Ribavirin Timing...critical to response??

Would love everyones opinion...Still waiting for the results to Amanda's repeat 20 week VL, Prove 3,  Group C, no-ribavirin...IF she has indeed experienced a breakthrough and I am able to convice them somehow to add Ribavirin at this point (triple therapy), do you think it will be too late?  I know there has always been a lot of talk about Ribavirin working its best at the beginning of treatment...and that later on it is not as important...my point is, is the timing critical here?  Wouldn't she have a better shot if she was to stop for a resting period and start over with triple combo from the beginning, down the road(hopefully if the virus did not become permanently resistant).......rather than adding it to the mix at this late in the game?  Not sure what they will or will not allow...if anything...just wondering what her best option would be at this point...

All advise as to what to ask for at this point would be greatly appreciated... Our apt. is Monday..  Still hoping this is a lab error and she did not breakthrough...but we want to be fully prepared.

TM

[mikesimon]

I never have believed in the theory that with treatment the virus becomes resistant. I know that it seems counterintuitive but I treated for over two years and when I treated the third time with optimal doses I responded probably just as if I were treatment naive. I know many people talk about the virus acquiring resistance but I don't buy it. I really cannot advise you with any degree of confidence because I don't know much, if anything, about the viral kinetics of the Vertex PI. I do wish you and Amanda the very best and I am believing that the best is coming and that your news will be good. Mike.

[Andiamo1]

Can't remember the details due to brain fog, but I did read a paper that said the virus does develop resistance, but reverts to the wild state very quickly when treatment stops.

There was an implication that if someone re-treated after 6 months or so, they would be starting fresh.  I hope Jim or someone whose brain still works remembers the paper and the link to it.

[jmjm530]

This is a good question for a liver specialist, although wouldn't be surprised if you get conflicting answers.

Most seem to favor a "wait" period between treatments, from 6-12 months. Not sure if the reason has anything to do with "resistance" or they just want to give the body, mind and soul a chance to heal before abusing it again. We did have  a few members, however, who treated almost immediately after relapse, but not sure how they ended up. Kalio1 comes to mind, and my best recollection is that she's still on treatment, or at least tapering off. Not 100% sure on that, although you could probably post to someone who is in touch with her, such as NYGirl.

I do agree with Mike, that there apears to be no resistance -- at least with SOC -- at least with the waiting period most people seem to take between treatments. We just have too many folks who re-treated successfully here. Is there any resistance if you re-treat right away, or with Teleprevir? That I really wouldn't want to venture a guess.

And as to your question about adding ribavirin at this point. Again, I don't think anyone has the answer to that, but my unprofessional guess -- and it's only that -- is that she should take a rest period of around a year and then start again with triple. Of course, she should discuss these options with a liver specialist.

-- Jim

[TnHepGuy_]

First in the decision tree should be if Amanda's current status (i.e. - liver histology) calls for something more immediate (i.e. - re-tx'ing) - or the possibility of waiting. Given that she's a cirrhotic, my guess would be a lean towards the former. That being said, if you were to wait for triple-therapy, I would imagine that your wait would me a matter of years - not months - given that FDA approval for Vertex is not anywhere that close (nor a given, for that matter). Unless, perhaps, as a previous trial participant she would have some sort of 'compassionate-care' exemption that would allow her access down-the-road before any approval?

What you also want to talk about and consider with her docs/specialists is the possibility of some kind of maintenance - low-dose interferon, alinia, statins - or a combination of them (all depending on how 'radical' your docs may be, given that only the interferon is currently approved for Hep C). If you are going to wait - or have to wait - you sure would want to try and do whatever is possible to slow/halt progression.

As far as adding the riba to the mix at this stage of the game, I'm assuming her body has already been exposed to it in previous tx's (and at SOC levels). If that's the case, any 'resistance' would already have occurred during those past tx's. So, if her docs are willing to go from double therapy to triple at this point in time, her labs would most likely tell the story of any 'riba-resistance' in a relatively short period of time.


May God's blessings and mercy be upon you, Amanda and her caregivers.


