm not sure I agree based on a few things I've heard anecdotally from at least one person in the field. In other words, I wouldn't discount it at all, and again, might want my doc to contact the Sweedish researchers and see if they have any data on late treatment high dose riba (HDR) intervention. As to increasing the Peg instead, not sure if that would be helpful since my understanding is that the role of the Peg is to knock the virus down and that already has happened with "Cruel". Not to mention the potential for more long term side effects from increased Peg. But of course you know, I'm no fan of interferon :)

Be well,

-- Jim

[jmjm530]

The reason I keep suggesting that your doc contact the Lindahl group is because that Pilot study is getting "old" (at least in HCV research years) and I haven't seen much published by them since directly relating to higher dose ribavirin (HDR).

I would want to know if they have more current data from a larger group, as well as if they've had success with HDR later in treatment, and if so, what doses they used, how long they extended treatment, and what SVR rates are they getting. You might also ask them if they are working with any U.S. doctors and/or know of a good HPLC lab here.

-- Jim

[FlGuy]

The way you feel about IFN is the way I feel about riba.  If Cruel is in week 25 (?) and planning to extend (think he mentioned that a while back) then maybe he's not so late in tx.  I just know that I wouldn't touch this plan with a 10 foot syringe. The effects of riba, while on tx, scare me. I must be at least partially copus mentus.

[FlGuy]

TJ:

You are in the 'induction trial' and takeing higher doses of riba (think it was 1600, or so).  Are they doing any 'special', other than cbc's to monitor your blood stuff?

[copyman]

i would think the extra riba would only be benificial in the beginning of tx. to knock the virus down early on. just my take on it .

[r4c7]

Curious.  I'm getting ready for an induction dosing trial because I'm early stage 3 fibrosis and feel I have to treat.  But all this talk is giving me second thoughts.

[jmjm530]

This discussion is about how effecive/safe increasing the ribavirin dose might be with a late responder like "Cruel". I don't see any connection to someone entering an induction dosing trial where I assume you will initially receive higher amounts of interferon but a standard weight-based dose of ribavrin. Induction dosing has been shown to be more effective than SOC in prior non-responders, and my guess is that they are also trialing it for first-time treaters as well but really not sure.

-- Jim

[FlGuy]

If it's the increased peg/riba 'induction' trial, keep a look out for tjaloha, he's about 8-10 weeks into it.
If I were looking for a trial, and vx was not available, I'd certainly consider the induction trial.  With current tx, docs got their heads together and came up with a modified and personalized regimen for me for me that has some  similarities.

[r4c7]

To clarify, the reason I mentioned 'induction dosing' is because its my understanding that there are two groups (out of four) in the trial that get high-dose riba starting from day 1.  

[FlGuy]

Think thaloha figured out he's either 1400 or 1600 riba - but it's a blinded study

http://www.clinicaltrials.gov/ct/show/NCT00394277?order=7

[SonicBandaid]

Yes, we use HPLC, but generally in a research context.  For folk who are not responding with adequate reduction of HCV RNA early in therapy, I tend to 'push' ribavirin dosing in the same way Lindahl has suggested, but do so guided by their haematocrit and haptoglobin back off promptly once the haemolysis becomes problematic.  The HPLC results I get are still a little slow for optimal management decisions, but once the throughput is quicker I will push ribavirin doses faster.

I think there is still a lot to be gained by trying to optimize the treatment regimen of individual patients, and personally, am not that optimistic about the protease inhibitors (in terms of them being a panacea anyhow), but hope to be proved wrong.
As to the commotion, a bit of vigorous debate may be healthy...
keep up the great work, Jim!
Sonic

[jmjm530]

The doses of ribavrin that we were talking about here are much higher than the 1400 or 1600mg/day that "FlGuy" mentions. I wouldn't be overly concerned about those doses if you are closely monitored and while I'm not familiar with your stats or trial specifics, in general a little more ribavirin just might provide you with a better chance of SVR as long as its tolerated.

-- Jim

[nygirl7]

I upped my own riba (the doc approved more for my weight AND then I decided to just start taking tons extra) and almost ended up in the hospital having to stop treatment because of anemia.

Dr. IRA JACOBSON in New York actually cut my ribavirin (at 46 weeks - not at any crucial point in my tx - at a point where if I was not continuing I would have been stopping anyway).

He said one of the BIGGEST dangers to us is becoming dependent on the EPOGEN and having to take it on a regular basis. That it is quite possible that your own body will stop accepting the epo that it does make on it's own already...and then you will die.

He simply refused for me to stay on the upped dosage (what he knew about even).

He said quite simply after the first 1 weeks it simply made no sense anyway.
Point of fact - you don't really know you are even a late responder UNTIL then anyway do you?

Now Dr. J is one of the most important Doctors in all the hep community.  He worries NOT ONLY about double dosing to get rid of virus but ALSO to make sure we are alive at the end of treatment to see the results of SVR.

I'm sure if you take triple dosed meds all throughout treatment it will give you a boost but at whata cost?

There are many many many complications that arise from these meds. They are HEAVY DUTY POISONS IN OUR SYSTEM. AND THERE ARE MANAY OTHER THINGS TO THINK ABOUT BESIDE BEING A LATE RESPONDER DURING TREATMENT.

BEING ALIVE IS OF UTMOST IMPORTANCE.

[jmjm530]

Given what you've said, it appears you're ahead of 95% of the docs here in terms of individualizing treatment. As to the "commotion", that is sure to come here any time you mention anything that may be outside the box of what most are told by their doctors, or whatever common 'wisdom' the discussion group has accepted. Occasionally respectful "debate"/discussion replaces "commotion" and that's when this place is at its best.

Back to the ribavirin. Given the fact that it takes ribavirin "x" days to get up to whatever therapeutic level is targeted, what do you think about the concept of pre-dosing ribavirin, let's say anywhere from one to three weeks prior to treatment -- and/or combining the predosing with prophylactic Procrit (epo) to allow an even higher starting serum riba level. I understand that ribavirin by itself will not kill the virus, but with this approach a patient would be in effect on HDR from the very first injection as opposed to however many weeks it takes to get there the way it's currently done, even with Lindahl.

Pre-dosing ribavirin is a concept I thought about early-on in my own treatment (therefore of course I didn't do it); then later read a post here from someone who said they were in a pre-dosing study (we never heard back from that person nor could I find that study); and then anecdotally -- "FlGuy", I believe, tried pre-dosing himself (1-2 weeks if I remember) on his second go at treatment -- and I think was non-detectible by week 2? which if correct, is pretty astounding given his first go-around, but maybe he can fill in the details.

Thanks again for your contribution here. You background appears to be a mix of both researcher as well as hepatologist, which makes let's say a double contribution.

-- Jim

-- Jim

[nygirl7]

Only problem is no doctor on the planet is going to prescribe prophalactyc (sp) procrit - hell we have a hard enough time getting it after our hemo plummets.

with the serious side effects and black box warnings that just came out recently - they aren't ever going to do it.

It makes sense to take riba first and build up the serum level BEFORE starting the interferon to me 100%.  But, with the anemia as dreadful in some cases as it can be - for me personally in my case - I know it wouldn't have been possible....without the epo and damn they really do fight NOT to give it to you under all costs and this means more time on the riba and more time on the epo.

