Resistance in 2-DAA combos

Following on from the discussion on resistance in another thread, I found this study.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf

"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."

I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx.  The viral superbugs already!  From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.  

The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.  

Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet.  We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.

dointime
PS - and thanks to willbb for waking me up.

[willbb]

dointime...From what I see from your posts you are certainly wide awake and very well informed :)

The reason for my query in the first place ... was in all the articles I have read in regards to resistance ..especially cross resistance ...there  are still many unknowns.

And I agree with you entirely  we are going to have to tread very carefully imho  through the resistance maze until more is known and  studied.

Again ..thx for the input...hope all is well with you

Will

[Trish77]

Very interesting information.  Thanks for posting that.  With the next trials involving new DAA's and pairing of DAA's, it's important to get the information out there.  

ON this one...that might explain why Vertex seems to have stopped pursuing Telaprevir in combination with the also non-nucleoside VX-222 then.  If they could see resistance mutations developing very early for both the Telaprevir and the VX-222, that's a problem.  

One of the benefits of pairing DAA's is that what one becomes resistant to, the other one is not and they fight off each other's mutations.  So the fact that they develop mutations early doesn't necessarily render both drugs ineffective - other studies of DAA pairing show that the resistant mutations of the one drug were still vulnerable to the other drug - however minimizing resistance where possible is desirable and being aware of the resistance risks will be an important part of treatment decisions.  If I could choose a DAA pair that was equally effective and developed resistance mutations at a lower rate, that would be a no-brainer.  The greater issue is when the treatment hasn't worked - you're left with resistance mutations to both types of DAA.  And when these drugs are still in trial, the questions to ask when considering a trial become more complex.  

Another thing to consider, before people get too worried, is that the life of resistant mutations needs to be looked at also on an ongoing basis and monitored.  From what I've read...and I'll find the reference....Telaprevir mutations have a shelf life and when testing has been done, they've found no existence of them in many cases 2-3 years later.  So resistance isn't necessarily a permanent thing but that remains to be seen for ongoing study.  

Lots to know, many questions remain and nothing to be complacent about, as you suggest.  

Trish

[dointime]

Thanks for weighing in on this, and on that previous thread.  I really appreciate all the help and insight that I can get on it.

I was wondering the same myself about the Vertex drugs.  This study does raise doubt where VX950 (telaprevir, incivek) is concerned.  

"One of the benefits of pairing DAA's is that what one becomes resistant to, the other one is not and they fight off each other's mutations."
Well that has been the theory, and it would be fine if it always worked like this.  But what this study shows is that each DAA pair must be evaluated on an individual basis.  Some pairs, like the one in this study, quickly select out dual resistant mutations.  We would obviously want to avoid those like the plague, for the reasons that you state.  

".Telaprevir mutations have a shelf life and when testing has been done, they've found no existence of them in many cases 2-3 years later."
This is ofcourse encouraging but it does not take into account a couple of things.  First there is the archival capability of viruses.  This was first documented in the HIV research - can't find a link for that right now but will look.  I heard about it from HR.  This is a kind of species memory.  Even if no mutations exist, the virus can 'remember' if it met the particular threat before and can figure out faster next time how to get round it.  The next thing is that many people have these mutations in their quasispecies from the start.  They may be too little to detect but they never completely go away.  So 2nd time out they are waiting to be selected again.  For these reasons I think that the whole argument about the life of mutations is fairly useless propaganda meant to calm us all down.  I think it would be better to just come clean and tell people that once they have resistance to a class of DAA then any drug in that class will be less effective for them in the future, although it may still be of some use in an intelligently targeted combo.

Lastly, I still remember one of HR's great posts a while back.  He sounded the warning bells then about these combos.  He said that while effective combos would eventually be found, there would be a period leading up when the danger would be for people who got unsuccessful combos and became multi-resistant to all the drugs.  There would be no help then for these people, while tx naive people would be stepping up and getting cured by the ultimately successful combo.  This was such an ominous prediction that I think it is well worth putting out there again, albeit paraphrased in my own words.  I wish medhelp was easier to search and I could find that post again as it has now come to such relevance.

dointime          



      

[willing]

46 days for the virus to effectively replicate  variants selected for  resistance to two "leaky" DAAs (in this case tela and vx222) seems in keeping with the predictions from Rong and Perelson:
http://www.ncbi.nlm.nih.gov/pubmed/20445200
It takes the virus a bit longer to figure out how to wriggle past two DAAs than one, but there's still no serious challenge.

However an important point for many null/partial responders wondering whether to risk triple or wait for quad is that the amount of ifn response required to reach SVR appears to be far less with quad than with triple. Data is still preliminary, but both the vertex quad results (87% rvr on naives)
http://www1.easl.eu/easl2011/program/Posters/Abstract3.htm
and the bms quad results (100% SVR on nulls)
http://natap.org/2011/EASL/EASL_28.htm
look very promising.

It looks likely that   those who can't tolerate ifn will need  to wait beyond 2 DAA tx (though  PSI 7977  may  be  a  game changer) but for the many null/partials left out by the recent approval of triple, quad looks good enough to do the job.

[willbb]

Willing: thanks again...your breadth of knowledge and ability to sift  through some of the science-speak is always very helpful...I hope to enter the guad casino and come out leaving millions behind  :)

Will

[willbb]

"millions of virons " that is

[gonnabhepcfree]

I am new to this site and came looking for information or anyone that might have been in the first part of a clinical trial -study drugs PSl 7977 in combination with BMS - 790052.  I was told by my Dr that my liver biopsy showed I was in stage 3 and now needed treatment..I am waiting for a call back from the office because what I was told was that I would be getting the Interferon and Ri bavirin with these two drugs but according to the papers I have for me to sign it only shows Interferon in something they call rescue therapy..Any input is welcomed..thank you ...

[SusieS2010]

Can anyone comment on the theory that once a patient fails inf, riba, and protease, the tests that look for the resistant mutations cannot find the minority populations that may still exist? So, it looks like the virus reverts to wild type, but when trying another protease, those mutations may come out and then we have cross resistance.

[dointime]

This is an interesting question Susie.  The following study shows that there are tests which can detect low levels of mutations but they are not in general use for hepC patients.  Maybe they should be, as this study suggests.

http://www.ncbi.nlm.nih.gov/pubmed/19026009  

[dointime]

To get down to my own situation, I am already resistant to NS3 class drugs (from telaprevir trial).  Soon there are going to be more like me from the ones who fail the current tela and boc tx.  So what are my treatment options looking like at the moment?  

Correct me if I am wrong here but I think we only have 3 DAA classes at the moment in testing, ie. targeting the NS3, NS5A or NS5B proteins.  I'm a bit hazy on class subtypes or if that is even relevant, so maybe somebody else can chip in about that.  Anyway the point is that I'm one class down and 2 left.  I am thinking that I can't afford to fail with a whole other class of drugs if I want to remain sensitive to treatment when my winning combo arrives.

So even if we (I'm a breakthrough, non-responder) get quad therapies with 90% efficacy I will want to be seeing 100% results in large scale trials before I jump into tx again.  That is if I have the liver time and don't die of old age or something else first.

Ofcourse if you have to go then you have to go with what is available, and it's very good news from willing that the quad therapies require less ifn response.  That suggests to me that these dual-resistant mutations are even less fit than the mono-resistant ones.  That would make sense as they are even more mutated away from the optimum form, the wild type.  Anyway they still have to be killed by something to achieve SVR.  Maybe that is where those drugs which boost ifn response will come into their own.  

dointime

    

[Trish77]

Great comments....makes me think.  I like that. :)

""One of the benefits of pairing DAA's is that what one becomes resistant to, the other one is not and they fight off each other's mutations."
Well that has been the theory, and it would be fine if it always worked like this.  But what this study shows is that each DAA pair must be evaluated on an individual basis.  Some pairs, like the one in this study, quickly select out dual resistant mutations.  We would obviously want to avoid those like the plague, for the reasons that you state.   "

It DOES work like that, in theory.  However, in practice could be another thing depending on the DAA's in the pairing and I completely, totally agree with you that each pair needs to be evaluated on an individual basis.  I think as we go along, we'll be asking more and very targeted questions about the DAA's as we continue to learn what it is we should be asking and how they work, i.e. which specific region of the virus does it target, how quickly are resistance mutations developing, do the mutations remain vulnerable to PR and differently-targeting DAA's, and so on.  

"".Telaprevir mutations have a shelf life and when testing has been done, they've found no existence of them in many cases 2-3 years later."
This is ofcourse encouraging but it does not take into account a couple of things.  First there is the archival capability of viruses.  This was first documented in the HIV research - can't find a link for that right now but will look.  Even if no mutations exist, the virus can 'remember' if it met the particular threat before and can figure out faster next time how to get round it.  "

Yes - please.  I'll now do some searching for info on that myself.  That warrants more information. That's totally diffferent than resistance mutations.  That's suggesting viral "memory".  That wild-type virons that survive go through a process like "ohhh...I recognize you...you've tried this before and I know what to do with YOU...MUTATE!" kind of thing.  I'd like to know more about that before commenting further...it does warrant an effort for better understanding of this to know whether it's something to take into account or not.  Interesting comment.

"The next thing is that many people have these mutations in their quasispecies from the start.  They may be too little to detect but they never completely go away.  So 2nd time out they are waiting to be selected again.  For these reasons I think that the whole argument about the life of mutations is fairly useless propaganda meant to calm us all down.  I think it would be better to just come clean and tell people that once they have resistance to a class of DAA then any drug in that class will be less effective for them in the future, although it may still be of some use in an intelligently targeted combo. "

True that some treatment-naive people have resistant mutations or resistant virons from the start.  Referring again to HIV, they've found recently that about 9% of those newly diagnosed with HIV already show resistance to some of the HIV treatment drugs.  HOWEVER, I have to say I don't quite agree that they should simply play it safe with regards to HCV by suggesting incorrectly to people that if they've taken a particular PI such as Telaprevir that they'll have resistant mutations forever if it's not true.  If you can scientifically prove they die off, why take away hope from people.  Viral load itself goes up and down all the time...a suggestion that virons die and re-populate constantly in our bodies.  Since mutations have been show to be weaker than wild-type, perhaps it's not inconceivable that some resistance mutations will die out over time.  If you are a person who has limited options, I'd not want that one taken away from me unless it was actually so.  It DOES warrant further study however....and if I was a person who had options and had already taken a Telaprevir PI and had other options, I would simply go with a differently-targeting DAA anyway for multiple reasons.  The rules of treating differently if having relapsed say so also.

"Lastly, I still remember one of HR's great posts a while back.  He sounded the warning bells then about these combos.  He said that while effective combos would eventually be found, there would be a period leading up when the danger would be for people who got unsuccessful combos and became multi-resistant to all the drugs.  There would be no help then for these people, while tx naive people would be stepping up and getting cured by the ultimately successful combo.  "

I think this is the uncomfortable truth, goes beyond that even and also needs some context added to it.  I think people entering trials with a double DAA should be as clear-headed as possible about what the risks vs. benefits equation and it will take some understanding in knowing what regions of the virus the particular DAA pair you're taking targets and what other options do you have if treatment is unsuccessful, potentially leaving you with mutations.  Beyond that, is the risk that virus mutations make their way into the general population, such as has been seen in the HIV community.  One extreme case had a fellow who was resistant to ALL HIV drug therapies and he died six months later as there were NO options for him.  I don't want to be alarmist, we're a far ways from that type of scenario, however it bears mentioning and bears some further understanding of the risks of taking DAA combos.  The context is simply that.  We're a long ways off from that....however we ignore these things at our peril and at the peril of others.  At the same time, just to leave this on a more optimistic note...some of these DAA pairs are showing incredible results with significant early UND and SVR rates.  So hopefully some of these pairs in trial do turn out to be close to that magic bullet.

