What after Teleprevir?

[Renee543]

I found this site when I started on the Teleprevir trials a few mos. ago. I did get a lot of great advice from many of the people. Unfortunately the Teleprevir did not work for me because of my phenotype tt, along with genotype 1.
The nurse said I was just "different". Made me wonder how many others out there are just "different". I have since found out a couple of other people did not make it because of their phenotype. This seems to be a big factor as to whether or not the Teleprevir will work on certain individuals or not. You have to have a viral count of between 0 and 1000 by week four or you cannot continue. Mine was 1200. No amount of pleading would make them continue because they found that if this protocol is not followed , the virus does reciprocate. Well mine has done that anyway, so not sure what the difference would have been.  My viral load went from 1200 to 949,000 since coming off the meds. Which means I will be back in the millions before long.
One thing I did learn is that they are going to be starting some new trials with "stand alone" drugs (without interferon).
So maybe there is still hope.  I really think someday there will be...in time for me? Who knows? In the mean time I am feeling so much better from getting off the Teleprevir.  I started taking all my supplements again and exercising. My platelets are still low but not as bad as when on txt. So for any of you that tried the new Teleprevir and it did not work for you. Hang in there.....
Reen

[Renee543]

Yes, I came to very same conclusion, without much help from the docs. All they told me was my phenotype was a "hard to cure" type. No other explanation..except the nurse did comment that I was "different". Oh really? ok that explains it all.  So like you I have been doing my own research and with the help of people like yourself on this forum. I finally see why I did not clear at week four. Also, that if I wld have continued the virus would have reciprocated into some mutant form that wld be even harder to clear in the future. So yep, gonna try and keep my immune system healthy and wait and see what's next. thx Reen

[streamline569]

I send you an email basically I was just wondering did you go for you blood work on the morning before your 5th shot or the morning after  your 5th shot. I'm doing my 4th shot on Thursday.

Good Luck to you on your results

[Gerbils]

Thanks for the valuable input as I await my 4th week tx results (tho I will have started shot 6). If my response is not strong enough I know that I will be done txing for now and will have to wait but consider your comments to be excellent indeed. I am hoping very much that I am und but am wanting to be realistic and have a "plan b" just in case.
G

[dointime]

"So the exposure to DAA is the reason they are so adament about taking you off txt by week four if you are not at 0-1000 viral load?"

Well .... if you are not at 0-1000 viral load then the tx is not working and it is deemed futile to continue.  That is the reason in a nutshell for taking you off.

Now I don't know, but if you are thinking that you might have cleared if you had just had a little longer on the tx then think again.  Your vl indicated that you had developed resistance and that your ifn response was not good enough to eradicate it.  It was over.  

When this happens it is best to terminate the DAA as fast as possible so that the resistant mutations do not get a chance to become stronger.

A lot of people thought the same as you about tela and jumped into a trial with both feet, including me, 4 years ago.  There was no phenotyping then and I had no clue about ifn response.  I got my education here on the board after my debacle with tela, same as you are doing.  Next time we'll both be good to go I think.    

dointime


    

[willbb]

I truly believe we will not have to wait 15 years....the landscape  seems to be changing rapidly. However rapidly could mean 3- 5 years or pehaps even somewhat longer.

Glad you are enjoying your life now and  that you don"t feel like "crap"  ..:)

Best to you
Will

[Renee543]

So the exposure to DAA is the reason they are so adament about taking you off txt by week four if you are not at 0-1000 viral load? My viral load is probably already back up in the millions. Not worried about the numbers but more on the way I feel now. I waited 15yrs because I knew I was a genotype 1 and would probably fail from all that I read on the subject. But I thought with the new drugs Tela and Boca that I stood a chance. I think many people are lead to think they are miracle drugs. And they are for some people. If it wld have worked for me, I would prob be one. I have corresponded with pp on this site that are clear but I wld be willing to say most all of them had a different genotype and phenotype than me. So the point I was making is that from all the studies I have read it does seem to matter.
And thank you Will for the encouragement. Like you I have no choice but to wait (not sure I can go another 15yrs though). I'm just enjoying my life now and just glad I don't feel like crap.
Thx, Reen

[willbb]

Renee...you and I are in the exact same boat...failed trial experiments with the lastest that there is so far and as you can see .there are others. However please keep the faith .I believe wholeheartdly that there will be something else for us in the future. I know it is very difficult to be patient,.. keep the faith.tho it will happen.

Best to you....
Will

[dointime]

"So how do you know, if you do not treat and find out? Kind of like a shot in the dark if you have this phenotype."