[jmjm530]

NY: I'm sure if you take triple dosed meds all throughout treatment it will give you a boost but at whata cost?
------------------------------------------------------------
I couldn't agree more. Often argued that very point in terms of people extending treatment beyond where study data proved it signficantly useful, and in fact have argued against it even in cases where it might have been significantly useful, but where folks had little or no liver damage. But 'keeping it real' you have been one of the biggest advocates of extended treatment (72 weeks) here at MH. Not a criticism, just an observation, and I understand it comes from your heart -- and yes from studies -- showing better results in some cases.

As to Dr. J.saying "That it is quite possible that your own body will stop accepting the epo that it does make on it's own already...and then you will die" you know I have nothing but respect for Dr. J.-- in fact recommended him to you -- but I really doubt that is what he said, or at least how you paraphrase it. And if he really means it, there are others equally qualified that use epo throughout treatment without those concerns-- my doc but one example -- because they get better results that way. At least one current study on this.

And lastly, back to Dr. J., I do remember he pulled your riba back later in treatment because of your side effects, as my own NP suggested to me as well. But I also remember that when you first saw him that he was impressed you were on a higher dose to start with and thought it was a good thing. I also remember -- and I hope this is right -- that your dose was 1000 mg/day which really isn't that high for a genotype 1, and in fact in some dosing protocols would be considered SOC even for your weight.

Hope this finds you well and glad to see you're as feisty as ever.

-- Jim

[Bill1954]

A quick personal history;

52-year-old Caucasian male
Currently 187 lbs (85 kg)
Diabetes M. type 2, current tight control (last A1c at 3.4)
HCV genotype 1a
Low initial VL (74,000 IU/mL)
Grade 3, Fibrosis stage F3-4 (Metavir) per subcutaneous biopsy Jan ‘05
Significant hepatosplenomegaly per U/S scan Jan ’05 and Aug ’06
Biochemical markers indicate synthetic function still intact (coagulopathy, protein production, etc).

Diagnosed HCV RNA positive 11/04. Commenced treatment with Pegasys 180/ ribavirin 1200 on 2/18/05.

SLOW RESPONSE: I was unable to achieve 2-log drop at 12 weeks; disused salvage of current treatment efforts with GI doc; based in part on 12-week CBC results, and my ability to subjectively tolerate Tx, we increased my riba titer to 1800 mg/day. This delivered a ratio of 15.5 mg/kg day.

Extended treatment to 56 weeks with this protocol, then promptly RELAPSED within 30 days post treatment.

Reduce body weight from 255 lbs (115 kg) to current 187 lbs (85 kg) between treatments. (new BMI 25.2)

Commenced new treatment Sept 12, 06 with PEG-Intron ~202 mcg/week, ribavirin 2000 mg/day (23.5 mg/kg), and intended duration of 72 weeks.

Currently in week 38/72. Undetectable per bDNA assay (<615 IU/mL) week 4, undetectable per TMA assay (<5 IU/mL) week 8.