Thanks.....appreciating the dialogue, it expands my thinking to be able to discuss and hear varying points of view.  Much appreciated.

Trish

[Trish77]

"Can anyone comment on the theory that once a patient fails inf, riba, and protease, the tests that look for the resistant mutations cannot find the minority populations that may still exist? So, it looks like the virus reverts to wild type, but when trying another protease, those mutations may come out and then we have cross resistance."

That's the million-dollar question.  I guess we'll have to see how sensitive the tests are and at what point we're comfortable with the results.  PCR tests have gotten down to the sensitivity of <2 and we've become uncomfortable with tests of <50.  So I'd rather know the sensitivity of being able to determine how many virons have mutated.  Clearly they've been testing for presence of mutations for awhile now, so perhaps that information is out there?  If we're comfortable with a diagnosis of SVR on a PCR with a specific sensitivity, then at what point are we comfortable also with a test result of no existing mutations?  I suppose that will be another question to be addressed.

Trish

[Trish77]

This is an interesting question Susie.  The following study shows that there are tests which can detect low levels of mutations but they are not in general use for hepC patients.  Maybe they should be, as this study suggests.

http://www.ncbi.nlm.nih.gov/pubmed/19026009  "

Excellent article backing onto Susie's question, had to read it quickly so will come back to it later - short, yes, but I like more time to *digest*. :)  This part....

"Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin."

I think if I had a previous treatment experience that failed, I might be looking to have this test done.  Excellent article, excellent information.

Trish

[dointime]

As far as I know, the only people who do the analysis of HCV genome sequences to determine the presence of resistant variants are the drug companies during the trials.  So far they have been cagey about releasing that data to trial participants, even after the trial results have been published.  I believe that data has sometimes been released to trial participants on request but only with the assurance of a confidentiality agreement.        

However things are changing all the time, so it might be worthwhile for anybody who has ever been in a trial to ask via their study doc if they can get their resistance data.  What would be really useful is if the same people could get tested again a few years later to see if their mutations are still present.

If anybody knows of another way to get this testing done that would be very interesting.  Getting tested for resistant mutations before doing tx would be ideal and save a lot of suffering, heartbreak and expense.  So come on Quest, Labcorp et.al. here's another way for you all to make loada money!

Trish - I hadn't even got round to thinking about the sensitivity of the test and whether I would be comfortable with that so thanks - sort of - for introducing that wrinkle.

dointime          

[willbb]

dointime...I am being tested for resistance..every 4 weeks as part of my(failed trial result) .. which they have put in writing that I will receive  when the trial is unblinded.

I have suggested  on the "questions to ask before participating in a trial" thread to ask for this in writing.prior to starting any trial.

Will

[dointime]

My own doc is a virologist who also works with HIV.  A few years back I asked him if he could do these resistance tests on me.  He told me he couldn't because my mutations, if I had them, would be at too low a level to detect.  He could only do this testing when people were in tx at the time and had higher levels selected out.  I understood from this that low level detection was not yet possible.  So either that was true at the time and has since changed, or my doc just didn't have access to the kind of sensitive lab work required.  

So thanks Susie for making me revisit this question and correct my previous post.  Low level detection of HCV resistant mutations is indeed possible.

dointime        

[dointime]

The guy who did the work on virus archival is Doug Richman.  He wrote a book which may talk about it but I have not read.  I saved HR's words at the time and that is how I heard about Richman's work.  Hopefully? HR won't mind if I repost them here:
"once resistance has set in, even in the past and even after no drug was given for prolonged periods of time its future use in a combo is clouded with a quick return of the resistant variant that has been" archived" as Doug Richman puts it. Same for HCV and HBV and HIV."

Here is the medhelp thread in which HR refers again to archived resistance:
(http://www.medhelp.org/posts/show/344760)  
"These are one way roads, just like you cannot normally shake  interferon resistance, you cannot shake off specific antiviral resistance, once it is established, EVEN IF A SEQUENCE TEST WILL SHOW THAT YOU HAVE RETURNED TO WILD TYPE AND NO MORE MUTATIONS CAN BE  "FOUND".

[dointime]

"One extreme case had a fellow who was resistant to ALL HIV drug therapies and he died six months later as there were NO options for him.  I don't want to be alarmist, we're a far ways from that type of scenario, however it bears mentioning and bears some further understanding of the risks of taking DAA combos.  The context is simply that.  We're a long ways off from that"

You have put it so well here.  The thing is - I don't see that I am a long way away from running out of options.  What I see is that if I become resistant to NS5A- and NS5B- targeting DAA's then it's game over for me.  That could happen in principle with quad therapy one time using these 2 drug classes.

" At the same time, just to leave this on a more optimistic note...some of these DAA pairs are showing incredible results with significant early UND and SVR rates.  So hopefully some of these pairs in trial do turn out to be close to that magic bullet."

I agree.  The key is to get a DAA or DAA combo that does not create resistant mutations at all.  This may have already arrived from Pharmasset in the shape of PSI-7977, as the study in my first post suggests.  It is early days but there's plenty reason to be hopeful.  In the meantime, the 'leaky' DAAs are not going to be on my menu.

Your posts really appreciated Trish.  Please keep 'em coming

dointime




      

[dointime]

".I am being tested for resistance..every 4 weeks as part of my(failed trial result) .. which they have put in writing that I will receive  when the trial is unblinded."

That is great!  - that you will get your data and that maybe it signals that drug companies are starting to see sense about the need to share resistance data with trial participants.  It had to happen really, didn't it.  But only when WE keep on asking till we make it happen.

dointime      

[SusieS2010]

"My own doc is a virologist who also works with HIV.  A few years back I asked him if he could do these resistance tests on me.  He told me he couldn't because my mutations, if I had them, would be at too low a level to detect.  He could only do this testing when people were in tx at the time and had higher levels selected out.  I understood from this that low level detection was not yet possible.  So either that was true at the time and has since changed, or my doc just didn't have access to the kind of sensitive lab work required."
....................................

Unfortunately, your doc's answer still holds true today if I understand everything correctly. There has to be pressure on the virus from a drug in order to find the resistant mutations. It is useless to look at them when a person has failed therapy and is off treatment. Advocates are talking with Vertex about the possibility of taking their Prove patients who did not clear, and putting them on treatment to look at what they find resistance-wise.

This makes me very very nervous about trying treatment at this time. I have always been first in line to try anything new, including drugs like thymosin which I had to get in S. America. I am so torn about doing triple therapy as I am quickly getting to the point where I will be too old to even qualify for a trial. I'm thinking my best bet is to wait for quad therapy or interferon sparing treatment since I lose all my neutrophils from Peg. Aarrgghhh. Decisions, decisions!

Thanks so much to all of you for this thread. It really gives us food for thought.  

[willbb]

Just as a side issue in as it pertains to what is being talked about in this thread,mostly aimed at folks reading it who are considering entering a trial.

Remember trials are set up with the main focus in mind ...for the drug company to experiment with a drug or drugs to gather data  in order to be able to get an approval from the regulating body. and hence sell that drug for profit. They must adhere to fairly rigid protocols and guidelines in order to somewhat protect the volunteers.

They want their participants to succeed ,for the obvoius reasons ..so they can get approval  . however always keep in mind..it is a data gathering exercise FOR THEM...not you or  even your study team.

We are all asked to sign a fairly extensive contract with the drug company  prior and such has many clauses in it to protect the company and to state to the participant very clearly what they want to be able to do and not do. This protects them from legal action.

  Interesting how we  will  always take a real estate contract to a lawyer to peruse ..however  when it comes to donating our bodies for science many of us either think this may not be necessary. or so trust the  contact nurse we have(as that is who we talk to most) that we don"t think  it is at all necessary.

I  didn"t hire a lawyer personally to go over my contract however .my neighbor is one and she was good enough to review it with me prior to the start of my trial  When I  discussed resistance testing and them revealing the results of that she suggested I insert a  sentence where they discuss resistance.

Their clause reads "The blood samples that have been collected from me at each study visit may be tested at a later time to see what specific kind of resistance has developed and when it developed......then a box to check ..yes  or no..I checked "yes" and just added


and my study team will be made aware of those results at the end of the study"  I initialed it and signed it   .My study team did not know if that would be accepted or not...however it was singed by the drug company with that sentence left in.

Sorry about the rambling post here...however I just thought if those that are entering a trial do all they can to protect themselves(be assured the drug company is) then it may be extremely beneficial to you down the road.

If you don"t fully comprehend the contract..please take it to someone that does....this is your body and your health.. and if the drug company does not want to agree with what your concerns are that may protect your well being (within reason)...possibly that is not the study for you. Just my cent worth.....

Best ..

Will

[dointime]

"There has to be pressure on the virus from a drug in order to find the resistant mutations. It is useless to look at them when a person has failed therapy and is off treatment. Advocates are talking with Vertex about the possibility of taking their Prove patients who did not clear, and putting them on treatment to look at what they find resistance-wise."

Susie, I know that you are very well informed and I accept that this is most likely correct - but that means I'm missing something here.  In the study I cited earlier, ie.
http://www.ncbi.nlm.nih.gov/pubmed/19026009
"Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1."

So my question is - if what you say is right, how do you think they could they get results from that study when the study subjects were not on tx?  At least that's how I read it.

As for Vertex putting the Prove people on tx again, as far as I am concerned that is a non-starter.  Sure I would like to find out about the state of my resistant mutations now after 4 years, but not that much  

I sympathise so much with your situation and the pressure you must be feeling to make the best decision for you.  To open it up a bit, have you checked out all the trial plans and trial arms that Pharmasset currently have on the go with PSI-7977?  I'm betting that they are not going to come out of all these trial arms without something that works, but it is whether you can wait that long or do one of their trials, a phase 3 maybe?    
http://investor.pharmasset.com/releasedetail.cfm?ReleaseID=586664
I have no interest in Pharmasset by the way, except to get a tx that works for me.  I don't even own shares.  

dointime

        

[SusieS2010]

Dointime, I am sorry that I confused you. I wasn't responding to the study you referenced. I was talking about all the talk about the virus returning to wild type and the resitance mutations disappearing in 2 years time.  Tracy Swan from Treatment Action Group and Jules Levin from NATAP are experts on this subject and that is where I am getting most of my information regarding resistance and the fact that no one can say that it is totally gone unless the patient is put on drugs again. . So, if your study says that there are tests, than we have a discrepancy in what Tracy and Jules are saying.

Ok, I just re-read the study and it does seem there is a difference of opinion here. Honestly, I don't know who or what to believe.

I am following Pharmassett but I am afraid that it will be a very long time before they are ready to take cirrhotic patients who are null-responders. Aarrgghh.

[foofighter]

Who or what to believe is right! My doc is expecting me to begin Telaprevir at Sept. appointment. Very positive about me responding, no concerns about resistance, even though I did not clear after 8 weeks of Boceprevir in Sprint 2 with a great interferon response.

He is a big gun, head of transplant at university, a good hepatologist that I like very much, so I hate to argue with him. But come on!

