pre-dosing ribavirin advice

[spectda]

I have a friend who is about to start tx after relapsing the first time. This person is considering pre-dosing ribavirin and wondering how long to predose and how much to take. There are some older threads about it but nothing recent so I am hoping for some more current info, opinions and recommendations. The person is stage 3 of course determined to do everything it takes.

tx will be with telaprevir triple therapy.
1rst treatment I believe became und late, I believe week 14 but not positive.
treated 72 weeks relapsed
had minimal drop in hgb (12.1 to 11.3)
took 1000 mg riba, weight 115, 18.8 mg per kilo

Thanks so much for the help,
Dave

[willing]

spectda: the iron hcv connection is not straightforward. Iron overload is definitely associated with advanced progression (though whether it's  a cause is less certain) and phlebotomy is advised to keep it in check. However whether iron has a negative effect on tx outcome seems more doubtful. From a recent mini-review:

"jn three studies in which hepatic iron levels were actually measured rather than estimated, hepatic iron in nonresponders was no different to responders....Thus, hepatic iron levels, when assessed by the most accurate method of quan- tifying hepatic iron, do not appear to influence response to antiviral therapy. This conclusion does not rule out a role for altered cellular or subcellular distribution of hepatic iron in blunting the response to treatment."
http://www.ncbi.nlm.nih.gov/pubmed/17914937

Clearly something is not working for her and it would be good to get a handle on it before diving into triple. If 19mg/kg isn't making a dent in the Hgb increasing further seems reasonable, but perhaps in conjunction with an rbv  serum test . From Lindhal's papers kidney function is the primary determinant of serum rbv concentration so perhaps she clears the stuff quickly. Definitely worth talking to one or more hepas before starting.

Elaine: good point about the risks of experimenting with unproven approaches but one can die waiting for solid evidence-based medicine to endorse  variations routinely tried. For example weight-based rbv didn't get the official seal of approval until the '07/'08 WIN-R studies though many here had concluded heavier weight put them at risk of inadequate rbv. If you look at the recent FDA approval it's pretty obvious the experts in charge don't yet have a clear view of what does or  does not work with triple.

There's a long list of  forum members who got SVR by doing 'outside the box' tx, several on this thread. There is a sea change coming however - whereas before you could just try again if it didn't work,  triple tx is a bit like hunting with one arrow. One will likely  be able to try the PI again in a future tx - but there's zero data on how soon. Thus for all the nulls and partials considering  triple, obtaining an optimal ifn response seems a good strategy.

[Cory255]

Ribavirin priming enhances efficacy of chronic hepatitis C re-treatment in patients who had not responded to previous combination therapy.

Ribavirin priming : Oral Ribavirin (1000-1200 mg) alone administered daily for 1 month.  

http://www.natap.org/2009/AASLD/AASLD_72.htm

[Bill1954]

Hi Dave--

I don’t have a lot to add to this, other than I want to wish your friend all the best in her endeavor; it sounds like she needs to put this disease behind her now. Thanks for posting this; it looks like there’s a lot of data to browse through.

--Bill

[Proactive]

" no epo with telaprevir." Thanks doc, please be informed I will be consulting a new hepatologist!!

If it was me (luckily 72 weeks worked--with high dose riba 21mg/kg(1600 mg/155lbs. +4000 riba pills-but who's counting(g))
I'd want to predose for 2 weeks, bring serum level up, and settle in at whatever dose kept my hgb @ 11.
jmho--but I'm a carpenter, Pro

[coeric]

last week i spoke with a hepatologist about predosing inf/riba with the telaprevir.  the doc said no, and that they would be following the FDA dosing recommendation. so then i said well how would you feel if i started on the inf/riba and if i did not get a rapid response could i then add the telaprevir?  and the doc said that would be alright. also the doc said no epo with telaprevir. anemia would be treated with dose reduction, just like in the trials.

[nygirl7]

I'm sorry I did not catch sooner that this person would be doing 3x therapy, we have ZERO members who have predosed with PIs. I wouldn't want to risk it, wait until you cant lift your head off the pillow from the anemia or you are so covered in rash you rip your skin apart. I've done both and just dont advise it for anyone.

[nygirl7]

If a doctor does not tell you to pre-dose do not pre-dose. There is not one study out there that supports this theory an dusing words like pharmacokinetics and synergistic doesn't make it real.

When I was a new member many years ago I listened to the sage advice of the forum guru (who actually had a study to point me to unlike this) ended up losing six full points on my hemo in just over one week and almost failed treatment by playing with ribavirin.  It IS A MAJOR DRUG AND SHOULD NOT BE EXPERIMENTED WITH WITH THESE NEW PIs that already have severe side effects associated with them.