Hemoglobin values have not dropped below 11.4, and have recovered to mid-12’s without EPO. Other CBC values are slightly suppressed, but not to the point that require intervention. Subjectively, I ‘feel’ quite well; mostly ‘nuisance’ issues (dry skin, persistent, mild mouth ulcers, etc.
~~~~~~~~~~~~~~
This current protocol has been developed WITH the blessing of my hepatologist and is my ‘on record’ assigned dosage. As mentioned above, I wouldn’t dream of doing this without MD’s full approval, and subsequent supporting labs.

Good luck to you in your efforts; my un-educated advice is to carefully weigh the risk/benefit analysis with your healthcare provider based on current liver histology, and any other factors present. There are many unknowns involved with these meds; including lack of full carcinogenesis/mutagenesis studies re: ribavirin, etc. Make sure you discuss known risks with your doc, and weigh carefully. Proceed with caution and respect these meds!!

I’ll have SVR info ready for you ~ August ’08… until then take good care, and let me know if I can offer you more info, I’m sure I’ve forgotten some here.

Be good,

Bill

[Bill1954]

Would you be so kind as to provide an overview on the significance of monitoring renal function as it pertains to establishing ribavirin titer?

[FlGuy]

Pre-dosed 1200 riba for a week before first peg.  Double-dose peg (360) for the first 4 weeks.  Backed off the peg to 180 and maintained the 1200 riba throughout.  Undetectable at week 2, going a total of 46 weeks.  In week 32 now. Also with guidance/cooperation of tx doc, a univ liverhead and a hematologist.

[FlGuy]

With that weight loss, managing a1c to 3.4, doing 56 and then 72 with that riba shows determination that I couldn't imagine in myself.  Good show.

[jmjm530]

In case Sonic is counting sheep -- I think it's around midnight in Australia -- Lindahl & Company used a pharmakenetic formula based on renal function to determine the initial riba titer in their pilot study. From what I have heard/read, the formula as then developed still needs a lot of tweaking and for that reason they underestimated the starting dose in most cases as later demonstrated by HPLC testing. They have at least one paper out where they put forth the thesis that renal function is more important than a patient's weight in dosing ribavirin. If interested, you can probably find it by googling "Lindahl" but let me know if you can't as I may have it on my hard disk somewhere. Currently, the only folks that I read about who are dosed by renal function are those treating with an imparired renal function such as dialysis patients.

Hope this finds you well,

-- Jim

[Bill1954]

Thanks for diplomaticaly referring to my efforts as ‘determination’. I’ve assumed it was primarily driven by neurosis…

Several of your responses lately have left me in stitches, by the way- You’re one funny dude. If I run out to Boca, will you autograph my whoopee cushion?

[Bill1954]

Thanks for your prompt response. I’ve put the study your referring to in the same place- *somewhere* in my hard drive ;o).

I was hoping Sonic could elaborate further, or possibly provide a redundant view.

Glad to hear you are faring well after your last bout with Afib. I recall you discussing your family history- glad to hear it “wasn’t the big one, Weezie”!

Take good care,

Bill

[FlGuy]

You need to get modern.  My kids (ok, it's me) have an electronic whoopee cushion.  It has a timer feature so you can 'set it and foget it' and leave the area and embarrass the people remaining in the room. Not sure if it's the Poppeil model, though.

[wyntre9]

Good thread.

I'm following this very closely coz of my circumstances; slow responder, not UND at week 12, UND between week 16-18.

Now on week 24, genotype 1A, expect to do 72 weeks.

Like Cruel, and others on any form of TX, I'd like to do everything in my power to successfully complete TX and get SVR without relapsing.

While I wouldn't consider changing riba dose without consulting my Dr., I am very interested in whether or not I should broach the subject with him.

Isn't it moot once UND is reached?

Is there any evidence that late responders can benefit from increased riba AFTER
having reached UND and THEN continuing higher doses for the duration of TX?


wyntre

[Bill1954]

NBC’s Today show features high-tech innovations a week or so before fathers day (coming up). I’ll look for an update on your model there? Possibly with downloadable ring tones? I’d love the option to personalize… Popiel, HAR!

[cruelworld]

first, i will do this only with full doc support and close monitoring and considering the danger, two cbcs a week sounds pretty safe. if i slow down the dosage ramp up to two weeks until doseage increase, that sounds safe to me, it will take 12 weeks to get there, but ill be alive. at that point i will still have 38 weeks of treatment left so i have time to get a good result. my doc already approved a 30% INF increase, i havent accepted it yet but if i did i would be virtually on the same regimen as "bil1954". im somewhat afraid of the upped INF,
but a 30% increase may be an acceptable risk. i was fearful that docs wouldnt preemptively prescribe procrit. your testimony confirmed this and thats bad.
should i search for a doc for this premptive approach or will simply none of them do it?

male 48
160 lbs lean runners body 6 ft
high viral load
3/3 liver damage
late responder week 20
no rescue yet
tolerating sides very well the last two months

while im here, i havent had a chance to see yet if yall came up with any other options for ladywhy. if not, the only suggestion i havent seen is a switch to infergen at 30% overdose and the increased riba would be obligatory. her situation needs attention from what ive seen, for any one with a fresh idea i think she could use it.

flguy, i dont know if you were just funnin me or not, but ive averaged only 2 or 3 posts per week since ive been here. i agree it was a little high lately but this, to me is acceptable from anyone so long as it doesnt last more than a day.
but i do apologize if you feel like i mucked up the board.
thanks everybody and paint yourself a picture today. a pretty on with one year SVR symbolism secretly embedded everywhere.

[FlGuy]

I was mostly funnin' you. Since I lack the expertise that many around here have, it's my lot in life.  These meds, as you know,  are serious business, stay close to the doc as you plan to tweak. Doesn't do much good to take the aggressive steps if you end face down short of the finish line.

[Bill1954]

Thanks for stepping in and saving the integrity of this thread- FL and I were helping it to  rapidly disintegrate.
Here is a link to the “Lindahl” study mentioned above (abstract only):

http://tinyurl.com/2hm64v

I have the full text study in print only somewhere; I’ll dig around for it when I have time. The P-dynamics or kinetics of riba aren’t discussed in detail here, so this paper doesn’t provide much info regarding timing. My hepatologist firmly believes that ribavirin is critical to the success of attaining SVR, and his dosing regime reflects that belief.

My uneducated understanding of mechanism is that riba invokes viral DNA “disruption”, inhibiting the ability of the HCV virus to continue replicating. Whether this has any significant effect after a patient achieves undetectable serum HCV RNA status is unknown to me, and possible something that Sonic Bandaid might want to elaborate on.

Advice on trying to salvage current Tx? It sounds as if you *are* responding, but slowly. These decisions are exasperating; the only thing I can suggest is*don’t* disregard the hard-won information and studies showing very limited chances of achieving SVR with SOC treatment regarding slow viral response. Does altering the dose/duration of these meds have any effect other than just scratching the statistical bell curve in terms of efficacy? Certainly a question better answered by someone more informed than myself.

Good luck and take care,

Bill  

[jmjm530]

Wyn: s there any evidence that late responders can benefit from increased riba AFTER having reached UND and THEN continuing higher doses for the duration of TX?
------------------
Nothing I could find in the literature, and in fact, most docs (and at least one study) will tell you that there is no benefit. That said, I have heard from someone in the field that they did have good results upping the ribavirin after reaching UND, and personally it would be an avenue I myself would explore IF warranted by significant liver damage and if tolerated. You might also have you doctor get in touch via email with Dr. Lindhal to see if they have any data on the effect of increased riba in late responders after reaching UND.

Cruel, some docs do believe in pre-emptive Procrit (epo) and I'm sure others could be persuaded if your plan warrants it. How easy to find that doc I really don't know but you might first start researching it out in order to be able to show your doc something in black and white that supports the position. Don't know how much liver damage you have, but my personal take is that only significant liver damage warrants a significantly agressive approach. It's the ole' risk versus rewards thing.