TnHepGuy

[debnevada]

have a look at a post about alinia from yesterday by ala girl....can you weigh in?

[dointime]

Travelmom - I don't know the answer to your question but below are some thoughts which I think are relevant and might help you decide.  It may depend on your daughter's VL results.  I mean, if her VL was just skimming UND like yours did then adding riba might put the final nail in the coffin for the virus.  But if the breakout is a large number and holding steady (as mine was) then maybe it's not as favourable.  But will you be able to get all the VL results or will you just be told if there has been a breakout?    

Anyway, viral resistance to VX certainly has occured if there has been breakthrough.  After VX dose termination a proportion of the viral breeding stock reverts back to wild-type within 7 months.  It is not yet known whether the hangover from the resistance would be a problem next time around when treating with the triple therapy but it can't be ruled out.  My opinion is that there will still be a small pool of VX resistant virus left and we don't know whether hitting it hard with the triple therapy next time around will wipe it out.  Personally I'm not counting on it.  

Next, as long as the VX is present it still has the function of preventing the resistant virus reverting back to wild-type.  So if the ribavirin were to be introduced at this time, there would be one less place for the virus to run to get round the riba+inf combo.  I believe I'd have had a better chance if I had continued on the triple therapy rather than plain SOC but would it have got me to SVR - I don't know.  In my case I had a 2nd breakthrough on SOC and I now know I should have high-dosed the riba (god help me for the rash).  In your daughter's case I don't know how her body deals with riba.  On her previous tx what was the reason for failure, relapse, breakthrough, slow/non responder?

Lastly I'd like to add something which mremeet wrote back in May but unfortunately I can't find the link so I'm going to paste the quote here and hopefully he won't mind.  

May 2007, mremeet wrote :-
The only caveat I might add in favor of continuing with telaprevir+SOC, would be for the following reason: ribavirin is thought to cause the virus to become genetically unstable. It is thought to cause the virus to mutate more often and in a more dramatic and uncontrolled manner when compared to its normal unhindered mutation rate. Mutations normally are what make the virus so hardy and adaptable to various natural and drug induced antiviral insults against it. Considering the virus' collossal population size (i.e. breeding stock) and rapid reproductive rate, mutations normally work in its benefit - to a point that is. If you can push the virus into mutating at a much more aggressive pace and with more significant types of mutations, then you can effectively cause it to mutate itself out of existence. The ribavirin may cause it to become "unfit" over time, causing huge numbers of the virus to have serious "birth defects" which can either hinder its ability to reproduce or stop it altogether. And those virus remaining that can reproduce will pass on their damaged RNA sequence to their offspring, thereby saddling them with the same defects the parent possessed. The cycle will continue to repeat over and over again while in the mutating presence of ribavirin and antiviral action of IFN, eventually resulting in eradication.

But under the circumstances described above, since the mutation rate has been increased, its possible a pre-existing VX resistant dominant population could be mutated out of its resistance. The traits of VX resistance would no longer selectively survive if the mutation rate was increased to the point where those traits simply could not be preserved nor retained from generation to generation anymore. And if that were to happen, the telaprevir could once again play a significant antiviral role, changing the stage so that there are now three effective antiviral actions at work simultaneously. Of course all of this is premised on the likely (and yet unproven) theory that ribavirin actually works in the manner speculated.
      



          

[dointime]

On further thinking about this - once the resistant variants are there they are there.  It doesn't matter how small the proportion, they have to be overcome for SVR to be achieved.  So looking at it purely in terms of efficacy, whether you dose them with the triple therapy now or after a resting period shouldn't make much difference.

There are ofcourse other considerations.  After you leave the study you would be free to tailor the tx much better, use rescue drugs, vary dosage, etc. which would increase the chances of SVR.  But do you have the time to wait for VX to be approved?  On the other hand, how tired is Amanda of this tx.  These drugs are hard on us.  Rotten choices, I know, sorry.
dt.    