That's the difficulty, isn't it.  If you are tx naive then you don't know.  The best way to find out is to do a 4 week lead in on SOC alone.  That gives you a measure of ifn response without exposure to the DAA.  It also ruins your naive status if you were considering a trial for tx naives.  The next best test is the IL28B.  It is an indirect test, so less accurate.  That is all we have to go by.  It is the state of the science.

I take my hat off to you for waiting it out for 15 years.  The last 15 years have been a wasteland in terms of HCV tx development.  I could understand your frustration.  Now suddenly with the approval of the 2 triples the world of HCV seems to be seized with 'irrational exuberance' and it is even harder to stand back and wait.

You couldn't know how this tx would turn out for you, but from it you have learned something really important about your ifn response and it has only cost you 4-6 weeks of toxic drug use.  You got off lightly, trust me on this.  It is horrible to have your hopes dashed but there is a lot more collateral damage that you have managed to avoid.  You remain fit to go for it another day, and that's a good thing.

Best wishes
dointime                    

[Renee543]

Did you look at the website I sent to cheesenrice above? The part of the study that stood out to me was the connection between IFN and phenotype. It stated:  
"Sensitivity to IFN is inversely associate with levels of ISGs; phenotypes may affect expression levels of ISGs, accounting for association between phenotype with clearance" But NOT always. So how do you know, if you do not treat and find out? Kind of like a shot in the dark if you have this phenotype. I know the IFN did not do it's job mopping up the virus with me. I doubt very seriously if I will ever do another txt with interferon. And yes, I am going to WAIT.  But I waited 15yrs. for the Telaprevir because I knew that my genotype 1A, I was not a likely candidate for the IFN/Riba txt alone. I really was hopeful for the Telaprevir...but the IFN failed me in the end.

[dointime]

We do know for sure that the triple therapy requires enough of an ifn response to mop up any resistant mutations which occur.  If ifn was not necessary it wouldn't be there.

Studies have shown that IL28B testing and phenotype are correlated to a person's ifn response.  The trouble is that it is still not possible using phenotype to accurately predict if a specific person's ifn response will be enough to get SVR in the triple.  We just have stats for probable outcomes.  

Anyway, ifn response, as indicated by phenotype, does matter.

Here's what a natap.org report said:

"This highlighted a clinical challenge in assessing drug resistance in HCV therapy, in that the ability to precisely measure the immune contribution to blockade of HCV replication is imprecise, but in contrast to HIV therapy the immunological effect can be very potent (as demonstrated by spontaneous clearance of HCV in some untreated patients). For example, in patients who had a good virological response to the lead-in period prior to bocepravir, the SVR rate was 79% regardless of the presence of RAVS, but in poor responders the SVR rate was only 34% in the absence of RAVs and 23% in the presence of RAVs. Further in the presence of four specific mutations that appeared highly associated with virologic failure (V36M, T54S, V55A and/or R155K), zero of 7 patients with a poor lead-in response achieved SVR. It appears that we must accumulate a great deal more information on resistance and immune response to accurately predict therapy success, or alternatively we must find combinations of drugs that are so good that these facts become irrelevant. Patients and providers in the future would likely prefer the latter option, but many patients today may not be able to wait for that."              

[susan400]

Phenotype does matter in whether or not one will be likely to clear.  Phenotype TT's have a more difficult time clearing the virus, no matter which drug it is that you use.  This subgroup is the most difficult strain to clear.  I really only heard about this new phenotype test during the last 6 mon., prior to that, I never knew it exists.  In the trial that I'm in now, my doctor told me about this test (I had heard it mentioned on these boards only).  I had it run over a month ago and I'm still waiting on the results.  It should be back any day now.  He's expecting that I'm a TT alele.  Anyhow, the trial that I'm in uses SOC on every arm and it is a trial specifically for null responders and they've had good success with getting the TT's to clear.  It takes a little longer than with the Telap and Bocep, but there here have actually been some clearances.  For those who don't know, I was a Telaprevir failure patient.  I was in the early Telap trials (Prove 3) and was randomized into group C, the no Riba group.  Since I only received 2 out of the 3 drugs, I did not clear.  Also, since I didn't get all 3 drugs, I was allowed into this trial.  I don't feel that I'm interferon resistant.  That's never been proven in me and I refuse to believe it.  I always get a response when I treat, I just don't clear.  And as far as TX's w/o interferon, I personally don't think that those treatments will be 'side effect free', just because interferon is not a part of the picture.  I get as much side effects from the Riba as I do from the interferon.  Susan400

[dointime]

"I tell you what, never again will I jump into one of the studies without knowing what the heck I am doing."