-- Jim

[r4c7]

Yes...I see Cruel is talking about higher riba doses.  I really like Cruel's attitude and willingness to beat this curse.  Incidentally, my stats 1b, 1,000,000 VL, early stage 3, grade 3, 55 yo male, 220 lbs., treatment naive. Would love to manuever into Vertex trials but can't get in. So Hoffman-LaRoche looks like the next best gig...start next month.

[nygirl7]

As far as Doctor Js comment - I may not speak as eloquently as he but I am POSITIVE he said that one of the possible consequences of taking Epo can be that your own body stops producing it and as you know you NEED epo for every day hemo issues.  Without it - there is a very high chance you will die.

this is why he pulled me off all of the extra riba (and in fact he said at this late in the date it did absolutely no good and that likely it NEVER did any good to do more than weight based).


I have been very proactive in saying and believing that ANYONE with stage 3 damage SHOULD  do extended treatment if they fall into the study parameters.  At stage 3 - with little negotiating room and such incredibly severe liver damage already done to the body --- I do not feel that it is worth attempting to "retreat" unless the 72 weeks fails.  It gives ONE MORE GOOD attempt at getting to SVR BEFORE using up the "retreat" card.

There is a vast difference between taking triple dosages of medicines and taking meds in a controlled environment at dosages.

Random helter skelter treatment and od'ing meds makes NO SENSE.  

The sides from the meds are too much a wild card variable to take a chance.  

Slow and steady wins the race and I learned that the hard way.  I NEVER want anyone to go through what I went through with the anemia EVER and the RASH and all of that was caused 100% by the stupid riba.  

Anyone who thinks it is just a little tiny pill is foolish that little pill has more powerful poison in it than I EVER believed possible.

[cruelworld]

since the lindahl study used high dose after UND i would assume at least they though it would benefit and it appears that it did. i would also guess that that
regimine created many rapid responders but dont know for sure. i personnaly beleive the effect will be strong even used after the late response to UND. i have a real problem though,
all i have is the abstract for that one study and no other documentation.
i showed it to my doc and so far he disregarded it mostly
can you help me with documentation to sell my doc. i will have him call them as you suggest
will i be able to find a contact for lindahl by myself?

oh by the way, going to the hospital with possibly fatal problems is not a very good excuse for leaving us here for a few whole days to fend for ourselves. luckily nygirl and others were here to take up the slack.
im beginning to think you just dont care about us anymore.
our new courtesy rules require that you be available 24/7 all year round
and dont you forget it.
in truth your ordeal doesnt sound like much fun, but im sure you can crack the code for healing and wish you the best. be well high priest!

[wyntre9]

"Thanks for stepping in and saving the integrity of this thread- FL and I were helping it to rapidly disintegrate."

I didn't mean to do THAT!  *LOL*

All,

Thanks for the references to the lindhal study - i will check it out.

NYG,

Your first hand experience with these issues is very helpful to those of us at the beginning of the 72 week trek.

wyntre

[cruelworld]

i appreciate you repeated warning. if anyone can give us that warning its you. i figured procrit had some drawbacks because of its high horsepower, but from what i see even on our forum it is used extensively and effectively without too much carnage. my riba ramp up will last 12 weeks, thats three months. im guessing that at least half the doctors will ok that as safe. i will up the dosage by one more pill every two weeks, plenty of time to stabilize. thanks.

[wyntre9]

It's such a short report I thought no one would mind my posting it.

Thanks for the link, Bill.

High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C.

Lindahl K, Stahle L, Bruchfeld A, Schvarcz R.

Department of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.

Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa-2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600-3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. At follow-up (>or=24 weeks posttreatment), nine of ten patients had undetectable HCV RNA and thus were cured by standard definitions. In conclusion, a high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation.

[Bill1954]

You might try to contact Dr K Lindahl in care of the Karolinska Institute at their general e-mail:

***@****

Karolinska Institutet
Phone:
[phone]
Fax:
[phone]
Postal address: SE-171 77 Stockholm
Visiting address:
Nobels väg 5, Solna
Alfred Nobels Allé 8, Huddinge

Best, Bill

[Bill1954]

If you or anyone else is interested in a hard copy of K Lindahl’s full text paper, you can reach me at: w dot keyes at att.net.

Keep in mind that the authors entered the caveat:

“…Side effects were more frequent and serious, in particular potentially life-threatening anemia, than those observed with standard combination treatment. Therefore, we do not recommend this treatment regimen outside clinical trials. In particular, patients with coronary heart disease and patients with cirrhosis would be at great risk…”

Take good care,

Bill

[ladywhy]

just returned form hep dr;s office. Doc is still away. Attempted to get NP to allow for upping riba from 1000 mg to 1200 mg. i have to have 12th week lab done..at this rate I'm 135000 VL. I am debating in my head about upping  the dose myself....just until Monday when I do blood work. My ins. is the worst. they do not continue paying for tx if not UND by 12th week...anyone know or think this may help drop the numbers....I know it's only a  few days but...I am really concerned about being taken off tx. This is such a hassle. NP told me even if doc were here he wouldn't do anything until 12th week...meaning changin' dosages. I am not so sure of that.. I hate 2nd guessing. I am trying not to control what I have no power over and go with the flow...but it's hard. I wish dr. had been here the last few weeks and maybe I could have upped before. I have no idea if just for a few days...the vl would come down dramatically...what d'ya think. Thanks for any and all feedback.
Yvonne

[FlGuy]

Maybe I missed some of your posts.  How recent (what week) is the 135,000 v.l. from?.  It sounds like you have an upcoming pcr, so that mplies that the prior was few-several weeks ago?  Again, maybe I'm missing something.  Not sure what impact adding a riba a day to show an impact on a pcr in 5 days would do.  In another thread I think your hgb was at 14.  Was that recent too? and what hgb did you start at?  In talks with my doc, and discussions around here, decreasing hemoglobin can be construed as almost kind of a good thing.  That is, the riba is likely getting to where it's supposed to go and hopefully doing what it's supposed to do.

[cruelworld]

remember, im not an expert and most of this is just a guess. first off, dont worry about the insurance and the drug cost, im sure the drug companies or some entity will help you with this, if needed. unfortunately youve got such a long way to go with vl i dont see how you could make it. maybe with double IFN
and upped riba starting today but even then its tough. the slight increase in self administered riba wont help much for the deadline either. i made a post on the other side for you and this dilemma. check it out and give it the rest of the day to get answers. can you financially cover the action for a month until other help arrives? the only thing that really scares me is mike simons recommendation to stop. there may be another angle. dont even think about giving up yet. just hold tight for a day or two, in the meantime prepare for the ins money to stop and work up a backup plan.

[Bill1954]

Yvvone;

I’m sorry to hear of your dilemma. It sounds as though our profiles are somewhat similar, slow VL response etc. I think it’s important to understand that there is a *reason* insurance actuaries are hesitant to pay for continuation of treatment after x days with poor response. They face the prospect of diminishing financial return based on years of data analysis. The same is true for patients- no point in continuing treatment and risking additional exposure to these meds for the purpose of achieving viral response under dismal odds. However, there seems to be a growing body of thought that fibrosis progression might be minimized through the continued use of IFN; for those of us with significant liver disease, this alone makes the continued long-term exposure to interferon an acceptable secondary outcome to treatment in some cases. This is a decision that you and your doctor need to discuss at length.