I thought maybe I could call Vertex and see if they could do a little review of my situation and advise my doc. Maybe if it looks like my only shot at this stage, they would use me for a guinea pig.

Will, great advice to get things in writing, in clear, concise terms. I got a verbal interpretation of confusing legalise in my consent which was wrong. Even though Doc said I would get info, I did not and never will.

[Trish77]

No concerns about resistance from the 8 weeks you were on Boceprevir or from the upcoming Telaprevir?  Has your doc indicated what kind of response he'll require from you before stopping the Telaprevir?  I have heard a 1 log drop by Week 4 and a viral load of less than 1000 at Week 4 as guidelines being used.  

I hear you on hating to argue with the big guns who are knowledgeable.  My hepatologist was but his ego was not super-sized.  He would discuss.  Not everyone's ego allows that.  I hope you get the dialogue you need, either with this doc or otherwise.  

[Trish77]

" Tracy Swan from Treatment Action Group and Jules Levin from NATAP are experts on this subject and that is where I am getting most of my information regarding resistance and the fact that no one can say that it is totally gone unless the patient is put on drugs again. ."

I'd like to know what they base this on as the data on presence of resistant mutations or not seems to have been done without needing the person to be on treatment.  Are they suggesting that data is unreliable or are they saying "the proof is in the pudding" so to speak?  Personally, I don't think the data is unreliable however I'd like to know the science behind both trains of thought.  

[Trish77]

"The thing is - I don't see that I am a long way away from running out of options.  What I see is that if I become resistant to NS5A- and NS5B- targeting DAA's then it's game over for me.  That could happen in principle with quad therapy one time using these 2 drug classes. "

To my limited understanding to date, I don't think it's as limited as that.  There are NS3/NS4A, NS4B, NS5A, NS5B - and potentially beyond that, I need to read up a bit more and I'm not as familiar with the less prominent ones.  Within those stated target areas, I do believe there are sub-areas of target as well.  The one study you posted above suggested that combining two DAA's that target the same area but different sub-areas were more effective than two DAA's of different classes.  So I think we need to look at them in an even more granular fashion and study resistance patterns in that way also.  We need a chart. :)

"The key is to get a DAA or DAA combo that does not create resistant mutations at all.  This may have already arrived from Pharmasset in the shape of PSI-7977, as the study in my first post suggests.  It is early days but there's plenty reason to be hopeful.  In the meantime, the 'leaky' DAAs are not going to be on my menu. "

Well, I see it slightly differently.  We don't have resistant mutations from INF and Riba but they are less effective than adding a PI with them that creates mutations.  I think the key is not so much to find a DAA or DAA combo that doesn't create resistant mutations but a DAA combo that is effective enough to mop up the mutations from the other in a way that kills them off effectively enough that they don't survive.  In the meantime, it's understanding what the risks are of choosing treatment with a DAA or DAA pair and choosing treatment regimens as wisely as possible.

Thanks for the reference to Doug Richman and the pointer to HR's thread.  I haven't had time to reference either but want to and plan to and I thank you for that.  There are pieces of this that I want (need? :) to understand better and I appreciate the info.

Trish

[child24angel]

This is what I've read,

Each person is unique, and therefore their medical history should
be taken into consideration. I don't know that an individual should continue
treating with a viral load at week 12?, just my opinion.

Victrelis treatment futility:


Discontinuation of Dosing:


If the patient has HCV-RNA results greater than or equal to 100 IU/mL
at TW12, then discontinue three-medicine regimen.
If the patient has confirmed, detectable HCV-RNA at TW24, then
discontinue three-medicine regimen.


Incivek treatment futility:


Discontinuation of Dosing


Patients with inadequate viral response are unlikely to achieve SVR,
and may develop treatment-emergent resistance substitutions
Discontinuation of therapy is recommended in all patients with (1) HCV-
RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4
or 12; or(2) confirmed detectable HCV-RNA levels at Treatment Week 24

[Andiamo1]

PIs do not create resistant strains.  HCV replicates rapidly and often mutates to resistant strains.  Wild type virus are stronger than mutants in most cases and are the dominant strain and the resistant strains do not survive.  SOC is broad acting and attacks all virions equally.  DAAs target wild type and rely on SOC to kill the resistant mutants that are usually weaker and more susceptible to SOC treatment.

If we have a weak immune system, the DAAs will kill all wild type almost immediately, but the mutants will survive and with no competition from the stronger wild types, they will proliferate.  Some of the mutant strains are strong enough to survive, but most are not and the virus mix will revert to mostly wild type within a couple of years.

[SusieS2010]

I have the same questions that you do. I will try to reach either Tracy or Jules and find out. But it seems like each question answered only leads to more questions and I hate to bother these people constantly. And, I think that some ofo their information comes from talking with their medical contacts.....kind of like a "hallway" consultation thing. I will email them today.

[SusieS2010]

Aarrgghhhh. I am trying to write an email and I am having lots of trouble asking the questions succinctly. If you can send me a question or two for  Tracy and Jules, I would be happy to send it to them. I am just too confused at this point to do this myself and I want to make sure that your questions get answered. For me, personally, especially since Tracy and Jules have reiterated exastly what dointime's hep doc (virologist) said I am ok with that for now. I think we willl have to wait until the latest information catches up to the docs.

[Trish77]

Hi Susie - I appreciate you taking the time to do this.  

My question is…. Are they saying that "Yes, there is testing for presence of resistance mutations and they do detect the existence, or not, of resistance mutations…..but we really don't know how reliable these tests are and the true test is when someone is on treatment and we see if it's successful as it should be with the tests showing no presence of resistance mutations"….

OR

Are they saying "The presence of resistance mutations only become visible while someone is actively undergoing treatment and that's the only time that testing for them makes sense or can be successful"  ?

Is that question coherent and making sense?  Thanks.

Trish

[Trish77]

Oh...addendum.  If question B is their response...what science, references, reading, information can they point to to help in understanding the science behind this?  

Are you comfortable with that?  Thanks again, Susie.

Trish

[dointime]

The good news and the bad news is that boc and tela are both in the same class of drugs, ie. they are both ns3 protease inhibitors which have mostly the same resistant mutations.  I think boc has one more all it's own on the ns3 protein.  

So the bad news part is that if you already have resistance from your boc tx then you are likely to be resistant to tela. and will be discontinued.

The good news part is that you are not running the risk of messing up your chances with a whole other class of drugs.  Your resistant mutations from both tx's, if you get them, will be limited to the ns3 protein.  So from this point of view you have nothing to lose.

It might be useful if you could get your resistance data from the boc trial, but that might take a while if you could even get it at all.  

I would certainly want to know the doc's thinking which leads him to have no concerns about resistance, and I would ask him to explain that, never mind who he is.  You are about to enter into what could be a long term relationship with this guy, so unless you can establish a level of communication with him into which you can bring your concerns and have them addressed then I'd say that that was a major concern in itself.  

Good luck.  Would be great to know how you get on,
dointime

  

[dointime]

"To my limited understanding to date, I don't think it's as limited as that.  There are NS3/NS4A, NS4B, NS5A, NS5B - and potentially beyond that, I need to read up a bit more and I'm not as familiar with the less prominent ones."

We agree that there are DAA's that target the NS3, NS5A and NS5B proteins.  Could you please point me at any DAA's that use another target than these?    

" Within those stated target areas, I do believe there are sub-areas of target as well.  The one study you posted above suggested that combining two DAA's that target the same area but different sub-areas were more effective than two DAA's of different classes. "

I presume you mean the PSI-7977 / PSI-352938 pair, but they were both NS5B nucleotide inhibitors targeting the same place presumably.  There was a NS5B non-nucleoside inhibitor in the other pair, so maybe you are talking about these 2 subtypes of the NS5B.  At this point I am at the limit of my knowledge on subtypes.  I don't know if resistance to one subtype implies resistance to the other but that is the question that needs answering.  I have to go and burn the midnight oil to research that question - unless some generous molecular biologist or researcher out there wants to chip in?    

" I think the key is not so much to find a DAA or DAA combo that doesn't create resistant mutations but a DAA combo that is effective enough to mop up the mutations from the other in a way that kills them off effectively enough that they don't survive."

Well, I'll tell you why I say that not creating the resistant mutations is the key.    
- because then you would never need to worry about resistance catching up with the combo, like happens with HIV.
- because you could retreat with the same drug with no worries about prior resistance.
- because you could have a monotherapy if your drug had strong enough antiviral properties, the beauty of it being less drugs, less sides.
And while there is as yet no 3-DAA or 4-DAA combo on the horizon, Pharmasset are already setting up to run a monotherapy trial arm with PSI-7977.          

I so appreciate having this debate Trish.  There was a debate about resistance on the forum 4 years ago when people like me began to fail in the Prove trials.  I started this thread to find out how much has moved on from then, now that we are on the threshold of multi-DAA tx - and therefore staring the spectre of multi-drug resistance in the face.

When I did the Prove2 trial, none of us had a clue.  We all believed that if we failed the trial we could retreat when VX950 was approved, so no worries.  We were never told about the risk of resistance.  I just want to make sure that the information that we have now is out there so that the same thing need not happen to others - as well as keeping myself updated with whatever knowledge people here are generous enough to share.  Every contribution helps and matters.    

dointime                

[SusieS2010]

Forgive me if you've seen this already but Jules has a report on HIV and HCV resistance written by Dr. David Margolis at the Mexico Workshop. If you haven't seen it yet, there may be some interesting stuff to mull over re resistance. It is in the second article he posted about half-way down. www.natap.org

[dointime]

What a great article Susie!  Thanks for posting

"However, the detection of resistance in HCV is challenging as mutant that exist at a frequency of less than 0.1% could not be detected by even ultradeep sequencing, and given the replicative capacity of HCV this could still mean that there are a billion mutant virions in the patient!"

So finally it is established that there is a level below which mutations can exist but the tests can't detect them.  This is a crucial fact, as you obviously realise, and I have more to say about it later.

Foofighter -
"HCV protease inhibitors when used with Peg-interferon/ribavirin have a 10-20% failure rate, and in these cases resistance mutations are detected about 95% of the time. Cross-resistance among current HCV PIs is widespread, "

From the article Susie posted I found the above which may be of interest to you.  Based on this you can say that from your boc failure you are 95% sure to have resistance mutations (some of which are known to be cross resistant with telaprevir).  Perhaps if you take a copy of the article with you when you next speak to your doc it will give you the confidence to put your point of view across.

dointime  

[dointime]

Concerning your treatment options, if I am reading you right, the big issue is the peg and losing your neutrophils?  I mean if it were me and I had to treat right away then the risk of developing resistance would be a negative but not enough of one to put me off the triple therapy.  The lowish success rate for non-responders would discourage me too, but I might still go for it as it is the only currently approved option.  But the neutrophils thing, well you are talking about ifn dose reductions, maybe neupogen, maybe runaway infection, maybe tx discontinuation. Mmmm - I'd have to be in pretty bad shape to choose to go down that path, and if I were in that bad shape I don't suppose a doc would let me anyway.

So supposing you pass on the triple because of the neutrophils risk, and you can't get into a trial because of age, cirrhosis, ifn nonresponsiveness, what then?  I see nothing for it but to wait for a quad therapy to be approved that is non-ifn or at least ifn-sparing.   I reckon that's 3-5 years away.  I am waiting for it myself.

If you did do the triple and fail or crash out then any resistance you picked up would probably preclude you from a later quad therapy where one of the DAA's was NS3 targeting.  Happily, I think you'd still be fine with the Pharmasset drugs, at least going on what I know about it them at this time.