I am sorry to hear your story.  Rest assured that there is almost certainly a combo in the pipeline now which will be an approved cure for you within 3-5 years.  I am also telaprevir resistant and waiting for that.  It is very important that you now WAIT if you can, and do not take the risk of becoming resistant to any other classes of drugs, as you are most likely resistant to the NS3 protease class after your telaprevir failure.  

I have now said this so many times that I am probably at risk of boring everyone to death but anyway here it is again.  You can't possibly know what you are doing when you do a trial.  By definition, a trial is only done because there is at least one important question that needs to be answered and the trial is there to find the answer.  So the outcome of a trial is UNCERTAIN.  

For some reason, the concept of 'UNCERTAIN' seems to be a difficult one to grasp for the way the human brain is wired.  There is so much written about trials in glowingly positive terms, eg. 'looking good', 'very promising', etc.  Well hope is a good thing.  I also hope and I dream that the combos in the pipeline now will produce 100% SVR results for everybody.  But when you (or anybody) puts their own body on the line to do a trial you need to be able to tell the difference between hope, speculation, and UNCERTAINTY.    

There are now going to be a lot of trials for the quad therapy coming up, with no ifn or ifn sparing.  Some of these will, I HOPE, lead to a cure with near 100% success.  The name of the game now, in my humble opinion, is to WAIT if possible for that.    

Just my 2 cents worth (ad nauseum, I know)
Best wishes,
dointime
    

[Bill200]

Why is that the case?  Trials better than post-approved results and why would noting results of IL28B make the results lower?  Was the sample size too small?

[SusieS2010]

Just remember that intent to treat (ITT) trials always look better in the end than does treatment once the drug is approved. We never see SVR rates as high as the trials show. Also in the arms of the trial that did make note of IL28B results, the SVR results were lower than in the arms where the IL28B results were not used.

[Renee543]

Thanks for your info, that study had some intersting yet conflicting views to other studies I have read. As the doctor said the data cannot form a basis. Probably because the study groups were so limited? Have you read this:http://hepatitiscresearchandnewsupdates.blogspot.com/2010/12/il28b-and-control-of-hepatitis-c-virus.html

In this study in 2010 it was for IL28B and the Control of HepC virus.
It states that the IL28B genotype can be considered, along with other factors (like you alluded to) in predicting patient responses to therapy with pegylated IFN-a and ribavirin. They review the studies that uncovered the association between IL28B and HCV clearance, the biology of IFN, the clinical implications of the genetic association, and the areas of future research (as stated in the first paragraph).

People with cc genotype have SVR rates more than 2-foldhigher that those with minor t (tt), like myself. The association of IL28B genotype with SVR was indepepndent of txt history.  In contrast to txt response, relapse was not associated with IL28B genotype.
It seems that an IL28B haplotype can be a strong determinant of patient's response to txt of HCV infection and can be represented by a single SNP

Something else I found interesting in this study is that they found that it seems there is correlation of IL28B genotype, baseline levels of HCV RNA, and txt response,  AND (this is crazy) although the c allele (cc) was associated with SVR (easiest to cure I was told), it was also, paradoxically, associated with higher viral RNA levels compared with the t allele (tt, like myself). AND that the higher levels of HCV RNA among patients with cc genotype might facilitate innate immune detection and control of virus during txt. This is interesting to me.
And as you mentioned; the kinetics of the txt response appears to be influenced by IL28B (so it is influenced by your phenotype) cc phenotype had the largest reduction.
Lastly sensitivity to IFN is inversely associated with levels of ISGs; IL28B genotypes may affect expression levels of ISGs, accounting for association between IL28B with clearance, there are people who carry alleles that are not associated with clearance who clear virus, as well as pts with alleles associate with clearance whose infection persists.
So DEFINATELY more studies should be performed to see if IL28B genetics, ISG expression levels, and other genetic factors involved in response to anti-HCV therapy. This just a few excerpts from the study. It's interesting to read the whole thing, especially if you are considering doing txt with Tela or Boca and you have a phenotyp ct or tt.
I don't claim to understand all of this from reading one study but I surely would like to understand why I did not respond to txt with Tela.
I am very happy for all the people who are SVR because of the txt. From the people I have heard from most all of them were cc or ct phenotypes.
I tell you what, never again will I jump into one of the studies without knowing what the heck I am doing.
Reen

[spectda]

Since you were stage 1 not long ago I would really suggest waiting a few of years for a proven (not experimental) combo that either does not rely heavily on interferon.