Regarding increasing ribavirin to decrease VL at the last minute: I know very little about this- again, your doctor is the one to help guide you through this. I’d carefully consider changing duration or titer of medication without your doctor’s blessing; at the very least, call/fax his office prior to any dosage changes informing him of your intentions so you remain on record. An action like that might jeopardize an otherwise good (?) working relationship with your doctor. In my humble opinion, your doctor will be much more effective down the road writing carefully crafted letters to your insurance company along with supporting studies (if he sees fit). As mentioned above, there is a good chance that you will qualify for financial assistance through the pharma’s Patient Assistance Programs if you are denied coverage by your HMO/PPO.

It just might be time to take a break and regroup; and remember that a well thought-out plan will almost always yield better results than hasty decisions.  

Good luck with your next viral assay results, and take good care—

Bill

[BThompson4]

I think it is insane to jeopardize your whole treatment by increasing riba so much.  

You might consider extending to 72 weeks at 1200 mg riba instead.  The Sanchez-Tapias study participants only did 800 MG/DAILY for 72 weeks, and got 44% svr.  You say you are 25% chance of reaching svr now; extend to 72 and do 1200 mg riba daily and your chances could go significantly over 50%.  You are having no problems with the current 1200; do it for 72 weeks and you will probably have much better chances than the 44% svr of Sanchez-Tapias' 800 mg riba group.

[cruelworld]

thanks for bringing out the fact of low 800 dosage in that study.
i wasnt aware. my estimated 25% chance was based on 72 weeks. maybe i lowered the estimate too much when accounting for stage 3 liver damage. in any case
12 a day does seem outrageous but i know i want to do at least 9 a day. my remaining dilemma is whether to go for a 30% INF increase as well. im leaning towards it. of course my worry is permanent problems, i dont feel so pushed that i have to accept that as the cost of doing business. thanks for the input.

[ladywhy]

Here goes my "poor me" story. I had bx last year, vl checked @ 2.9 mil. Before I started tx...NO TESTS were performed.(though I DID ask if I should have any) So it is anyones guess what my vl load really was. 4th week cbc..Hemoglobin was 14.6..just now looked it up. Talked to NP at Hep's office and she "assured" me that not everyones HMG drops and told me to let it go, "I'm being anxious over nothing.". (???) I just looked at her and said...oh... I try not to talk to much about this website and just say the research I have done.... Luckily this am I had a moment before heading to doc office and read about the Lindahl study...brought that up to no avail. As I posted elsewhere..I am 5'7" (a wee 1/4" less..actually) and 175 lbs. Which I despise advertising:<(  
..anyway....should I bump up to 1200???
It doesn't seem like that much to me compared to what amounts others are taking at their weight doesn't seem like it would be such a big deal. But there is no point to it if it won't work magically in what 5 days. The last PCR i posted was only 10 days ago. Do I...or don't I... That's the big question.Yvonne
i am 1a...got the fibrosis thing between stage 2 and 3...I know I;m not good with medical jargon.

[BThompson4]

I am geno 1a and did not clear until between weeks 20 and 22.  I do shot #50 tomorrow.  Like you, I would consider adding more riba to the 1200 daily I take now, but I am post-transplant and lots of times post-transplant treaters can't handle the riba as well as other people.  

Hopefully, extending treatment will have as good results for me as increasing doses (and often extending) have for others.  I already got a huge plus from treatment as my 36 week biopsy showed no significant fibrosis (assuming the biopsy was accurate, but there is no way to control for that!) significantly improved from the F2 fibrosis I had one year before starting treatment.  That probably translates to at least the last 36 weeks of treatment with very little liver damage (certainly not F3 or cirrhosis), something that should make it a little easier for me to get to svr (the virus will have fewer places to hide in a less damaged liver).  So I should at least emerge from the 72 weeks in decent shape to wait for vertex if it is approved.  I realize and appreciate that the situation is a little more dire for someone at stage 3 fibrosis, and that the virus could be hard to get rid of in that stage.

Some researchers like extending to 72 weeks for geno 1's because it gives more time to kill and replace infected liver cells.  So, theoretically at least, and there is probably no way to prove it, just extending to 72 without increasing doses could be enough to get the job done, though increasing doses would obviously give you a better chance if you can stand the side effects.

There is a fairly recent study out there that looks at svr rates for people who treated at 1600 mg riba daily (I think they also got more interferon, too) for 72 weeks and compares them to people who treated for 48 weeks.  Maybe someone can post a link to it.

Good luck with your treatment!

[FlGuy]

Riba is usually dosed at 13-15 mg per kg. You are at the low end of the range at 1000. Would have expected doc would have put 2 and 2 with your hgb, response, BMI and the dosing. If it was me (I'm a relapser so I'm not a fan of standard of care) I'd probably give it a try.  Are you sure about the insurance restriction?  Have you pursued it further?  That might be where the real opportunity is

[GoofyDad]

Wow lot's to read - I admit to skimming much of it. Two points:

1) To me the biggest issue (mentioned in this thread but I'll highlight it) is that people metabolize Riba at different rates, and talking about daily dosage doesn't get the job done. If it were me I'd be thinking, if I ain't on EPO, I wanna be. Meaning up RIBA until EPO is needed (or at least right at the cusp)

2) There is much debate on the mechanism of riba, and it's hard to theorize whether it's important early, late, or or middle when you don't know how the cr@p works.

3) Ok I lied on my number of points - While it doesn't seem that riba has long term affects, it's siblings -  EPO and extended severe anemia - do.

[ladywhy]

"Are you sure about the insurance restriction? Have you pursued it further? That might be where the real opportunity is"

I'm not getting what you mean? They are now paying only for my Pegasys injectables...they said i maxed out my prescrip. plan and the riba was on that. They are paying for the injectibles cause they put it on "medical". I appealed that decision by stating that I could not do one without the other. I was denied. Told I could do a 2nd appeal....
12 weeks without a 2 log drop - they do not continue to treat. Period. The wiggle room is the fact that I was not ordered tests before txing. (I've since changed docs) I may very well have a two log drop, the vl coulda been 5 million,...who knows what a whole year can do, do you understand?...So maybe that could be a loop hole. I asked Dr. if I needed any tests before I started...the answer was no. I'm sorry if I keep repeating the same thing all over these posts...I'm just never sure who read them. I am self insured and obviously I don't have the best plan. Thanks for your input..as of tonite I went to 1200 mg.
Y

[cruelworld]

bthompson - sounds like youve got your treatment tweaked out. how long did it take
for the new liver to get to stage 2?

goofy - 12,345 words converted to 32.  cool
what do you think is the risk factor of a 30% INF increase for the next 12 months
towards long term sides?  high, medium, or low?

[FlGuy]

I double-dosed IFN for 4 weeks, 2 shots the same night.  I didn't think the additional sides were all that bad.  As for the long term side effects, well, I guess having a third arm now has it's benefits.  Having three testicles is a bit awkward though.

[Valtod]

CruelWorld:
Thanks for bringing out the fact of low 800 dosage in that study (Sanchez-Tapias).
----------------

Please see this chart from Ferenci's study of G1 delayed responders (UND after week 12) on Pegasys and weight-based RBV 1000/1200 mg/day:
http://www.natap.org/2006/images/110606/Figure3-4.gif

I often look at this chart when I need psychological reinforcement to go on for 72 week. Do you see the last bar? These are 13 real people, delayed responders like you and me, who went for 72 weeks. Only 3 of them relapsed, the other 10 achieved SVR. You and I could be one of these 10! For a G1 delayed responder 23% relapse ratio is extremely good news. Especially, when you look at the previous bar – 19 delayed responders, treated for 48 weeks (SOC), and 12(!) of them relapsed. This is 63% relapse ratio. "63% vs 23%" – I often remind myself this when I have to reach for the next injection. (I'm currently in week 60).

I think you should read the whole article:
http://www.natap.org/2006/AASLD/AASLD_34.htm

Please notice a very interesting detail – those who extended treatment after week 48 REDUCED the Pegasys dosage 25% to 135 ug/wk for the last 24 weeks. And yet, most of them achieved SVR.
See http://www.natap.org/2006/images/110606/Figure1-2.gif