Ofcourse there's always the real possibility that you do the triple and get SVR.  I am not in a position to know how bad the neutrophils risk really is, only you.

Well I thought I'd just let you know my thinking on this.  You are far more experienced than me at this tx business but sometimes it just helps to bounce stuff off of other people.

dointime


    

        

[SusieS2010]

Glad you found it helpful. I look forward to what you have to say later. When I asked Jules the questions he referred me back to his site. I hope Trish sees this too.

[foofighter]

Agree, good article! But I still can't wrap my head around it.

Trish, Doc is not concerned about resistance from my exposure to bocep hindering my success with Telaprevir. Feels I have a good shot at clearing. I am concerned about both--failure with telaprevir and ruining future attempts.

Dointime, I don't "technically" know my status as far as an official PI failure. It is possible that I would have become undetectable at week 16 which would have been 12 weeks of PI. I had a great SOC response (4 log at week 4), but only a one log drop after addition of PI. Then stalled at <25 through week 12 (quit/fired at week 13 due to sx).

Maybe the Incivik will have that extra mojo to get rid of the final few? Or does my exposure to Bocep negate everything extra Telaprevir might have? My last dose was Feb 13, 2009. If I treat I will be going in at a bmi of 25 (last attempt I was at 28). Maybe try bumping up the interferon also. And I will not try to work this go round. Willy mentioned success for someone on the fourth attempt by changing things up. Shock and Awe has worked for Pam, Gauf, DD and others.

Willing thought I should give it a try. And he has such an amazing grasp of this stuff.

Maybe I am grasping at straws. I just don't know what to do. Like so many others that have been waiting, and not knowing how much longer they can continue to wait. Rambling now, sorry.

[mikesimon]

".....But the neutrophils thing, well you are talking about ifn dose reductions, maybe neupogen, maybe runaway infection, maybe tx discontinuation..."


Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C

"Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC 55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. Conclusion: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. (HEPATOLOGY 2010)"

http://www.ncbi.nlm.nih.gov/pubmed/20830784

[dointime]

" I am concerned about both--failure with telaprevir and ruining future attempts."

I wouldn't be concerned about ruining future attemps with NS3-targeting DAAs because you may well have done that already with the boc. tx.  As there is no way you can tell, that issue will be clouded for you going forward anyway, whether or not you do the tela.

"Maybe the Incivik will have that extra mojo to get rid of the final few? Or does my exposure to Bocep negate everything extra Telaprevir might have?"

Your resistance data from the boc trial might have gone a long way to explain what was happening during the time that you 'stalled' in the boc trial.  In the absence of that data I don't think this question can be answered.  I think that you have just got to assume that you did develop some resistant mutations and hope that a Shock and Awe regime with incivek and lashings of ifn can overcome them this time.

"I just don't know what to do. Like so many others that have been waiting, and not knowing how much longer they can continue to wait."

As time is pressing and you have not mentioned any other health issues which might be showstoppers, I'd have to agree with Willing that you give it a shot.  You will know very quickly if it is working or not, via the discontinuation rules, so not much to lose at all by going for it.

Good luck
dointime

[dointime]

Hey Mike

Well b*gger me, and glad to see that you are on the case as usual at the cutting edge of the science.

"Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia."

I'm surprised because I remember somebody on tx who was hospitalized very sick with infection and put on intravenous antibiotics.  It was blamed on neutropenia and her tx was discontinued.

This looks like a very important study for anybody threatened with an ifn reduction because of neutropenia.  Many thanks for posting,

dointime
    

[SusieS2010]

That was me the summer of 2008. Totaled 5 weeks in hospital with upper respiratory infection that finally responded to levaquin. I had zero neuts and it took the neupogen months to get me back to a low normal number. Of course I was already 63 years old but I didn't have poorly controlled diabetes.

[dointime]

That sounds really really scary Susie.  No wonder you are thinking twice about jumping in again.

I'm in no position to argue with the study posted by mikesimon but it does fly in the face of what has been the conventional wisdom on neutropenia.  I suppose that's why they felt the need to do the study in the first place.

dointime  

[dointime]

It is 4 years since my Vertex trial when I first found out that I almost certainly had resistant mutations and there were implications for my future tx.  I had questions then and those questions are much the same now.  With the help of the people who posted on this thread,  here’s what I make of my questions now.

Question1
What Now?

Reply1
I’ll leave this one till last.
------------------

Question2
How can I find out if I have resistant mutations and which ones I have?

Reply2
The situation regarding the testing for resistant mutations is still unsatisfactory because the tests are not generally available and the drug companies who do them during trials do not readily share this data – but see willbb’s post for advice on how to obtain it from them.
------------------

Question3
Will my resistant mutations go away given time, or will I always be resistant to the DAA used in my tx, and indeed the whole class of DAAs to which it belongs.

Reply3
This is still a hotly debated issue, however I can find no evidence which gives me confidence that once resistance is present it will ever go away.  Indeed, the work on viral archival indicates that it will persist.  The studies that there are, indicate that some mutations are much more persistent than others, therefore this question may have to be addressed on an individual mutation basis.  In addition, some mutations already exist in tx naïve people.  Current testing sensitivity is able to give a positive reading at low enough levels to test tx naïve people, but cannot give us and may never be able to give us an UND reading with enough confidence to be sure that no viable mutations are present.   The usefulness of such tests is still not explored, and in any case until they are made available to us it is hard to see how much headway can be made on this question.    

------------------

Now back to Question1 – What Now (for me)?

Reply1
My challenge for my next tx is to kill my wild type virus AND my resistant mutations.  I am assuming that my resistant mutations are still there as I can’t be sure that they are not.  My doc and I are obliged to sit down and speculate on which particular mutations I might still have.  Then we have to come up with the drug combo that will kill them - without creating a whole new set of mutations which might survive the tx and make me multi-drug resistant.  As my ifn response is poor, I cannot depend on the SOC component of a combo to trap any mutations which might arise.

Have you ever heard of such a minefield!  No wonder I am not the only one confused, bewildered and occasionally wondering if there will ever be light at the end of this tunnel for me.  

However there is a possibility emerging which might sideline this whole mess.  Unlike  HIV treatment, HCV tx has a duration and an end point.  We only need a drug combo which does not create resistance for the duration of the tx, say 6 months.  The study in my first post shows that one of the combos showed no resistant mutations in 4 months.  If we can get a combo which does not create resistant mutations for the duration and which also has strong enough antiviral properties then this would be the way forward.  Nor is it just pie in the sky.  

http://www.natap.org/
“So far there appear to be at least 3 HCV polymerase resistance mutation patterns, again suggesting that combinations that avoid resistance may be approachable.    

So with a bit of luck I can wait for this.  There are others who can’t wait and must navigate the current resistance minefield somehow.  To that end, the information that is posted here on the forum by people currently in this process is invaluable.  Thank you so much to all who posted here and good luck with your individual challenges for your next tx.  

dointime      



  

[SusieS2010]

A special thanks to you, Dointime. Your analysis, thoughts and opinions have helped me greatly. While I'm still not positive about what to do, you have helped me get a clearer picture in my head of what can possibly happen if I decide to treat now. BTW, I am leaning towards waiting for an inf sparing quad therapy trial. I really appreciate the time you have spent on this and the fact that you have freely shared it.

[mikesimon]

I was probably more sensitive to this issue than most because of the immunosuppressive drugs I was taking during treatment 2000 - 2004.
I have read basically the same thing several times. I recall the first time I saw the premise that neutropenia in the HCV treating population doesn't expose patients to the risk of bacterial infection that we'd expect it would. That was maybe 8 years ago.

Mike

[SusieS2010]

I've read the same thing as Mike has read, although it wasn't my experience. Maybe those articles mean that the "normal" (if we can call it that) drop in ANC does not cause  risk of infection if it is from the interferon as much as neutropenia would cause infection from other reasons for the neutropenia. Oy, lousy sentence, sorry.

[dointime]

It is this kind of  high quality information that you have posted that makes this forum such a valuable resource for me.  I remember at the time of the Vertex stage2 trials, that we on the forum had good early information about VX950 from the anecdotal evidence provided by the trial participants.  A lot of that information was subsequently validated when results and studies were made public.  In the interim, it helped a lot of people to make the right decisions about their tx and participation in the trials.  Especially, it warned people to steer clear of the no-riba trials which later became notorious.

As you say, you have had more reason than most to look into the neutropenia question.  I am grateful for the heads up on this topic.  It cannot be said, however, that Susie's  experience is an isolated case.  I know of one other for sure to whom the same thing happened while on tx and who was in a critical condition in hospital for some time.  So I still have questions on why the findings in the study you posted have not been more widely adopted - - as it is not cutting edge as I assumed but an 8 year old idea.  Also what then are the factors causing these runaway infections during tx if neutropenia is not to blame?    

dointime   .                      

[curiouslady1]

So, from someone who is not completely understanding of this level of scientific density in discussing the issues, what is there to do?  I am 64, lab tests still mostly normal, completely tx naive, 1a, diabtic, overweight, FLD, Graves, LP and OLP with lots of itch, fatigued.  Friend of 40 years ago just died of liver failure.  Should I wait?  Should I go for it?  The tx sounds gruesome and is beginning to sound like a temporary fix.  But how long can one last before another virus driven disease rears its ugly head to say nothing of the conversion to cirrhosis?

[SusieS2010]

I am wondering if the studies that showed no increase in the rate of bacterial or viral infections in patients with neutropenia from interferon mean just that.......no increased rate. However, if one does get an infection then having extremely low neutrophils makes it much harder to recover from the infection.

Curioslady, the treatment is definitely not a temporary fix. It wither works and you are cured, or it doesn't work and you have no choice but to wait for another treatment to become available either through a trial or FDA approval. As a treatment naive patient without cirrhosis, if you loose weight and get your diabetes  under control, you would have a very good chance of cure with the available treatment.Most people do not have their neutrophils get so low that they are in danger. There is also medication for that if the neutrophils are falling.

[curiouslady1]

Does anyone know the characteristics of the 21% that fail the triple with Tele and SOC?  We hear of the 79% rate of SVR but not about the characteristics of non responders.  

[willbb]

Does anyone know the characteristics of the 21% that fail the triple with Tele and SOC?  We hear of the 79% rate of SVR but not about the characteristics of non responders.  
-------------------------------------------------------------------------------------------------------------------------------

First of all.. the number is not as  specific as 79%.. Data in trials  has shown success rates of anywhere between 32%  -90%   taking a course of triple therapy,depending on many many factors......race,,sex,,weight ..age,,IL28B gene marker,IR(insulin resistance),being tx. naive,or relapser ,null responder,amt. of liver damage   and there are others that are just unknowns at this point.

There have been people with many negative predictors that have gone on to SVR  and conversely many with lots of positive predictors fail treatment.

In  other words .. all the mysteries have yet to be solved.

Will

    

[Trish77]

"Glad you found it helpful. I look forward to what you have to say later. When I asked Jules the questions he referred me back to his site. I hope Trish sees this too. "

Sorry for the delayed response - Canada Day Friday meant three day weekend then right back intot the thick of things, my first time back in here in days.  

Susie, I did see your response....fabulous article.  I thank you for providing that from your sources.  I have some comments to catch up on and some reading up to do, however  wanted to at least check in and acknowledge and thank you for the article.