I would be very careful and selective about participating in a trial after treating with telaprevir and having it not be unsuccessful. There are many unknowns in these trials including of course knowing which drugs you are getting.

The success rates without interferon although making strides are not yet at a point where personally at stage one I would want to risk digging a deeper hole for myself or cause resistance issues that might decrease my chance for SVR later.  

There are so many good drugs in the pipeline right now that should be available in the next few years. I really believe the right combo will give you the prized SVR before your disease advances too far.
Best of luck,
Dave

[cheesenrice]

the main reason they tested was to establish a reference - after establishing that they found the info to be inconsequential

[cheesenrice]

if your failure was due to genotype 1 then nobody with genotype 1 would succeed - if your failure was due to tt then nobody with tt would succeed - this is not the case - your failure most likely resulted from poor viral kinetics and/or interferon insensitivity

[cheesenrice]

i dont post my opinion i post what the experts say - and i posted this info before - this is for telaprevir which is what the op asked for - boceprevir is different


Graham R. Foster, FRCP, PhD:
In a retrospective, exploratory subanalysis of the REALIZE study, Pol and colleagues[3] evaluated the relationship between IL28B genotype and SVR among patients infected with genotype 1 HCV who received telaprevir-based triple therapy following previous peginterferon/ribavirin treatment failure (Capsule Summary). As discussed previously, the REALIZE study enrolled treatment-experienced patients with previous relapse, partial response, or null response to peginterferon/ribavirin therapy.[1] Patients were randomized to 2 treatment arms involving 12 weeks of triple therapy with telaprevir plus peginterferon/ribavirin with or without a lead-in phase of peginterferon/ribavirin followed by 32-36 weeks of peginterferon/ribavirin (arms pooled for current analysis) or to a third arm of 48 weeks of peginterferon/ribavirin alone. As expected, SVR rates were higher among patients with IL28B CC vs CT or TT genotype in the peginterferon/ribavirin arm (29% vs 13% to 16%). In the telaprevir-based arms, SVR rates were high across all IL28B genotypes (CC: 79%; CT: 60%; TT: 61%), and although the rates were numerically higher with the IL28B CC genotype relative to non-CC genotypes, IL28B genotype was not significantly associated with SVR in a 2-step multivariate analysis (CC: P = .169; TT: P = .792). Within previous response subgroups, SVR rates with telaprevir-based therapy were also similar across IL28B genotypes. Among this subgroup of REALIZE participants for whom IL28B genotype data were available, previous relapsers experienced the highest SVR rates to telaprevir-based therapy (85% to 88%) relative to previous partial responders (58% to 71%) and previous null responders (29% to 40%), who had the lowest SVR rates.



In my opinion, the clinical take-home message from this study is that in patients with previous peginterferon/ribavirin treatment failure who are considering a telaprevir-based regimen, there is little to be gained by assessing the IL28B genotype because its ability to predict the likelihood of response is relatively muted with telaprevir. Thus, I would not recommend ordering an IL28B genotype in our case patient. There may be individual patients whose decision whether to undergo retreatment might differ based on a 60% vs 80% likelihood of achieving SVR, but I suspect that with such high SVR rates, the majority of patients in the more favorable previous response categories (ie, previous relapsers or partial responders) would want to undergo retreatment rather than base the decision on their IL28B genotype.



Paul Y. Kwo, MD:
I agree completely with Dr. Foster. When patients come to the clinic after failing peginterferon/ribavirin therapy with good viral kinetic history and want to know their IL28B genotype, I tell them that there is little value in obtaining this information because we already know that they responded poorly to peginterferon/ribavirin. Therefore, if they previously experienced a < 2 log10 IU/mL HCV RNA decrease, it is irrelevant whether they have a favorable or unfavorable IL28B genotype because their clinical interferon response phenotype is poor.



The analysis is strengthened by the high proportion of participants who consented to genetic testing, which provides confidence that these data are valid.



The role of IL28B in predicting SVR to telaprevir-based therapy among treatment-naive patients infected with genotype 1 HCV was also reported at the EASL 2011 meeting in a retrospective analysis of the ADVANCE trial conducted by Jacobson and colleagues.[4] The ADVANCE study was a placebo-controlled phase III trial in which 1088 treatment-naive patients with genotype 1 HCV infection were randomized to the following 3 treatment arms: telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin alone for 12 or 36 weeks; telaprevir plus peginterferon/ribavirin for 8 weeks followed by peginterferon/ribavirin alone for 16 or 40 weeks; or peginterferon/ribavirin for 48 weeks (Capsule Summary).[5] In both telaprevir-containing arms, the duration of treatment with peginterferon/ribavirin after completing triple therapy was determined by whether patients did or did not achieve extended rapid virologic response during triple therapy.