6 weeks ago I went to see Dr Nelson at Shands in Gainsville, FL. He's considered an expert on current and experimental treatments. Based on Ferenci's and other studies and his own experience, he suggested reducing my Pegasys dosage with 25% and extending Tx to 72 weeks. He had no doubt that reducing Peg and RBV dosage to 75-80% after week 36 would NOT affect the chances for SVR.

Initially, I was reluctant to accept this protocol but after I did my own research on the Internet, now I tend to agree. Especially, after I studied carefully the Replicative Homeostasis viral kinetic model by Richard Sallie, I see why after some very low level of viremia is achieved, reducing the amount of INF and RBV molecules per unit blood makes sense.
http://www.virologyj.com/content/pdf/1743-422X-2-10.pdf
http://www.virologyj.com/content/pdf/1743-422X-2-70.pdf
http://www.virologyj.com/content/pdf/1743-422X-4-29.pdf

Also, I'd suggest checking out Sanchez-Tapias' presentation (especially page 18):
http://www.vhpb.org/files/html/Meetings_and_publications/Presentations/MADS62SanchezTapias.pdf

----------------
Wyntre:
Is there any evidence that late responders can benefit from increased riba AFTER having reached UND and THEN continuing higher doses for the duration of TX?
----------------

No, there is no such evidence. Any induction approach or tweaking of dosage makes sense only in the beginning of Tx, especially the first couple of weeks. After having reached UND, dosage increase will not bring any benefit (but prolonging Tx duration will). Actually, reducing Peg and RBV to 80% can be safely done after week 36 (or week 48 in case of extened Tx). See above.

----------------
BThompson:
So, theoretically at least, and there is probably no way to prove it, just extending to 72 without increasing doses could be enough to get the job done, though increasing doses would obviously give you a better chance if you can stand the side effects.
----------------

Well, all the studies below prove that extending to 72 week WITHOUT increasing doses is the way to go for delayed responders. For theoretical background, see the Replicative Homeostasis articles mentioned above. And, no, increasing doses after reaching UND would not obviously give you a better chance.

72 Weeks Pegasys/RBV in Genotype 1 Improves SVR Rate For Patients With Early Viral Response (2 log reduction at wk 12) But HCV RNA >50 IU/mL
http://www.natap.org/2006/AASLD/AASLD_34.htm

72 Weeks Peg/RBV for 'Slow-Responders' Improves SVR Rate
http://www.natap.org/2006/AASLD/AASLD_32.htm

In Patients Who Clear HCV RNA At Week 12 (between week 8 and 12): SVR is Higher After 72 Weeks Than After 48 Weeks Treatment: Results of a Randomized Controlled Trial
http://www.natap.org/2007/EASL/EASL_32.htm

Prolonged Pegasys+RBV Therapy to 72 Weeks May Improve SVR in Patients Who were HCV RNA+ after 4 weeks & slow responders
http://www.natap.org/2004/AASLD/aasld_25.htm

72-Week Treatment More Effective than 48 Weeks for Patients with Detectable HCV Viral Load at Week 4
http://www.hivandhepatitis.com/hep_c/news/2006/082906_a.html

Efficacy of 72-Week Treatment for Genotype 1 HCV-Positive Patients
http://gastroenterology.jwatch.org/cgi/content/full/2006/825/1

Good luck ot everyone!

[BThompson4]

When I said

"So, theoretically at least, and there is probably no way to prove it, just extending to 72 without increasing doses could be enough to get the job done, though increasing doses would obviously give you a better chance if you can stand the side effects."

it was only in relation to guaranteeing svr.  Naturally, the longer the better.  I wonder if we will ever see studies beyond 72 weeks.

Thanks for your articles citations and input.

[BThompson4]

It took 4 1/2 years for my liver to get to F2 after transplant.  I did great the first year and a half (all liver panel measures were in normal range).  My quarterly pcr's were great in that time period, all ranged from 60k to 250k iu,/ML.

Unfortunately, the hep c hit like a ton of bricks at the 1.5 year mark.  I got sick and stayed in bed for about a week and all the liver numbers jumped.  Viral load went over 2 million (and a year later over 3.5 million) and bilirubin jumped to an average of 2.5.  In a few months and alt and ast both jumped out of range, with the highest being ast 84 alt 150.  Was F1 in biopsy June 2004 and F2 in June 2005.

[cruelworld]

so it is your opinion, that in the lindahl high riba study those 90% SVR rates were the result of the first four weeks of heavy dose. all the other high dosing could have been normal dosing and they would get equal success? that was my initial point when i refered to high dosage throughout , everybody does it (doctors prescribe it)
and beleives in it, but there is not one shred of evidence to prove it after und is reached.

its easy to assume it but, the real custom studies to prove this point have never been done i guess. the greatest question of all time, to dose or to double dose, or maybe to no dose. WOW! its a razor thin line.....you had to come throw a big monkey wrench in my plan didnt you. you saved it all up for the last minute. ive never been flamed so hard in my life. thats cold man.

i do recognize the logic of less viremia, less medicine. but i beleive until that type of specific study is done we will not really know the answer. since it hasnt been done may be a bad sign. maybe the scientists are so convinced of this empirically proven, less virus less medicine theory that the studies to answer this question will never be done and the new SOC will trend towards high up front dose and reduced dose later. the idea is beautiful, once proven it could save us a lot of misery. i still plan to up my doses based on the stone age approach,
when operating blind (as we are now , no proof) more is better and im refering only to dosage later in treatment. surely a study will have to be created
to answer this, if the high level scientists beleive in it. when is that one coming? itll probably be to late too talk me out of high later dosing. what a contrarian you are, you have confounded me. are you sure you didnt make this all up and those research papers were faked up by you? cold cold blooded you are.
the last question, what is your dosage history to week 60 and plan for the last 12.

  

[GoofyDad]

Heck, I don't know. I tell fart jokes for crying out loud. I wouldn't venture a guess - but I'd say we do what we gotta do. I hammered myself pretty hard with anemia, and it's taken over a full year to come out of the hole - and I'm still not 100% back. May never be. But I was dying - stage 4, swollen spleen, the drug cocktail was the lesser evile.

So I'd factor liver stage, weight, odds of clearing into the equation, and evalaute my tollerance for risk. Pre-existing conditions that suggest auto-immune issues? That's another one. Time to wait for vertex? Emotional tollerance for relapse? All things to consider - as I'm sure you have.

They do say riba helps against relapse.

It's a tough spot you're in. Good luck.    

[GoofyDad]

"I guess having a third arm now has it's benefits. Having three testicles is a bit awkward though."

But imagine the three nutz without the third arm to give everyone their due during private time? What a waste that might be. On the other hand, with two nuts and the third arm you could pick your nose without missing a beat.....just be careful not to grab the wrong tissue when the fat lady starts singing.

[Valtod]

A simple cost/benefit analysis tells me that there won't be treatment (with intent for SVR) duration longer than 72 weeks.

The 72-week treatment benefits a relatively very small segment of patients: genotype 1, very low VL at week 12 ( < 600 IU/mL, according to some studies, or at least > 2log drop), UND by week 24 (preferably earlier), tolerable side-effects (so they can continue beyond week 48), still UND by week 48 and 72 (EOT).

So genotypes 2 and 3, RVR, EVR, non-responders, relapsers, drop-outs - all this vast majority of cases will NOT benefit from 72-week regimen.

The longer the treatment, the more discontinuations because of side effects, financial reasons, worsen quality of life. Basically, the longer the treatment, the higher the risks and the smaller the group it may potentially benefit.

Realistically there are probably only 5% of all the HCV patients who start PEG/RBV treatment (with intent for SVR) who would ultimately finish and benefit (achieve SVR) from a 72-week regimen. Any further extension of the treatment beyond 72 weeks would benefit probably only fraction of a percent. It doesn't seem reasonable that researchers would go in this direction - the risk and cost too high, the overall benefit too low.

So 72 weeks really seems like the upper limit of the PEG/RBV treatment length. Of course, protocols for long-term maintenance with lower dosage of PEG do exist even now. But this is completely different issue from treatment with intent for SVR ("cure").

Now the real battle is optimizing (and individualizing) the initial dosage and frequency in order to achieve as early as possible viral response. Induction and adding protease inhibitors like VX-950 could do exactly that. So the tendency in the future will be to shorten treatment, not to extend it even further.