Tele has the rash and riba has the anemia and BOTH of these things have always been associated with riba to begin with. It's just foolish and I hope that other people wont make the same mistake I made by listening to people who think they know more then doctors.

No disrespect meant but seriously.........who the hell do we all think we are anyways?  Talking about and surmising is one thing but recommending changes to a brand new protocol = that equals NUTS.

Warning warning danger Will Robison.................................................

[Trish77]

Ribavirin is not new territory to be taking it with a PI.  SOC drugs were trialled together with the PI's, these are known substances and the SOC drugs of riba and INF work together with the PI, so having them all at max effectiveness is desirable. This isn't adding a drug that has never been used with the PI's before so you're not introducing a wildcard here, you're taking something that already has an established integral relationship with a PI throughout many many trials.

Pre-dosing ribavirin is ribavirin mono-therapy for X number of weeks in the hope that when you take your first INF injection, the ribavirin is already at maximum synergistic capability. Everybody's response is individual, however this approach is based on what we know of the pharmacokinetics of ribavirin, it's steady state levels and it's synergistic relationship with INF.  The risk to this is relatively low, seems to me - you've spent extra dollars for X weeks of ribavirin to have anywhere from limited to maximum effect when you take that first INF injection.  

[spectda]

I found this boce FDA advisory committee information regarding bone marrow suppression informative and interesting especially since my HGB, WBCs, ANC and Platelets all declined to extremely low levels during my boce trial.  

The quickest hgb decline I had was during the lead-in which would make sense when red blood cells are being destroyed from ribavirin rather then suppressed from boce. I continued to have a steady decline in hgb and platelets until I was forced to stop tx at 43 of 48 weeks.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/AntiviralDrugsAdvisoryCommittee/ucm252341.pdf
"Overall, most of the adverse events reported in these trials have been well-described for pegylated interferon and ribavirin therapy. The most important safety concern during the clinical development of boceprevir has been the decrease in hemoglobin above and beyond that observed with pegylated interferon and ribavirin alone. The anemia appears to be part of an overall bone marrow suppressive effect of boceprevir as evidenced by the increased frequency of neutropenia and thrombocytopenia in boceprevir-treated subjects compared to PR-treated controls. Further details regarding anemia observed in this development program are described detail below."

[spectda]

I completely agree that we should always be careful with advice and understand that many people who read the information here might not understand that we are not physicians.  

Nevertheless, a lot of people might have been saved an extra tx or two or three if they heard some of the stories here and educated themselves well and found the right doctor to treat with the first time. I know for me the advice was invaluable in my advocating for myself through tx even though I was in a trial.

As you mentioned triple therapy is new territory, especially outside the strict guidelines of the trials. As always people should educate themselves and discuss with their doctor what their approach will be.

My guess is that many of these doctors, especially the ones who have overseen these trials will get more creative with treatment before long rather then following the guideline strictly. I have already seen someone post that their doc will use a lead in regardless of whether they use tela or boce.

-Dave

[child24angel]

I'm all for reaching SVR as much as the next person,
I mean no disrespect to anyone.

I mean, what is going to happen to people when we
start giving advice on triple therapy with Boce or Tela?

There is no evidence, that I'm aware of ,of pre-dosing with riba
while using  triple therapy.  Boce and Tela have there own
set of rules in this game and can knock down your HGB alone.

I have a few friends starting TX also, without giving out
stats, I find this interesting, but also guarded,

I just don't know about pre-dosing...riba with triple therapy Dave.

Good luck to all
Elaine

[Trish77]

If I were going to pre-dose ribavirin, I'd do it for 4 weeks.  Many of the articles I read show steady-state concentration at 3-4 weeks.  So I would go for the 4 weeks to get maximum effect.  Perhaps that's why the study coeric has posted chose a 4 week lead-in? Just a pondering thought.

Definitely take the riba with fat content foods, however I have a feeling your friend knows that.

Since your friend shows a history of tolerance to ribavirin at 1000mg over 72 weeks no less, I'd increase it to 1200mg - 4 weeks of pre-dosing at that level won't take long to give an indication of how things will go.  I think your friend could handle the potential fatigue of a higher-dose riba if it meant kicking viral a$$.  Weight-based dosing is fine, but your friend has the benefit of "lessons learned" from past treatment.  Bringing the riba dosage down after 24 weeks *if necessary* is possible when the dosage is 1200 at a weight of 115 pounds.

And I'd be willing to kick in with procrit maintenance to keep riba at higher levels.

Alinia and SAMe for good measure.....if your friend is willing to add them in.

That's my penny's worth.