Dointime...have some addendums to your thought-provoking posts.  Will add more later.  Lunch at work is way too short for this at the moment. :)  

[dointime]

You have had the recent death of a friend from liver failure and I imagine that this has jolted you into taking stock of your own situation.  Unfortunately there is no fast track to get you through the dilemma that you are in.  Well I guess there is one - you just trust your doc and do whatever he says.  I know people who have had great success and been cured this way and never had one clue about even what a PCR is.

However if you really want answers to your questions then you have work to do.  Take a deep breath. Take some time.  Read the posts on this forum and follow up on the links and studies.  Acquaint yourself with the issues involved in the questions that you are asking.  You can't do this overnight.  There are no shortcuts.  Come back on the forum and ask your outstanding questions just one question per thread.  That makes it easier for people to focus their answers.  By posting here you already took the first step.  You'll be fine.  

All the best
dointime              

[dointime]

Susie, I am really laughing at your last post re. the neutropenia study because I have a horrible feeling that you might be right.    

As you say, no increased risk of infection with neutropenia sounds just fine.  That is if you miss out the part about "however if you do get an infection then you might die from it".  

Sorry about the laughter but this has really tickled my black sense of humor.  It is far from funny though.  I must have read that study over a dozen times now and I still find it hardly credible that sane researchers could mean this interpretation.  I feel bad for you though because you have a known risk with neutropenia that you are struggling to get to grips with.  Indeed anybody on tx could be looking at this risk.  My turn to say Aarrgghh!  

dointime    

[curiouslady1]

Thank you all for discussions on this and other threads and the provocations from me that you have tolerated.  It has helped me consolidate in my mind the most important questions to ask about current trials and treatments when I consult with a very busy physician in a research facility tomorrow.  When your time with the physician is at a premium, you want to make sure that none of it is wasted seeking information which is available elsewhere.  

[Bizzybee99]

Amazing level of knowledge here, definitely out of my league.  Thanks to all for sharing so freely.  I am learning a lot that will directly assist with my decision to Tx now, or to wait.
Being a Geno1a,  Null responder (significant drop in VL, but didn't achieve 2 log drop by week 12) with previous Tx (IFN/Riba), and most likely not progressed beyond a stage 2, one would think it a no brainer....wait!  But, my doc is telling me that since I have made dramatic Immune health improvements with other Tx (for me/cfs), that I would now respond much better to tx for the HCV, especially with the new DAA thrown into the mix.  So, I'm working on making the best decision.

I really hadn't put the threat of resistance very high on my list of variables influencing my decision about Tx.  After reading this thread, it seems that maybe I should.  I would like to clarify a few things on what's being said about resistance if I may?  First off, am I hearing that creating resistance to one DAA, will definitely NOT create resistance to other subtype DAA's in the pipeline?  Also, how long do you guys think it will be before effective DAA's not requiring to be used with IFN, will be on the market (phase 4)?

Thanks much everyone

[dointime]

" But, my doc is telling me that since I have made dramatic Immune health improvements with other Tx (for me/cfs) "

Hi Bizzy.  I'm sorry, I don't understand what you mean by other Tx (for me/cfs)  Can you please explain more fully why your doc thinks that your ifn immune response has improved since your last tx?

It is true that the triple therapy (SOC + 1 DAA) has shown a higher SVR rate in trials than SOC (ifn/riba) alone.  

On your question about creating resistance, I think it would be helpful to get more specific.  There are 2 triple therapies currently approved.  Both use DAA's which target the NS3 protease.  If you fail tx with either of these then you may very well be left with cross resistance to any DAA in the same class (ie. which targets the NS3 protease).  For the 2 approved DAAs,ie. incivek and victrelis I have not heard of them creating cross resistance to other classes of drugs, however this is a specialist question which you should ask your doctor.  It is quite possible that there will be drug combos in the pipeline which will have a DAA in it of the NS3-targeting class.  A combo like this might be less useful to you if you were already resistant to this class.

How long?  Have a look at the clinical trials currently underway.
http://www.hcvadvocate.org/news/newsLetter/2011/advocate0711.html#5
Also look at what Pharmasset are doing.
I am guessing that the Ultimate Combo will probably arrive in stages.  I think we will get successful ifn-sparing combos before we get no-ifn combos.  That might be good enough for many people.  I think that these combo trials need to get through phase2 before an educated guess can really be made on which combos are going to go through to phase 4, and the timescale.  People talk about 3-5 years till approval and that seems not unreasonable to me.  I hope so because I am waiting too.

I have to tell you that I am delighted to hear that you are incorporating the resistance issue into your decision-making process for your next tx.  I'm not a doctor but I am glad to get the opportunity to point you in the direction of the questions which you should ask your doctor.  I think it is high time that these questions about resistance were taken firmly out of the closet and got to grips with, not just at select meetings by researchers but by every doc and every person using the new DAA's.  I really hope that this is already happening but I just don't know.      

Good luck,
dointime        

      

[willing]

willbb: seems a very wise approach to handling your trial participation contract. If lab rats had rights - which they apparently don't - any information collected from the patients would become part of their medical record. Thanks for providing a good model for how to handle this.

dointime: unfortunately that 'dark humor' appears to match what pts here have posted. Most get by on tx  with  depressed (sometimes severely) white blood cell counts. *Very* rarely someone runs into a particularly nasty bug while in this depleted state and has to - immediately - be pulled off ifn. You don't need  'em till you need 'em.

foo: considerable additional information surfaced at the approval hearings. I believe you are quite right to question your Dr's cheery assumption that if Vic didn't work for you Inci will. Other than sx, the two drugs, are so similar,  with essentially identical resistance profiles, that it's hard to see justification for that argument.  Another possibility is that you were among the minority of pts with dominant baseline resistance - most of your virus may have been  PI-resistant before you took the first pill.  The Vertex submission, (page 5) cites this in 1% to 2.7% of pts and the paper dointime linked above found as high as 8.6%. For the very good drop you saw on ifn to be followed by such a lukewarm drop after the PI strongly suggests the PI wasn't finding much to shut down.

A key question is how much stronger did resistance get because of the discontinued Vic. With mathematical certainty  the relative proportion of resistant virus increases with your first PI pill : wild-type goes down but resistant variants do not.  The Vertex submission notes that "Predominant baseline resistance to telaprevir is rare (< 1% to 2.7%) and does not necessarily preclude achieving an SVR with a T/PR regimen." However obviously if you are now walking around with 85% resistant variants the Inci is not going to have much to work on. Getting some sequence data before diving into the pool seems well worthwhile!

all: since I'm following  a completely ad-hoc, dataless,  use of a PI I should probably be worried about resistance but somehow  just can't  get there. If I relapse, the stragglers will likely be 99% PI-resistant. Any residual wild type sequence would have had to survive 18w of PI, a hard thing  to do.  If that happens I'd likely stay away from NS3/4A PIs in the future, but that doesn't seem much of a restriction.

The really strange thing is that though we're now somewhere around year 8 of testing boce/tela there doesn't seem to be any PI re-treat data, Effectiveness of a PI after a failed attempt remains a pencil and paper exercise regardless of the data showing gradual fading away of resistance.

[Bizzybee99]

Thanks for your response.  

People with real me/cfs typically have severely malfunctioning immune systems, and as a result they tend to have multiple reactivated and opportunistic infections.  I unfortunately have HCV in the mix as well.  I wanted to knock the HCV out hoping that too would allow improvement with the me/cfs.  I was very sick with me/cfs and a severely malfunctioning immune system when I did HCV Tx with Combo 6 years ago....this likely had a lot to do with why I failed that tx.  I'm only mild-moderately ill now with greatly improved immune function....therefore, I should have much better odds with Tx success.    

If a person doesn't clear with one of the new PI's, they will likely then have a resistance to that class of PI.  What I wasn't understanding is how many of the PI's currently in trials would fit into that class.  In other words....If I do Incivek tx now, and I don't clear and then have resistance to that PI....what percentage (if any at all) of the new ones currently in trials, would I also have a resistance to?

I have several variables involved in making the decision to Tx now....Resistance is on the list, just not at the top.  

Thanks for your help.

[dointime]

Bizzy : ok thanks for explaining.  I know nothing about me/cfs so that is really interesting.  To get an idea of the percentage you are asking for, you would need to go through the drugs currently in trials and see which ones are NS3 protease inhibitors.  These websites might help:
http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html
http://hcvdrugs.com/  

willing: I think that your odds of SVR this time are really good.
But anyway, you say: " If that happens I'd likely stay away from NS3/4A PIs in the future, but that doesn't seem much of a restriction."
It would be a big restriction if you were in a hurry to treat and the only candidate combo in the offing contained an NS3 protease inhibitor.  There is going to be an unsatisfactory situation from now until we get a good enough combo to make resistance and ifn response irrelevant.  In this interim period, people who need to treat will have to go with what is available at the time and may be out of luck if they already have resistance to one or more of the combo ingredient drugs.

"Getting some sequence data before diving into the pool seems well worthwhile!"   Willing, how do you advise that this data could be obtained?        

dointime

[dointime]

PS
" If that happens I'd likely stay away from NS3/4A PIs in the future, but that doesn't seem much of a restriction."

We have a good example right now that this can be more than a restriction, it can be a showstopper.  Currently, the 2 approved triple combos are the only game in town.  However, anybody who has previously treated and become resistant to an NS3/4A PI can't go again and hope that one of these combos will get the job done the 2nd time.  Only people who have a good ifn response and tweak the tx to max it out (like foo) will have the chance that 2nd time round the SOC component will kill the mutations.      

dointime        

[cheesenrice]

Paul Y. Kwo, MD:
Sullivan and colleagues[13] conducted a study investigating the evolution of treatment-emergent drug-resistant variants in telaprevir phase III trials of treatment-naive and treatment-experienced patients (Capsule Summary). In this study, resistant variants in the HCV NS3 protease were identified by population sequence analysis in patients treated with telaprevir-based therapy who failed to achieve SVR; patients were then followed over time to estimate the median time to loss of detectable resistant variants.

Among 388 patients without SVR and with population sequencing data available, 74% had resistant variants at the time of treatment failure. The results of the follow-up analysis were reassuring in that resistant variants were replaced by wild-type virus over time in most patients, with a median time to wild type of 7 months. Within 1 year after treatment failure, 71% of patients had only wild-type virus detectable by population sequencing; by 16 months, 96% had only wild-type virus. Different resistant variants appeared to exhibit differing levels of replication fitness, although this finding will have to be confirmed in larger studies. In particular, R155K appeared to be quite fit with a median time to loss of 10 months. It is unfortunate that this mutation appeared to persist for a longer duration because R155K confers a high level of telaprevir resistance.


One caveat regarding this study is the use of population sequencing, which has a 20% detection threshold. Although that threshold is fairly high, preliminary data with more sensitive techniques have shown that resistant variants do decline to much lower levels over time.[14] There is general consensus that these resistance associated variants are present at very low levels at the beginning of therapy and use of the DAA agents select for their enrichment during treatment. For boceprevir, telaprevir, and other DAA agents, it will be necessary to establish whether the viral quasispecies returns to its baseline distribution of predominantly wild-type virus with minimal levels of resistance associated variants in patients who fail to respond to therapy and discontinue treatment; however, establishing this outcome with more certainty will require additional studies and longer follow-up. This study provides preliminary reassurance that the natural history is to return to a wild-type viral population after withdrawal of telaprevir.