If you're a delayed responder, it means that unfortunately you're ALREADY on suboptimal treatment. (You wouldn't be delayed responder otherwise.) In a way, going for 72 weeks regimen, AFTER you're already proven a delayed responder, is a desperate attempt to recover from a battle already half-lost.

All the best!

[Valtod]

CruelWorld:
So it is your opinion, that in the Lindahl high riba study those 90% SVR rates were the result of the first four weeks of heavy dose. All the other high dosing could have been normal dosing and they would get equal success?
------------

Many things are not clear from this study. First, it's not said when they became UND (week 4, 8 or 12?). Second, they say the "mean dose of ribavirin was 2,540 mg/day at week 24". Why the mean does of RBV induction is measured at week 24 and not at week 48 (EOT)? One possible explanation is that the high-dosage was indeed maintained only until week 24.

If I was experimenting with higher RBV dosage (definitely not as high as Lindhal!), I'd maintain it until UND, and then doubling that time for clearing the "total body viral load". Let's say you start with VL 1,000,000 IU/mL. At week 4 you have a 3log drop - 1000 IU/mL. At week 8 you're UND  < 5 IU/mL. That means that at this point you still have around 10,000 IU virons in your blood - total body viral load. So if we assume that you maintain the same half-time of viral decay, in 5-6 weeks you should reach total body viral clearance. Since the half-time of viral decay is not measurable after UND, let's give it 2 more weeks. So by week 16 the main battle should be won. After this moment any dosage increase would be meaningless. In fact, now you can probably safely reduce the RBV to normal level.

I'll repeat the obvious conclusion of Ference's study: "Those, who extended treatment after week 48, REDUCED the Pegasys dosage 25% to 135 ug/wk for the last 24 weeks. And yet, most of them achieved SVR." And this study is the one of them all with the most promising SVR/relapse ratio at week 72. It almost seems that reducing dosage after week 48 actually gives you better chance for SVR.

Please see also the following 2 studies. They're mostly concerned with reducing RBV in the first 20 weeks down to 60%(!), which implies that reducing it after that should be even a lesser problem.

"Neither early virological response nor SVR were adversely affected by ribavirin reduction as long as the cumulative exposure was greater than 60%."

Ribavirin Dose Reductions Due to Adverse Events Do Not Compromise Sustained Response in Some Patients
http://www.hivandhepatitis.com/hep_c/news/2007/012607_a.html

Effect of Reducing Pegylated Interferon and Ribavirin Doses During Re-treatment for Chronic Hepatitis C
http://www.hivandhepatitis.com/hep_c/news/2007/020907_a.html

[Valtod]

what is your dosage history to week 60 and plan for the last 12.
----------

My initial dosage was all wrong, that's why I'm here on "the delayed responders' row" :-) Being afraid of severe side effects (which I did have 3 years ago during my first Tx), I started with low dosage of RBV - 800. After 2 weeks I increased to 1000. After 6 weeks I finally reached 1,200 which was the right dosage for my weight. I also did some experiments with Pegasys - every 6 days instead of weekly.
So the result was VL baseline: 2,474,790 week 6: 55,143 (1.65 log) week 12: 647 (1.93 log) week 18 UND (2.21 log). Bad news - slow response. (Somewhat) good news - no plateau.

If I knew what I know now and could do it again, I'd do it exactly like FLGuy:
"Pre-dosed 1200 riba for a week before first peg. Double-dose peg (360) for the first 4 weeks. Backed off the peg to 180 and maintained the 1200 riba throughout."

[jmjm530]

Valtod: So it is your opinion, that in the lindahl high riba study those 90% SVR rates were the result of the first four weeks of heavy dose.
----------------------------------------------------------------------

Except that a reading of the full-text Lindahl study does not bear this out, with the caveat that I'm basing some of this on memory and a brief recap of the study over at the Clinical Options site here: http://tinyurl.com/2mb8lz  

When I made the decision to emulate the Lindahl study back in 05, I did order up the full-text version and it became bedside reading. I highly recommend that anyone considering making any treatment decisions based on any study -- or discussing a study with their doctor -- to order the FULL-TEXT version before coming to any conclusions.

But back to issue...

The Lindahl concept was to increase riba dosing until a pre-set therapeutic serum riba level was achieved as measured by HPLC testing. Initially, they used a pharmacokinetic formula based on renal function for the starting dose, but later found that the formula underestimated the amount of ribavirin needed. For that reason, the participants were not started at a mean initial dose of only 1520 mg/day and then gradually titered up. The mean serum riba concentration at week 4 was only 8.6 µmol/L, just a little more than half of the target concentration of 14.7 µmol/L which was not achieved until WEEK 24. This doesn't conclusively prove that higher early doses of ribavirin did not effect the SVR rates but it certainly makes a case that it was not the first four weeks of heavy riba dosing that made the difference, but rather the therapeutic dose of 14.7 µmol/L that was not achieved until week 24 and continued through week 48. In fact, the mean week 4 hemglobin rate was a respectful 12.4 from a starting mean of 14.4. It was not until week 24 (coincidental with the therapeutic serum level of 14.7) that the mean hemoglobin dropped below 10 to 9.7 and I should add that by week 4, 8 out of the 10 were on epo and by week 12, all 10 were on epo. Put this all together and it argues that the dramatic SVR rates in the Lindahl study were NOT a result of the first-four week dosing, but of a high-serum riba level obtained AFTER that point.

What's more -- and here's where my memory comes into play -- I don't believe the RVR figures for the Lindahl study were all that dramatic. If so, then their dramatic results are all the more suprising in light of all the RVR studies, EXECEPT that a different mechanism may be at play here -- higher dosing of ribavirn LATER in treatment.

Of course, the above is for discussional purposes, I ain't no doctor, but if we are to speculate, it's always better to do it with the facts at hand based on what the study actually showed which can only be found in the full-text study.

The other point, which I made earlier, is that we haven't heard much from the Lindahl group lately in terms of follow-up or if they expanded the study. Certainly that should be of interest to anyone researching this out for themselves and something to pursue. I certainly would if I was factoring this into any treatment decision.

-- Jim

[jmjm530]

Fourth paragraph should read in part: (the word "not" in the above post should have been omitted)

For that reason, the participants were started at a mean initial dose of only 1520 mg/day and then gradually titered up.

[jmjm530]

For clarity, the fifth paragraph should read in part:

If so, then their dramatic SVR results are all the more suprising in light of all the RVR studies, EXCEPT that a different mechanism may be at play here -- higher dosing of ribavirn LATER in treatment.

[jmjm530]

Admittedly, hemoglobin drop/anemia is a crude barometer of serum riba levels as opposed to HPLC testing, but it can be a guide in the absence of HPLC testing.

With this in mind, the mean hemoglobin rate of 9.7 between weeks 24 and 48 -- while taking epo -- highlight how extreme the Lindahl approach is compared to what most of us (but not all) experience.

On a personal note, as much as I wanted to emulate the study back in '05, I was unable to tolerate hemoglobin levels under 11, and if it were not for the epo, I doubt if I could have remained on 1200 mg/day which was my riba dose for most of treatment. So, even if I titered up the riba more gradually (I short cutted their protocol to catch up) I would have been a Lindahl failure. That said, others here have been able to tolerate hemoglobin levels below 10 while on epo, but that's when you start getting into transfusion territory and it should again be pointed out that 2 out of the 10 participants required two transfusions each.

-- Jim

[nygirl7]

On 1600 a day (double my body weight requirements) I needed epo 2x a week at 40,000 just to maintain a hemo of 10.

Anyone trying for over 2000 of riba a day is going to end up with serious problems.

By the way FLGuy have I said I love you today? Thank you for making me laugh with your side effect profile.

[jmjm530]

Since when/why did you do 1600 mg/day of ribavirin? I remember you were initially prescribed 800 mg/day by your doctor (4 pills) and many of us here suggested you speak to him about upping your riba to 1000 mg/day (5 pills) per one very common protocol for geno 1's. 1600 mg/day is a far leap from 1000.

-- Jim

[jmjm530]

The reason I made the above post is that in the past you have made subtle -- or not too sublte :) -- references (usually in the context of ribavirin threads) to the fact that you were given irresponsible advice here regarding your riba dose and were chastised thus by Dr. A. What you were saying was contradicted by my memory, so I just did a little digging.