Trish

[Trish77]

"i recall jmjm doing something like 2gm of riba - he ended up in the ER, but he got SVR.  "

Jim not only ended up in the ER, he had to go off ribavirin for a little while to recover after ramping up to 2000mg riba/day over a very short period of time.  I recall he didn't recommend his particular approach and wouldn't do it quite that way again.  

High ribavirin to what you can safely tolerate is useful and adherence to ribavirin is more important in the first 12 weeks than INF, according to some sources - operative word, of course, is safely.

[FlGuy]

We had a plan to keep hgb between 11 and 12.  If I recall, the first Aranesp was around week 4 ish.  The double peg was planned until undetected. I got to und after week 2 with the results received  after weeek 3 shots.  I stayed with the double peg through week 4 and then single for the rest of the way.  The Tx was designed by a liverhead and executed with a GI and hematologist.  For TX#2 I went to Pegasys.  Glad I did,  double PegIntron would have kicked my butt.

I think it was Spacecst who did a variation; a few doubles and then single Peg every 5 or 6 days instead of 7.

[coeric]

hey, if there are any labs out there listening, we sure could use a test for serum concentration of ribavirin.  i saw on the clinialtrials ******* a notice about a trial that was recruiting for a trial to compare standard dosing with serum concentration dosing.

i recall jmjm doing something like 2gm of riba - he ended up in the ER, but he got SVR.  

[spectda]

I assumed your doc supported the approach because since you had the preemptive aranesp. When did you start taking it?

[spectda]

That's really good information. Did you switch ifn from pegasys to pegintron? You're lucky your doc supported that approach. that must have been one hell of a ride!

[spectda]

Iron levels they were very high pre-tx and phlebotomy was used to reduce them? could that have kept the hgb level high and had an effect on either viral replication or tx efficay?

Willing-Besides the other suggestions you made (Checking IR seems advisable as does throwing alinia/ntz and SAMe into the mix), do you not believe increased riba will help? I know of another person who is at about week 30, weighs 105, taking 1200 mg per day (20 mgs per kilo) and has not dropped below 13 g/dl hgb.

[FlGuy]

I treated twice.  The first was a normal SOC and relapse.  Treatment two was "enhanced" with pre-dose riba, more riba, double peg, pre-emptive Aranesp all with the intent to get to und fast.

[spectda]

Thanks everyone,

FlGuy-Did you treat more then once? If so was there a difference in how quickly you became und when you predosed, did you increase the riba?

Bali-How long did you pre-dose? (the link had some good information)

Thanks for the great information from everyone on predosing and tapering.

What does everyone think about the riba dose considering that there was so little hgb drop (.8 g) even through 72 weeks of tx.

[willing]

where they found 81 G1s willing to experiment with 24w of tx is is a puzzle, but the results from  that Japanese study seem as expected. Of of the various key roles  rbv plays, one is to enhance ifn-triggered pathways:
http://www.ncbi.nlm.nih.gov/pubmed/20303352

It also takes rbv a couple of weeks to reach steady state concentration. If you want those early, important, ifn shots to have maximal impact it makes sense to ensure there's adequate rbv around. I did two weeks, and suspect it may have helped with early decline (about a log/day over 1st 48h)  

However in her case, inadequate rbv doesn't seem to be the issue since she was already at 18.8. Checking IR seems advisable as does throwing alinia/ntz and SAMe into the mix. Also, even if opting for tela, doing a 4w lead-in seems a good idea in her case so she can gauge whether the combined non-PI drugs will be adequate for the PI mop-up.

copyman, nygirl: there's now good support for that view in a remarkable  paper out of the Rehermann lab mikesimon posted  a while ago

http://www.ncbi.nlm.nih.gov/pubmed/21040725

though many manage to reach viral eradication by EOT, for others the process can drag on for up to eight years, with the body's native immune response clearing  the residual virus. So the tapering argument starts to look a lot like the Iraq/Afghanistan pull-out debates.

[nygirl7]

You know looking back that 'false positive' I had at week 4 EOT - I've always wondered if it was what you said the sudden stop provided a way to come in and my immune system wasn't doing what it had to do yet.

I dont know but everyone I've seen who had a very low (60 or lower) VL at EOT 4 weeks later was UND again and then SVR.  So I think it happens more than we are aware of.

[Bali05]

http://www.hivandhepatitis.com/2010_conference/aasld/docs/1214_2010_a.html

[copyman]

I also think tapering off the meds at the end of TX is just as important. Especially with the interferon. A hepatologist put it to me this way, "it gives your immune system time to get use to working on it's own". Of course this was a theory of his and he would never admit it publically. I figured it made sense and wouldn't hurt so I did it. I tapered off over a month lowering the ML of the shot, 3/4, 1/2, 1/4, 1/8 doses weekly. This was done after the FULL TX was over. This was an added month.

Best of luck