In the current analysis, IL28B genotype was assessed in deidentified samples from patients treated in the ADVANCE trial; as a result of requirements for the deidentification procedure, only samples from white patients were available. Although the analysis is limited by the fact that samples from only 42% of the ADVANCE population were available for IL28B determination and only white patients were included, the results showed that the addition of telaprevir to peginterferon/ribavirin increased SVR rates across all IL28B genotypes, with the largest increases observed among patients with the IL28B CT or TT genotype. The SVR rates among patients with the CC genotype were 90% with 12 weeks of telaprevir-based therapy, 84% with 8 weeks of telaprevir-based therapy, and 64% with peginterferon/ribavirin alone. Among patients with the CT genotype, SVR rates were 71% with 12 weeks of telaprevir-based therapy, 57% with 8 weeks of telaprevir-based therapy, and 25% with peginterferon/ribavirin alone. Finally, for patients with the TT genotype, SVR rates were 73% with 12 weeks of telaprevir-based therapy, 59% with 8 weeks of telaprevir-based therapy, and 23% with peginterferon/ribavirin alone. However, as noted previously, these results should be interpreted with great caution as they are based on a very limited dataset. For example, the SVR rate among all white patients treated in the peginterferon/ribavirin control arm of the ADVANCE study was 46%; however, the SVR rate was only 38% among the subset of white patients in this arm with IL28B data available.



Although the pattern is consistent between this study and the other telaprevir and boceprevir analyses, these data cannot form the basis for a change in practice.



Graham R. Foster, FRCP, PhD:
In my opinion, the global take-home message from all of the IL28B studies presented at EASL 2011 is that the more potent the DAA regimen, the less impact IL28B genotype has on likelihood of response. There is another report on the combination of TMC435 plus peginterferon/ribavirin that will be discussed later in this module and also supports this assessment.[6]

[Renee543]

I don't really know more than what I read and what the doc tells me. But from what I understand they related my failure to respond to the triple therapy to my genotype1 and phenotype tt. That is what they specifically told me. I was all for continuing to treat because I was so close to the 1000 cut off. I was only 200 over and they would not let me contiue. I wanted to just continue with the interferon/riba, even though the doc told me the odds would not be that good but the drug company (Johnson & Johnson) said NO. I guess they did not want me messing up their criteria with going beyond the bounds of their specific study.  I felt maybe, just maybe it may have worked. I am interferon sensitive because the IF does not work that well with me. It is supposed to come along and mop up any virus left after the Teleprevir finishes...but it did not do a good mop up on me. I think the Teleprevir did get my viral load down from 8 million to 1200 but the IF did not work. They said it was because of my genotype/phenotype...hard to cure. And my regular Gastro doc told me that this 0-1000 is the cut off for all Teleprevir pts.  I would like to know if anyone else out there has tried Teleprevir with genotype 1 and phenotype tt and it worked? If so that may support the fact that there is more at play.

[willbb]

There was a significant difference to those that added incivek  in regards to the IL28B marker...especially to those with CT and TT.

[lynda607]

cheese,

Why do you think Vertex and Merck compiled data using IL28B and went so far as to publish it on their prescribing guide?  I'm sure they didn't need to take up additional space in their prescribing guide with irrelevant information.  IL28B does make a difference and it may seem insignificant to you but when a person is trying to beat the virus 10 -15 percent is huge.  If I were considering treating with a protease, the IL28B would not deter me but facts are facts and we need to know the facts.

Reading a lot may make you informed but it does not you an authority.

Please look at the charts for established data - info does not format when copied and pasted.

Vertex page 15 &16
http://pi.vrtx.com/files/uspi_telaprevir.pdf
Merck page 19 & 20
http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf

[cheesenrice]

i think the jury is still out on the fruitless or not - maybe its not so sad that they discontinued your trial - minimizing your exposure to telaprevir may allow for retreatment down the line

[cheesenrice]

i probably dont know as much as you think - lol - i havent tried the triple therapy yet - failed 3 times with combo - i do read alot and i found that most experts dont do il28 testing with telaprevir - also it looks like you were in a triple therapy trial with telaprevir + inf + riba so im not so sure about you doing it again - many believe it would be fruitless