[TravelMom]

Well got the official call tonight...Amanda has experienced breakthrough....We are obviously devestated...We have been fighting this battle for the past 5 years....treatment after treatment and .I am just emotionally exhausted.  She is only 19 and has such huge dreams...I cannot let her down...She did indeed  respond (for the first time on anytihng)...she never even dropped a log in previous treatments...so I feel if she takes some time off and we are able to get her in a compassionate program of some sort with triple therapy, that may be the answer...I don''t know...at this point I need to just recollect my thoughts and feelings and try and relax...I am a mess.. I just need some time to take this all in...Thank you all.

Love to all of you,
Jodi

[jools57]

I am so sorry for Amanda's breakthru...as a mom, I feel your anguish...I will be praying for you and Amanda. You deserve some rest...you are a wonderful mom!!!
Blessings, and hugs,
Julie

[mremeet]

I'm so sorry to hear about the breakthrough. I was afraid that was going to happen, I always felt Vertex should have excluded her and put her on the short list for phase 3 where she could definitely get access to all three drugs. But that's water under the bridge now, I just hope Amanda can recover as well as possible in the meantime and you guys can set your sites on a future course of VX950+IFN+riba (with rescue drugs as needed). Or SCH503034 (or equivalent) +IFN+riba, that might be an option too. Keep the faith and keep thinking things through and remain aggressively proactive. Sooner or later she can put this virus down and get back to living out her life, and eventually getting you some grandkids too! It'll happen, just keep your chin up and don't take no for an answer, if'n some bureaucrat tries to give you no for an answer. God bless you and Amanda...

[cruelworld]

you alls fighting efforts are much admired; fearless, spirited and invincible.
be proud, while this battle may be a sacrifice the war is far from lost. you are finally
seeing real progress.
consider it a small temporary setback.
its just a matter of time before final freedom.

[Andiamo1]

I am so sorry to hear about Amanda's breakthrough.

[Willy50]

First, I'm very sorry that you got the news.  I'll only say that this is a setback but not the final play.  You'll regroup and get Amanda an SVR.  She cleared this time and wasn't even on optimal dosing.  Next time through you'll get it.  You both deserve a break and some time to regain your balance, regain your strength and plot a new course.

I'll try to stick to your question now; I don't know if there is really much data on the subject.  First of all there are relatively few people who were in the no-ribiviren arms in the Vertex trials.  To my knowledge none of them were offered triple therapy following a breakthrough or inadequate response failure.  Vertex may have theory on whether to treat with triple therapy mid course or whether it is better to wait, regroup and hit the virus with a triple therapy attack after a resting period.  I'll note that a study will be presented on some aspect of the viral mutations at the AASLD in November and that there was some presentation in a recent conference in Chicago a day or two ago.  Whether there are answers yet I don't know.

It could cut both ways.  I don't know the stats yet on the dual therapy (INF and TVR-no ribiviren) but from what Vertex mentioned in a teleconference the response rate (as distinquished from the SVR rate) may have exceeded the SOC response rate.  IF so...... Vertex should have expected quite a number of breakthroughs.  It might be worth mentioning that even if response rate was good without the addition of ribiviren the breakthough rate still may have been quite high.  We still don't know the answer to that yet.  My point is that IF they tracked those in that arm closer with PCR's they may have been able to make a successful mid course correction and add ribiviren and perhaps an increased dosage to prevent a breakthough.  What seems obvious, even with the lack of data is that ribiviren is a very important ingredient; probably necessary for most of us.  Unfortunately since there are relatively few people who treated with that dual therapy this is also a question that may not soon be answered.  

It's off topic but I wonder what will happen to those who failed in the control arm and were "rolled" into triple therapy.  

At this point the next question is what is Vertex going to do?  What do you and Amanda want to do?

I heard in a a recent teleconference that Vertex was kicking around a shorter treatment course for the Phase 3 trials. How would they achieve that; possibly with an increased dosage in the initial stages of treatment and closer tracking of the viral kinetics of the treatment.  There will be lots of new ideas and also new compounds coming.  I know you'll get this virus licked yet.  