Graham R. Foster, FRCP, PhD:
The critical question is whether resistant variants will re-emerge more rapidly if patients are retreated with the same agent or a closely related agent. Further studies will be needed to answer that question. The results of this study also suggest that genotype 1a HCV resistant variants decay more slowly than genotype 1b resistant variants: the median time for resistant variants to become undetectable was 10 months vs 0.8 months, respectively. In addition, patients with genotype 1b were less likely to have resistant variants at treatment failure relative to patients with genotype 1a infection (54% vs 84%). These differences likely reflect the different sequence changes needed for telaprevir resistance in genotype 1b vs 1a virus. The clinical significance of this finding remains to be determined.


Paul Y. Kwo, MD:
The finding that genotype 1b HCV is less problematic than genotype 1a seems to be a theme that is echoed by several presentations at the EASL 2011 meeting. In my opinion, we are entering an era in which genotype 1 subtyping will be clinically important, similar to the emerging finding that genotypes 2 and 3 are clinically distinct.


Stefan Zeuzem, MD:
In a similar analysis of boceprevir resistance associated variants, the frequency was also numerically higher in patients with genotype 1a vs 1b HCV (Capsule Summary).[15] This study used population sequencing in patients who failed to achieve SVR with boceprevir-based therapy in the phase III treatment-naive and treatment-experienced trials; however, the current analysis was cross-sectional at the time of treatment failure and did not report on time to loss of resistance. In addition to investigating the frequency of resistance associated variants by genotype 1 subtype and by type of boceprevir failure, this study also evaluated the relationship between the response to the 4-week peginterferon/ribavirin phase and the subsequent development of resistance. Among patients who failed to achieve SVR, resistance associated variants were detected in 68% of patients with < 1 log10 decline in HCV RNA vs 31% of patients with ≥ 1 log10 HCV RNA reduction during the 4-week lead-in. Therefore, the key finding is that patients who are less sensitive to interferon have a more than 2-fold higher likelihood of developing boceprevir resistance associated variants.


As Dr. Foster noted, long-term follow-up will be crucial for determining the clinical impact of these variants. It will also be important to compare these 2 protease inhibitors for potential differences related to resistance. One key factor that may impact the emerging data would be different exposure durations of the 2 drugs. This could in theory affect the decay of the variants, because longer exposure to the resistance selecting drug may allow the virus more time to gain secondary compensatory mutations that may increase viral fitness. Although the trials investigating both drugs had very strict stopping and futility rules, they did differ with the potential for longer exposure in the boceprevir vs telaprevir trials. In the boceprevir treatment-naive study, the stopping rule was based on detectable HCV RNA at Week 24, which equates to 20 weeks of boceprevir.[8] In the boceprevir treatment-experienced study, the stopping rule was based on detectable HCV RNA at Week 12, or after 8 weeks of boceprevir.[9] [Editor’s note: The prescribing information for boceprevir recommends a Week 12 stopping rule for all boceprevir-treated patients.[12]] By contrast, in both the telaprevir treatment-naive[5] and treatment-experienced[1] studies, the first stopping rule was based on the HCV RNA level after only 4 weeks of telaprevir; therefore, the boceprevir trials had the potential for much longer drug exposures relative to the telaprevir studies.


Graham R. Foster, FRCP, PhD:
The key take-home message for the treating physician is: if the patient is not responding well, stop. treatment early and do not persist with ineffective therapy. Minimizing exposure to futile therapy may turn out to be very important to protect future treatment options.

[foofighter]

Rad info y'all.

Thanks to everyone chiming in with their insights and offering up the latest info for all to consider regarding this issue. Especially with docs not up to speed on this topic yet. This is such a great board with so many brilliant people.

Willing, hope you are hanging in. Has nausea been a problem for you? Sending good vibes your way.

foo

[Willy50]

Interesting thread.  It is a little odd that after so long the subject remains speculative.  It is absolutely certain that many people who are or will soon be treating with a PI may fail TX for some reason; pick a percentage; 20-30%?  These people will presumably have resistance to PI's.  It seems a little irresponsible to not have a better understanding of the consequences of this failure group.

My recollection of the early vertex info was that they knew resistance was going to be an issue before the exposed the first patient.  In the first trials...... 14 day mono-therapy some of the viral loads were creeping back up at about one week.  I think resistance was happening in all patients at 14 days

I also believe that the lessons learned in the no-riba arms were recently repeated in the Quad therapy trials of VX-222 and Telaprevir.  The quad therapy arms will probably do OK (If they are able to "only" treat for 12 weeks and stop).  The no IFN & riba arms were discontinued when participants experienced an unacceptably high rate of viral breakthrough.  I believe this is why they limited the size of the arms to only about 25 people.

I really wish that this was understood better.  They could have offered some people a free re-treat w/ a PI and had a better understanding before providing the drugs to doctors who may not understand the ramifications of this, or likewise the patients who will suffer the consequences.  It seems to remain untested speculation.

I do see that they are stressing the importance of compliance and timing of doses and the reinforced importance of discontinuation criteria.  So I guess that it is on their radar.

If they can tell us that resistant revert to wild type only, why not test that hypothesis?

How easy would have it been to answer; VERY.

willy

[willing]

foo: thanks for the good wishes and back at ya with your upcoming re-tx. Sorry if I seem to be adding more confusion to the topic and  congrats on the BMI - your plan sounds like a good one. Per Inci on-label protocol, hovering at  lt 25 to w12 would simply  put you in the non-eRVR category where odds are still in the 60-66 range. However any insight your Dr. or others can give into why you didn't see more of a PI-based reduction after that great ifn drop would be good information.

dointime: though the NS3/4A field is getting crowded there is no shortage of candidates that target  other sites including NS5 (BMS790052) and nucleoside (PSI7977,938) and non-nucleoside (R7128) NS5B inhibitors.  Resistance to NS3/4A will not be an issue with any of these. I'm guessing phase III trials for BMS790052 and R7128 by next year.  If I have to go through this again (and thanks for the good word)  it would definitely be better to do quad, but even if the NS3/4A drug class becomes ineffective there alternatives look like they will be  out there.

Getting accurate sequence info is  a problem but one can start by asking a simpler question. Never mind the minority variants only detectable with ultra-deep pyrosequencing. Instead one just can ask whether one's dominant 80-90% strains exhibit any of the major PI-resistant variations. (A156T etc.). Only a yes question there would preclude even trying tela/inci. The second question is a much simpler one to answer. Contacting labs that have published results in this area and have a medical center affiliation seems be a good place to start.

Willy: agreed - there seems to be no rush to test whether re-tx with a PI works. There may be an ethics issue enrolling pts.  Over the next year there will a growing group who have failed triple. Will  they be better off retrying triple or waiting, letting some of the PI-resistant variants fade away  and retrying with quad?

[Willy50]

I'm afraid that their failure to find out the answer means something; like they don't want to prove what they already fear; archived resistance.

It would seem to me that the ideal person to "test" this on would be a past trial participant.  They would have incredible records; possibly daily or weekly PCR records.  They would offer a free trial to say 10 past failures, lets say failures from no riba arms and attempt triple therapy this time.

They would then have the ability to cure the people whom they may have stuck with a potential resistance problem, they would have stellar past records and new records to compare them with, they would be potentially curing a person whom they had saddled with a problem and......possible ace in the hole..... lets say if Vertex did this small trial and a they could also add VX-222.  At this point the no riba arm failures would have a great chance at getting treated and CURED (vertex probably knows the quad therapy cure rate at this point) so that potentially 9/10 who did this could be treated and cured.

In the bargain Vertex and the world would have an answer, and to my way of thinking they could have done this some time ago.  One presumes curing this group of people would be considered an equally ethical consideration.  Many trials won't touch this group and if they may require some special attention or face different response rates when they treat retreat w/ a PI there does not seem to be any data to drive by, not even recommendation of more PCR's or a different discontinuation schedule, or gathering of more blood samples to test to see if archived resistance is an issue.  

I'd like to see the "dream solution" created for all these TX failures that will certainly occur when people TX and fail w/ a PI. I'm sure it is being considered.  I've yet to hear about any actions being taken.  If it is a moot point and archived resistance is not an issue after a few years doesn't it seem that they would have should have proven this point in a scientifically proven trial?

Willy

[cheesenrice]

Graham R. Foster, FRCP, PhD:
To investigate the predictors of response to telaprevir-based therapy among treatment-experienced patients, my colleagues and I[2] conducted a retrospective subanalysis of the REALIZE study comparing the use of previous response categories (null, partial, or relapse) vs HCV RNA response to a 4-week peginterferon/ribavirin lead-in phase as predictors of SVR (Capsule Summary). The current subanalysis was restricted to patients treated in the control arm (n = 121) and in the telaprevir arm that included a 4-week peginterferon/ribavirin lead-in phase: peginterferon/ribavirin for 4 weeks followed by telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin for 32 weeks (n = 240). The importance of the REALIZE study was that it included true null responders whose HCV RNA decreased by < 2 log10 at Week 12 of peginterferon/ribavirin, as well as patients who experienced some degree of viral suppression (partial responders whose HCV RNA decreased by ≥ 2 log10 at Week 12 but remained detectable during treatment) and relapse patients (HCV RNA undetectable at the end of treatment but detectable after stopping treatment). Enormous efforts were taken to establish a previous treatment history before patients were enrolled. The question posed by the retrospective analysis was, “Is it better to examine the patients’ previous treatment response or to give the patients a quick 4-week lead-in of peginterferon and ribavirin to characterize them as responders vs nonresponders?”


This analysis concluded that if there is a very clear history showing how the patient previously responded to peginterferon/ribavirin, one can obtain a good prediction of how the patient will respond to retreatment with telaprevir-based therapy. Specifically, previous relapsers experienced a 90% SVR rate with telaprevir-based therapy. By contrast, the SVR rate was 58% among previous partial responders and 30% among previous null responders.


When assessing SVR rates based on response to the 4-week peginterferon/ribavirin lead-in, it is interesting that some patients who ultimately did very well with telaprevir-based retreatment initially responded rather poorly through 4 weeks of treatment. For example, 10% of previous relapsers experienced a < 1 log10 reduction in HCV RNA after the 4-week lead-in phase; however, 62% of these patients achieved SVR with subsequent telaprevir-based therapy. Likewise, previous partial responders who experienced a < 1 log10 HCV RNA reduction during the 4-week lead-in phase achieved a 56% SVR rate with telaprevir-based retreatment. That finding raises concern that if treatment response predictions were based on the 4-week lead-in response in this population, clinicians may discontinue therapy in a significant minority of patients who would otherwise have achieved SVR. Thus, I would counsel our case patient (a previous relapser) that a 4-week lead-in phase would add very little value and would not be helpful in determining her optimal course of therapy.


By contrast, response to the 4-week lead-in phase had much stronger predictive value among previous null responders. The SVR rate following telaprevir-based therapy among previous null responders who experienced a < 1 log10 HCV RNA decrease during the 4-week lead-in phase was 15% vs 54% in the subgroup who achieved ≥ 1 log10 HCV RNA reduction with the lead-in.


Therefore, in my practice, I plan to treat all patients for whom I have identified a well-characterized previous null response with a 4-week lead-in of peginterferon/ribavirin prior to adding telaprevir; if they do not exhibit an adequate response to the lead-in, I will discuss with them the limited value of continuing treatment. However, if they do respond, I will encourage them to initiate a telaprevir-based regimen. On the other hand, I will not assess the HCV RNA response at Week 4 in previous relapsers and previous partial responders because I do not think the information will alter my management plan. There are also patients for whom I do not have sufficient information to accurately characterize their previous treatment response; in those patients, the 4-week lead-in might provide some additional information, although this approach should be used with caution, bearing in mind that if their previous response was partial or relapse, a poor response to the 4-week lead-in may not portend a low likelihood of SVR.


