Hepatitis Researcher, Pre-Dosing Ribavirin

[St. George]

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?

[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.

[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

[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

[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.
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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.

[jmjm530]

MO: You tell me nothing about you
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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]

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: I'm his opinion on pre dosing with riba and he said it was "VooDoo.
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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]

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.

[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!

[mikesimon]

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

[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.

[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

[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.

[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.

[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

[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]

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

[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?  

[St. George]

ha ha 350 lbs.  What a rapier wit.

[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.

[jmjm530]

Cruel: this may be rude
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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  

[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".

[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.

[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.
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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