Still.....I'm very sorry it was not on this tour...at least not at this point.

best,
Willy

[TravelMom]

Thank you all for your thoughts and prayers...we are all faced with the same battle..slowly we will win, one by one...I am glad I have all of you on my side..

Love,
Jodi

[Myown]

So very, very sorry to hear this. I can't even begin to imagine the pain a mother must feel when something like this happens. We know Amanda only through this forum and yet I'm sure all are weeping for her as I am as I type this. I admire your strength and we will continue to pray for your Amanda and her victory.

So very sorry,
MO

[TravelMom]

Just uploaded a pic of Amanda...on my profile..

[mikesimon]

My heart aches for you and Amanda. Mike

[dancegirl54]

Jodi, I'm stunned and so, so sad. There is always hope and I know you know that and I truly believe that WE WILL see our children clear.  WHat a beautiful photo!.  I am emailing you outside of here Amy's blog.  Maybe Amanda wants to get in touch. Amy is coming out of denial a little bit. She had another dr appt but hasnt shared with me yet.
Bless you

[nygirl7]

Oh TravelMom my heart breaks for not only Amanda but for you too.  You've been such an incredible STRENGTH and have shown so much class during all of this.  I really wish I did have a magic wand...I would use it immediately on your daughter.

God I hate this disease.

[nygirl7]

Oh she's just BEAUTIFUL - we have to think of something.....oh the heart break.

Maybe you could get in to see Dr. Jacobson in New York?  He is really so on the cutting edge (as he's the lead investigator on most of the studies) he might know of something that a regular doctor might not know.

He doesn't take insurance but as he offered me he didn't mind working in conjunction with my doc who took insurance guiding him along for free.  He's that kind of man.

[dointime]

Oh cr@p cr@p cr@p !
Sorry, I have nothing constructive to say, just gutted for you and Amanda.
dt.  

[TnHepGuy_]

debnevada - sorry that I haven't had the time to go over that alinia paper yet. I look at it when I can and post any thoughts.


TravelMom - so very sorry to hear about Amanda's breakthrough. Hopefully she and you are doing as well as can be hoped for through all of this.

I've been thinking about 'resistance'. In Amanda's case, she's been on virtually every approved tx/combo out there and never reached undetectable - that is until VX-950 entered her system (along with the peg inf). It may not be riba or VX-950 that she has the most resistance to - it could well be interferon. Viral suppression occurs basically via two routes: externally (medication) and/or internally (immune system). It's possible that the VX-950 lowered her levels enough that her immune system and the interferon were enough to suppress (though not completely) the virus. And over time her already weakened immune system wasn't able to 'hold' things enough as the virus began to overcome the interferon. If this line of thinking is true (only a guess and no way of truly telling), then there's possible good news in there somewhere - in that she can still use VX-950 as part of any future tx's (as well as riba). And there's the possibility that if she were to try a triple-tx of those (VX, inf & riba) that the addition of the riba may be enough to 'assist' in suppressing to the eventual point of elimination the interferon-resistant virons (though, I would push for the other version of the peg inf from the one she just used, if at all possible, to try and throw a any-and-all curve-balls possible at the virus).

Just continue to push her caregivers and keep learning all you can.


TnHepGuy

[debnevada]

your daughter is a beautiful girl.....i like what tri hep had to say and i find that most hopeful.

i'm so sorry.

deb

[FullOfHope77]

I would immediately start her on SOC and continue as she has the VX still in her system and the additional riba WILL help I'm convinced. I'm either ARM B or D (starting to think B now since the 2 weeks of placebo have been replaced with the real thing again). But your daughter can benefit from all 3 if she could get it but the SOC is better than nothing IMO.

[worry06]

I cried when I saw your post, it is so.... unfair....  I have've followed Amanda 's treatment for a while, and I pray everyday for her.  I also have a daughter infected at birth, so I can feel your pain right now.   She is so beautiful, thank you for let us know her..  I will be praying for you and Amanda.  