Paul Y. Kwo, MD:
I agree completely that the 4-week lead-in will be very useful in patients who do not have an accurate viral kinetics profile from their previous treatment course, with the important caveat noted by Dr. Foster that if the unknown previous response was relapse or partial response, basing the retreatment decision on the 4-week lead-in response may discourage therapy in a considerable proportion of patients who would have benefited. For example, in the REALIZE study, previous relapsers with a less than 1 log10 IU/mL reduction in HCV RNA after the 4-week lead in went on to a high SVR rates (62%). If one had relied on just the lead-in period to decide whether or not to add telaprevir because you did not have accurate pretreatment viral kinetics—that is, if one chose to stop treatment and not add telaprevir—one might potentially deny a relapse patient a very good opportunity to achieve SVR. In well-characterized null responders, I concur with Dr. Foster’s approach of using a lead-in in this setting as well.

[cheesenrice]

cont.
Stefan Zeuzem, MD:
In considering the poorer SVR rates among previous null responders, there are 4 key factors that potentially impact their retreatment response: liver histology, HCV subtype, IL28B genotype, and response to a 4-week peginterferon/ribavirin lead-in phase. It is important to distinguish between the relative contributions of each of these factors in order to determine the best individualized treatment approach for previous null responders. A careful dissection of an individual patient’s likelihood of response to retreatment with a protease inhibitor–containing regimen can allow clinicians to better counsel patients on the relative benefit of initiating retreatment at the current time vs waiting until newer, more effective therapies such as quadruple regimens are available.


As noted earlier, fibrosis stage did not appear to be a significant factor in previous relapsers; however, in previous partial and null responders, SVR rates were impaired in patients with cirrhosis. The significance of IL28B genotype is also likely to be limited in this setting because the majority of patients with a null response to previous peginterferon/ribavirin will have the unfavorable CT or TT genotype. However, this analysis of the REALIZE trial showed convincingly that among previous null responders, response to the 4-week lead-in phase of peginterferon/ribavirin alone identified subgroups with a notable difference in SVR rates with telaprevir-based therapy. Based on these data, I agree that previous null responders may represent a population in which response to 4-week peginterferon/ribavirin lead-in could be an important determinant of whether to proceed with treatment using protease inhibitor–based triple therapy or to wait longer for more effective options.


Paul Y. Kwo, MD:
For previous null responders, the risks of offering therapy to those who have a poor response to a 4-week lead-in include the adverse effects of peginterferon/ribavirin and the generation of resistance associated variants. Also, preliminary data suggest that more effective regimens with combinations of DAA agents may be available in the future for this group of patients. The most challenging patients continue to be previous null responders with advanced fibrosis. This group exhibits poor response to peginterferon/ribavirin and they often have many negative predictive factors, yet these patients are most at risk for decompensated cirrhosis, hepatocellular cancer, and the need for liver transplantation. In the absence of other available protocols or for this group it may be reasonable to consider retreatment despite the lower likelihood of success.


Graham R. Foster, FRCP, PhD:
I agree entirely, particularly when considering that in the United Kingdom 20% of patients are dying on the wait list for liver transplantation. In that context, a 15% chance of response may well be worth taking even among this group with a poor initial response to a peginterferon/ribavirin lead-in phase. Therefore, it is important to counsel the patient on their options, provide them with all of the data, and help them to make the most informed decision possible.

[dointime]

Willy:
"I'm afraid that their failure to find out the answer means something; like they don't want to prove what they already fear; archived resistance."

Great post Willy and I agree.  I am disturbed that I don't see archived resistance brought up in any of the expert discussions on resistance.  I wonder, is that because it has been shown to be irrelevant or because it is such an awkward question that there is collusion to brush it under the carpet?  Foster alludes to it here in cheeseenrice's post:
"The critical question is whether resistant variants will re-emerge more rapidly if patients are retreated with the same agent or a closely related agent."  

"I'd like to see the "dream solution" created for all these TX failures that will certainly occur when people TX and fail w/ a PI."

I think it will surely happen that we will get the Dream Solution eventually which is good enough to make resistance and ifn response irrelevant.  My whole intention and attention in this thread is directed towards people who will have to tx before this happens.  As Foster puts it, again in cheeseenrice's post:
"Minimizing exposure to futile therapy may turn out to be very important to protect future treatment options."
We have all been accustomed to being able to retreat with SOC.  I think it is critical to get the message out there that there are issues with retreating with a PI.  You want to play your valuable options wisely and not run out of options just when you need them most.  We have already seen this happen during the development of the HIV drugs.      

cheesenrice:
Excellent and comprehensive information provided in your posts, many thanks, just the kind of detailed info on the issues that is needed.  Do you have a link to where you picked it up please?  

dointime

[dointime]

" but even if the NS3/4A drug class becomes ineffective there alternatives look like they will be  out there."

I agree that these alternatives might be fine for you and for me.  My whole point in this thread is about timing.  It is about staying at least one step ahead of the available options.  With people already failing 2-DAA combo trials, some including the classes of drugs that you cite in your post, these alternatives might not be so fine for them.

In addition, a combo that "looks like it will be out there" is still a far cry from it being available.  It took 4 years from the VX950 phase2 trial that I did to the arrival of Inkivek on the shelves.  That is a long time to be out of options for somebody who needs to treat.    

" Never mind the minority variants only detectable with ultra-deep pyrosequencing. Instead one just can ask whether one's dominant 80-90% strains exhibit any of the major PI-resistant variations. (A156T etc.). Only a yes question there would preclude even trying tela/inci. "

Interesting proposal.  You suggest that if the dominant strain is wild-type then go ahead and try tela/inci.  I presume you mean retry?  In this situation, what do you see killing the minority variants that there might be?  The PI is not going to do it, and if SOC could do it then presumably it would have done it first time around?  Do you mean that you just proceed on a suck it and see basis and hope that there are no minority variants present?  I wouldn't do that, but it's all about that timing thing again.  If you have to go you have to go.      

"Contacting labs that have published results in this area and have a medical center affiliation seems be a good place to start."  
Thanks for this suggestion.  I think there is a great unmet need in this area so maybe this will work for some.

dointime

[can-do-man]

Was just going thru some of it here

http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Berlin%202011/Tracks/From%20Podium%20to%20Practice/EASL_EA/Pages/Page%201.aspx

[foofighter]

My concern also, how long? Before approval of the next best thing/how long before your liver says "uncle."

I got all excited about the above info a few weeks back, thinking it tipped the scales towards treating in spite of a PI failure. Now that you guys have dissected it, I realize it is not saying what I thought it was.

I am taking the pertinent info from this thread and get it off to my doc. I am also going to send a copy to the IRB in charge of the Sprint 2 trial at my location. He sent me a letter (based on info my trial doc gave him), that no one in the trial should be concerned about mutations after only 8 weeks of exposure.

I am going to ask doc if he could request the test for the major PI-resistant variations. Can't hurt to ask.

[Willy50]

Dointime, I would venture a guess that many "no riba" arm participants could be treated with triple therapy RIGHT NOW and be cured, especially if what they say about mutations reverting back to wild type.  Vertex might even know at this point the likelihood at this point, but at minimum might also be able to add VX-222 or soon one of their newly acquired nukes to eradicate the virus.  In exchange they would get some data on the possibility or archived resistance, or lack of it.  I would think that this would be vital info, especially as wholesale numbers are starting to be treated with PIs in triple therapy.

Cando; I couldn't get your link to work>

Foo..... I don't see the type of rigorous proof to back up your doctors statement.  

http://pi.vrtx.com/files/uspi_telaprevir.pdf
"Telaprevir treatment emergent resistance substitutions emerged in the majority of isolates from subjects who did not achieve SVR (Table 8): in almost 100%
of subjects who failed during 12 weeks of T/PR and in the majority of subjects who failed on PR after Week 12 or who relapsed."

also....
page 15
"Persistence of Resistance-Associated Substitutions
Persistence of telaprevir-resistant NS3 amino acid substitutions has been observed following treatment failure. Of a combined 255 treatment-naïve and
previously treated subjects from Studies 108, 111, and C216 in whom telaprevir-resistant variants had emerged during treatment, 103 (40%) had detectable
resistant variants by population sequencing at end of study (follow-up range 2-70 weeks, median 45 weeks) and results for loss of variants were similar
across the three studies. In the combined studies, 46% of the telaprevir-resistant substitutions in subtype 1a and 16% of the substitutions in subtype 1b were
still detected by the end of study: 29% of V36, 16% of T54, 38% of R155, 14% of A156, and 44% of V36M+R155K variants were detected at the end of
study.
In a 3-year follow-up study of 56 treatment-naïve and prior treatment-failure subjects who did not achieve SVR with a telaprevir regimen in a Phase 2 study
and had telaprevir-resistant variants after treatment failure, variants were detected by population sequencing in 11% (6/56) of subjects (median follow-up of
25 months). Telaprevir-resistant variants V36L/M, T54S, and R155K were detectable (present at greater than 25% of the viral population) in some subjects
at 24 months. By 36 months, V36M, T54A/S, and A156N/S/T variants had fallen below the level of detection by population sequencing in all subjects. At
36 months, 3% of the subject isolates that had the R155K variant still had detectable R155K variants by population sequencing.
The lack of detection of a substitution based on a population-based assay does not necessarily indicate the substitution has declined to the pre-treatment
level. The long-term clinical impact of the emergence or persistence of detectable INCIVEK resistance-associated substitutions is unknown. No data are
available regarding INCIVEK efficacy among patients who were previously exposed to INCIVEK, or who previously failed treatment with a INCIVEK containing
regimen."
=========================
That is what Vertex has to say about it.  It *feels* as though your doctor is saying something different.  They aren't saying it is or it isn't.  They are just saying there is no data to prove one way or another.

willy

[can-do-man]

Willy, you might need to first go to clinicalcareoptions.com and log in then paste the link. Heres the tiny url link..........

http://tinyurl.com/3czbkm8

Hope this helps.

Stay well
zach

[willing]

there's plenty of uncertainty. Some items that appear a bit clearer than others are :

- failed triple tx always increases (at least temporarily) one's proportion of resistant virus

- the longer the resistant virus can thrive in the absence of wild type the fitter it will become. For example if one  persists in doing 48w of a PI with either no ifn or no ifn response one can quite reasonably expect near 100% resistant strains and also ones that have had plenty of time  to improve their game. Under those conditions, PI-sensitive wild type may never be able to make a comeback.

- even complete resistance to NS3/4A PIs will not affect tx with drugs that target other viral proteins

- ideally one would like 99.99% wild type as the start of triple. If instead one has 99.99% PI resistant variants one can expect little but sx from the PI - there's nothing for it to work on.
For anyone who suspects past tx may have left them with a burdensome enrichment of PI-resistant variants testing seems a good idea.

- The  available Merck/Vertex data indicate that provided triple tx is terminated quickly enough,  PI resistant variants do not become fit enough to dominate and are usually  replaced by wild.

Does any of this help those facing tough decisions, eg is it worth trying triple with odds of only 30 or better to wait for quad? Say one has a VL of 800 with Inci at w4. Do you quit to avoid resistance or continue to w12 (per protocol) and encourage emergence of resistance that much longer?. Seems there' still  a lot of shooting in the dark iinvolved.