What really happened is as I stated above. You were originailly prescribed 800 mg./day by your doctor and myself and some others suggested you talk to your doctor about increasing your dose to 1000 mg/day, which you did, and which is a common protocol for your weight given you're a geno 1. Nothing out of the box here. Later, your hemogoblin tanked at 1000 mg/day and you apparently refused a dose reduction back to 800 mg/day as recommended by your doctor and also which was one of my suggestions as a back-up when I originally suggested you up your riba to 1000/day. Somehow, and not sure how this happened, you managed to get all the way up to 1600/day as you just posted, but it was not based on anyone's recommendations here. You know I love you and don't want to start any discord, but just want to set the record straight for future threads regarding the advice people get here regarding ribavirn, at least as it pertains to you. The threads supporting the above statements follow:

http://www.medhelp.org/forums/hepatitis/messages/40109.html
Posts C5 and C19

http://www.medhelp.org/forums/hepatitis/messages/39456.html
Post C27

###

[jmjm530]

That should have been Dr. "J" , of course , not Dr. "A".

[Valtod]

Jim, thanks for the full info on the Lindhal study. Now, after I read your post, I start to think that in their experiment they actually use the RBV as the muscle drug, instead of the PEG. So the whole synergy between PEG and RBV is reversed. I'd guess that the Replicative Homeostasis model does not apply here and that the 'error catastrophe' model, challenged by R. Sallie, is actually valid here. In other words, the very high and consistent RBV concentration leads to genetic meltdown of the virus, destroying its ability for maintaining replicative homeostasis. Then the PEG role is just dealing with the minuscule amounts of RBV-resistant variants (which inevitably will appear at such high level of mutagenesis).

It seems the Lindhal experiment is unique, counter-intuitive for most of the researchers and quite dangerous. No wonder it didn't enjoy further development and will probably remain a cul-de-sac.

[BThompson4]

The relapse rate for gen 1's going 48 seems to me to be way too high, and it always has been.  The practice of going 48 weeks for treatment naive patients (the 2-log drop requirement at 12 weeks is a sick joke, if you ask me for people going 48 weeks; you better be und or very close if you want a decent chance to svr on a 48 week treatment) leads to way too many relapses of people who are ostensibly kicking the virus' butt during treatment but fail miserably within a few days or weeks of completing their 48.  This board is full of people who relapsed after 48 week SOC; could they not have benefited from longer studies?

I disagree that it is not worth the effort to go for longer than 72 week studies.  Berg only got 44% svr for people who went 72.  That number might not be able to be improved on, but how would you know without studying a longer treatment.  Study populations would have to be large of course; and assignment to extended groups would be based on patient's viral load response at week 4 or similar early period.  You could also pre-select a population of patients with lots of damage, non-tx naive, large size, etc.  This would make it easier to get more patients that would likely benefit from extended treatment and fill a large enough subset of difficult-to-treat patients to make the study worthwhile.  

Dr. Cecil needs to publish on his findings with difficult to treat populations, although it would be tough to get comparable data in a review of people who have already treated.

[jmjm530]

Not sure if "dangerous" is the right word, but to split terms, but let's use "significantly more dangerous" at least for discussional purposes. Still, at that point in time -- with the absence of the newer protease inhibitors even in trial -- Lindahl presented an interesting model for those who wanted more than the 40-50% chance of SVR presented by SOC. That's what certainly grabbed my attention, as a stage 3-4 (so I was told) who had only around a 40% chance of SVR going into treatment. Had I been able to tolerate the ribavirin, I had planned on flying to Sweeden for HPLC testing while trying to emulate the study best I could based on my hemoglobin levels. But "significantly more dangerous" or not, there may be some lessons from Lindahl that might be applied in a more tempered form. But here's the kicker in terms of what is dangerous or not. My understanding is that the riba researchers may feel that more than 48 weeks of interferon is the real danger, and I'm not sure that isn't correct. While the ribavirin can do havoc with hemoglobin, I wonder if the long term effects are any worse -- perhaps better -- than staying on interferon for 72 weeks or even longer. Keep in mind that 9 out of 10 in the pilot study completed treatment and the 10th member dropped out for reasons other than the riba dosing. Good thing they didn't include me in the study or I'm sure I would have woosed out :) Be well and thanks for the discussion.

-- Jim

[cruelworld]

bthompson - i agree with you about longer treatments, if i still have energy when i get to 72, i plan on going further 3-6 months in taperdown mode. i want to give it everything ive got on this first round. it all is related to sx. i presently dont feel that the interferon is hitting me so hard that i will have permanent sides. this could be pure folly that i live to regret of course. the only other reason i would go past 72 is, if i fail ive got to jump right on maintenance dose anyway, whats the difference from a taperdown dose?
it may be an unavoidable fact that tough customers simply have to overdose and overexpose to get out of jail.

jim - i am afraid of the 72 or more but i do so firmly beleive that if i maintain
an exersice endurance level (defeat fatigue somewhat) all through, it gives me a good chance of no permanent sides. if the treatment feels later like its taking me down to nothing,
i will become worried then. my doc offered me more INF and i may do a little
extra at the end but im staying on reg doses for less exposure.


valtod - again i do beleive we are somewhat blind, but ill take the vote for overdosing with riba only, and im sticking to my plan, it may not improve my numbers as much as i hoped but it will help some, at least. i do seriously appreciate your contrarian contribution when i first saw it i was hoping it would start a fist fight. i guess everyone is taking their ADs today! keep up the good work though. i havent even looked through any of it yet, but i will.

see yall freaks later    yee haa

[wyntre9]

Thanks everyone for all the great info!

Wyntre

[SonicBandaid]

Sorry Guys, I missed this important bit of the thread, and only caught it by accident; jmjm530 is right, being on the other side of the equator pushing out zzzzs does make it difficult to respond promptly to what is said (as was complained about in another post), but I was also away for the weekend, scubadiving in Shark bay, a place aas far away from the internet as is possible.

with regard to: "Would you be so kind as to provide an overview on the significance of monitoring renal function as it pertains to establishing ribavirin titer?"

With people with normal renal function, the creatinine level probably doesn't matter too much, but in those with any impairment (the elderly, those with diabetes/hypertension/pre-existing kidney disease/post transplant (due to the effects of CyA/Tacrolimus [also FK-506 or Fujimycin], the impaired glomerular filtration rate will impact significantly on ribavirin clearance.  The clinical importance (that is, if you have impaired renal function you will tolerate high ribavirin doses less well because you will develop high serum levels of ribavirin due to poorer renal clearance, and therefore are at increased risk of haemolysis) of this has been demonstrated in many studies, including one from Lindahl's group.

I don't routinely measure renal function serially (but do check it before initiating therapy) in all patients but will do so if any of these issues are operative. Sorry about the delayed reply, Bill1954.
Cheers,
Sonic

References

1. Dumortier J, Ducos E, Scoazec JY, Chevallier P, Boillot O, Gagnieu MC: Plasma ribavirin concentrations during treatment of recurrent hepatitis C with peginterferon alpha-2b and ribavirin combination after liver transplantation. J Viral Hepat 2006, 13:538-543.
2. Bruchfeld A, Lindahl K, Stahle L, Soderberg M, Schvarcz R: Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003, 18:1573-1580.
3. Jain AB, Eghtesad B, Venkataramanan R, Fontes PA, Kashyap R, Dvorchik I, Shakil AO, Kingery L, Fung JJ: Ribavirin dose modification based on renal function is necessary to reduce hemolysis in liver transplant patients with hepatitis C virus infection. Liver Transpl 2002, 8:1007-1013.
4. Jen JF, Glue P, Gupta S, Zambas D, Hajian G: Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000, 22:555-565.