W

[TravelMom]

What can I say to all of you ...your support and advise is just unbelieveable...I wish I can reach out and give you all a huge hug... we went today for some labs and within the week or so will decide our next (if any at this time) plan of action.. Thank you all for everything...the past year or so I have not posted as much as I used too...I am just exhausted...but when I see this outpouring of love and support it gives me so much strength...Thank you my friends... Jodi

[jmjm530]

At this point, you want to arm yourself with as much knowledge as possible, and align yourself with those who can implement this knowledge.

Two doctors come to mind who may be able to come up with a plan on the cutting edge of current knowledge and drug availability.

One is quite near you. Dr. Ira Jacobsen at Cornell.
http://www.cornellphysicians.com/imjacobson/
He doesn't accept insurance directly, but you could submit his bill to your insurance plan if they accept out of network. In any event, a one-time visit -- even out of pocket -- should pay dividends not only in terms of present direction, but as a way of making yourselves known for future treatments.

The other doctor is a few hours away in Boston, Dr. Nezam Afdhal.
http://bidmc.harvard.edu/display.asp?leaf_id=11676

In addition to running many trial, Dr. Afdhal is in posession of one of the few Fibroscan machines in the country.

My suggestion would be to make an appointment with both, and listen to what they have to say. Not only will this give you both exposure to those at the cutting edge, but I think it will also give you both somewhat of a sense of empowerment at a time when things don't look very good.

Right now, we're really knocking on the door of major breakthroughs in HCV treatment.

Those who get to the right doors sooner, will have an advantage. While no guarantees, everything I've read and heard leads me to believe that in the next few years just about everyone will be able to be cured. The silver lining is that Amanda relapsed in 2007. You both should be optimistic that things will change in the not too distant future.

All the best to both of you.

-- Jim

[TravelMom]

Amanda is in good hands...Dr. J, NYC..

We have met them all and love him the best...I have spoken to Afdhal, met with Gish and Cecil...I have traveled the country and ended up in Dr. J's hands...we trust him completely... Thank you.

[jmjm530]

You've certainly consulted with the best. As "Tn" suggested, "push her caregivers" so you will get the attention you deserve. If you haven't already, you might want to email Afdhal with an update.

-- Jim

[susan400]

I'm so sorry about this news.  I sent you an email.  I know how disappointing it is.  I'll keep praying for you and Amanda.

Susan

[Andiamo1]

Is Amanda stage 3?  When I applied to the trial, I was told that I needed a biopsy and that I would only be accepted if I was below stage 4.

I have been stage 3 for many years now and did not progress to full cirrhosis. I attribute that to the fact that I treated so many times and took good care of myself.

I sincerely hope Amanda has the same experience if she has to wait for the next trial.

Eric

[charm27]

I have been praying for your beautiful daughter for some time. My wish for you is that your spirit is not broken. I pray that Amanda's problem is resolved soon. I pray there will be an answer.

[TravelMom]

Thank you Susan, prayers for you as well...you have always been a wonderful support to Amanda and I... We will find an answer sooner or later.. for all of us..

Andi - Amanda is stage 4, cirrhosis...Cirrhotics were allowed in Prove 4 as long as they were fully compensated...Amanda's platelets were just over 100...so she just made the criteria

Charm - Thank you for your prayers...I hope treatment heals you..I see you start in 2 weeks...so good luck my friend...please keep me posted...as a Geno 2, you have much better odds than many of us Geno 1's.  Good Luck and Happy New Year to you.

[charm27]

Please dont thank me for praying. I have been praying for you for some time.

One heart feels another you know.

BTW Im 1A not 2 do you think I would get off so easy? naaaaaa

Be Well
And keep your spirit!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

We are ALL pluggin for Amanda 24/7.

[pln]

I am so sad to here this news. I came on here to day to find this post and see how Amanda was doing.I am very sorry. This is only a setback, Amanda WILL get her svr. Looking at your profile Amanda is beautiful. I will be praying for you and Amanda, you are a wonderful mom!!!
Pam

[TravelMom]

Thank you so much for your good wishes...  How are you doing my friend?  Well I hope.

Jodi