[dointime]

ca-do-man: Many thanks for link.  Lots of info there to digest.  In the interferon lambda section I found this quote by Foster -

"In my opinion, the question is not whether interferon will continue to have a role in the treatment of HCV, but rather how large the proportion of patients will be who continue to depend on it for treatment. The irony is that current DAA agent trials may be generating patients who will ultimately depend on interferon-based treatment because it is possible that some of the emergent resistance mutations will adversely affect response to subsequent regimens. Such cases may require additional agents combined with DAA agents."

So Foster is admitting that DAA tx will produce some people with drug resistance who's future DAA treatment is compromised.  And the very people who are trying to avoid using interferon could end up with interferon being their last resort for tx.  

foofighter:  You have difficult choices on your plate.  Arming yourself with all the pertinent info is the best way that I know to help you make the right decision for you.  I would be very interested to hear how you get on with the request to your doc for the test for resistant variants.  

willy:
"Dointime, I would venture a guess that many "no riba" arm participants could be treated with triple therapy RIGHT NOW and be cured, especially if what they say about mutations reverting back to wild type."

I would agree.  Those people might assume after 4 years that their chances for SVR with the triple would have reverted by now to the same ball park as for tx-naives.  For me as a person with poor ifn response my chances of success would still be low, but for people with good ifn response, well they might consider it worth thinking about.

One caveat I would add is that the no-riba groups got VX-950 for 12 weeks regardless of when resistance/breakthrough was detected (it was double-blind).  So there is a question mark about how fit their resistant variants became in that 12 weeks.  So getting a test for resistance would be helpful before embarking on the triple tx.

----------------
I have another question that is bugging me.  It is emerging that people really need these resistance tests before they can make intelligent choices about retreating with the DAAs.  So where are Quest, Labcorp, et.al with that?  They are in business and here is a large unmet requirement getting larger by the day.  So what gives?

dointime        

[Willy50]

Dointime, with the records that Vertex would have on patients viral responses during the trials I would venture that participants could be selected that would virtually be a guaranteed RVR responder to triple therapy, or even quad therapy.

In that they presumably have a pool of responders who would like to be cured, the probable means of providing a cure (I'm guessing a 90% or better chance since they can selectively pick or pass over candidates) and...... I believe a need or even an obligation to provide data on what happens to people who retreat w/ a PI.

Clearly, I and other people are wondering what is going on with this.  If there is a reason for not testing and a back up plan why not express it so we can move on?  Since an opportunity and a need exists...... and it appears that no attempt has been made to resolve this enigma, you have to wonder just why that is.
---------------------

Yes....... SOC may remain a viable source of finishing off the virus but potentially it will be needed in shorter dosing periods.  It may not be the ideal form of TX but it will remain an important tool until such time that the antivirals can finish things off without the old school methods.  Right with the addition of PI's the SOC dosing is virtually cut in half and it will get better.

I believe that I heard that some things are being looked at to predict which groups of people (alelle) or types of responders may be able to TX w/ triple therapy for only 12 weeks.  I also believe that they are starting to dial in response guided therapy to shorten the TX time further.

willy

[Trish77]

"I have another question that is bugging me.  It is emerging that people really need these resistance tests before they can make intelligent choices about retreating with the DAAs.  So where are Quest, Labcorp, et.al with that?  They are in business and here is a large unmet requirement getting larger by the day.  So what gives? "

I don't think the requirement has become apparent yet.  This isn't watercooler chat and the two PI's have only recently received FDA approval.  All the others are still in clinical trial.  How many people do you know of that have requested such tests?  As the demand grows, however, I bet there will be a response to this by the labs.  Supply and demand.

[Trish77]

I've been swamped and haven't had time to post but read what I can in this thread ongoing.  Solid and useful discussion.  One of the things I've been concerned about  and wanting to toss into the mix for discussion is this.  

It concerns me is the threshold being used by treating doctors using the PI's in deciding to stop treatment with the PI if still detectable at >1000 at 4 weeks.  I believe the literature for Incivek is to stop treatment if less than a 1 log drop at 4 weeks (will look for reference but if someone has it to either confirm or revise that impression...great)  so I'm wondering where the docs have come up with this threshold of stopping treatment with the PI at 4 weeks if still DET >1000.  We talk about resistance so it concerns me to stop across the board if DET at >1000 at 4 weeks when chance of SVR is still entirely possible and largely to the positive rather than the negative.  It would seem the odds are greater at wiping out resistant variants to continue treatment a bit longer than 4 weeks depending on viral load, than stopping at 4 weeks with known viral load existing.

[dointime]

" and it appears that no attempt has been made to resolve this enigma, you have to wonder just why that is."

Willy:  Agreed.  My own feeling is that this whole question about resistance and retreatment is being downplayed by all the drug companies, not just Vertex, although Vertex is one of the few in a position to do something about it.  I mean, the drug companies do publish some resistance info. but there is a shortage of making it clear what the implications might be for the future tx of those people who become resistant.  Let's face it, the drug companies need people to step up to the plate for the trials, so why would they want to point out anything about what happens if the subject fails to get SVR.  

If Vertex does nothing, we are still going to get people coming through who have retreated with a PI, so we will eventually find out how it works.  In the meantime, Vertex is one of the 2 front runners in the PI stakes and has to maximize the window of time that it has to make money before the 2nd generation of PI combos eclipses their triple.  I can see why they wouldn't want to rock that boat.  

------------------------
I think that there has never been a better time to wait for tx - for people who can wait and for whom there is a low probability of success with the current triple.  I realise that this might sound like heresy, because there are so many very good reasons for treating sooner rather than later.  However, that now has to be balanced against the implications for future tx of becoming resistant to one or more PI's.

For people who can wait 1-2 years, I think that waiting for the phase 3 trials of the next generation combos is a good option.  We will by that time have a much better idea of who the front runners are, what the success rates are, and also the resistance data.  For people who can wait 3-5 years without becoming PI-resistant, their chances for an approved cure at that time look very good.  

The main thing that I want to see is for the issues surrounding PI-resistance and the implications for retreatment to become part of the dialog for anybody who is deciding with their doc on their tx.

dointime  

[lynda607]

No log drop mentioned with Incivek.  Futility rules state discontinue Incivek if vl is 1000 IU/mL or above at week 4.  Vertex had to base that on trial information which we are not privileged to.

RVR still remains the most important factor in SVR even with the addition of a PI.  Adding a big gun like a PI makes RVR more important because it is directly killing the virus and without an RVR chances of SVR will diminish and resistance will increase.

However, I also feel consideration to continue if not RVR at 4 weeks should be made on a case by case basis.



  

[lynda607]

Clarify above statement:

"without an RVR chances of SVR will diminish and resistance will increase".

without an RVR or under 1000 IU/mL at 4 weeks SVR will diminish and resistance will increase.

[willbb]

For people who can wait 1-2 years, I think that waiting for the phase 3 trials of the next generation combos is a good option.  We will by that time have a much better idea of who the front runners are, what the success rates are, and also the resistance data.  For people who can wait 3-5 years without becoming PI-resistant, their chances for an approved cure at that time look very good.  

----------------------------------------------------------------------------------------------------------------------------------

I just would like to echo my sentiments to dointime"s statement here.. I have felt this is the more sensible approach to treatment for some time now.. given the current landscape and uncertainty of resistance still...Especially for those with little or no damage  . the benefits vs. risk of treating should be weighed very carefully  IMO

Will

[Bizzybee99]

Indeed achieving a 1 log drop vs viral suppression < 1000 by week 4, are two very different measurements.  I thought it was 2 log drop by week 4 and clear by week 12.  Are the stats getting tighter, or am I just learning new facts?  

[lynda607]

"In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL. See Laboratory Tests (5.6) for a description of HCV-RNA assay recommendations.
For the purpose of assessing response-guided therapy eligibility at weeks 4 and 12 (see Table 1), an “undetectable” HCV-RNA result is required; a confirmed “detectable but below limit of quantification” HCV-RNA result should not be considered equivalent to an “undetectable” HCV-RNA result [see Laboratory Tests (5.6)].
Treatment-naïve patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 of INCIVEK combination treatment may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total) [see Clinical Studies (14.2)].
2.2 Dose Reduction
To prevent treatment failure, the dose of INCIVEK must not be reduced or interrupted. Refer to the respective prescribing information for dose modification of peginterferon alfa and ribavirin [see Warnings and Precautions (5.7)].
2.3 Discontinuation of Dosing
Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions [see Microbiology (12.4)].
Discontinuation of therapy is recommended in all patients with (1) HCV-RNA levels of greater than or equal to 1000 IU/mL at Treatment Week 4 or 12; or(2) confirmed detectable HCV-RNA levels at Treatment Week 24 (see Table 2).
Table 2: Treatment Futility Rules: All Patients
HCV-RNA Action
Week 4 or Week 12: Greater than 1000 IU/mL Discontinue INCIVEK and peginterferon alfa and ribavirin (INCIVEK treatment complete at 12 weeks)
Week 24: Detectable Discontinue peginterferon alfa and ribavirin

[Bizzybee99]

Thank you Lynda,

What are they referring to with the statement "Week 4 or 12"?  

After reading this most informative thread, there is no way I would participate in double or even triple DAA trials.  Some phase 3 trials may be ok.

[lynda607]

At week 4 if vl is >1000 IU/mL recommended to stop all treatment.  If Detectable (1000 IU/mL or less) at Weeks 4 and/or 12 they are recommending continuation of treatment but with an additional 36 weeks for a total of 48 weeks.

Severity of liver damage dictates how much time a person can wait for better treatment and the decision to continue even with a viral load of under 1000 IU/mL would be a tough call or at least that's how I see it.  It's very obvious anyone with a detectable viral load at week 12 but UND at week 24 on SOC only has a much greater chance of relapse.  The PI is designed to directly kill the virus whereas interferon ramps up the immune system to do the job.  So, one of the burning questions is will the immune system respond adequately enough to the interferon to mop things up and finish the job and do you want to chance it?

[Willy50]

Not a lot more that I would add.  This is all speculative.

From my posts though I think that you can infer that I believe that the resistance issue is not as great a specter as it may loom in some minds.  The fact that it isn't being addressed before many people are being treated w/ PI's is a little disconcerting to me.

I believe that many people will be able to treat and be cured, the same rules may apply w/ triple therapy as did with SOC; you may be able to wait if you have minimal staging damage.

I think we may have to wait a little longer than 1-2 years though, and some people probably shouldn't wait.  Even the best of trials doesn't contain "winners" trial arms in all trial Phases or arms.  Some are not so good; look at the recent VX-222/telaprevir ongoing trial in which both "no IFN &Riba" trial arms were discontinued.  There will be risk in treating and there will be risk in waiting to treat.

In 3 more years we will still be faced w/ the same dynamic;
...not all of our questions will be answered and better treatments will be on the horizon.  : )

willy

[BeatTheBeast]

This thread is extremely informative.  My heartfelt thanks to everyone who has posted.

I do think in a year we'll have a lot more information about how to optimize the current triple therapy (with PI) protocol, and of course more information about other DAAs/combos will also be forthcoming.

So my strong belief is that people whose liver disease is fairly early stage should wait at least a year and perhaps longer before treating.

BTB

[Trish77]

Can you provide the actual link for that please?  I like to know the source of the information, it provides context.  Thanks and much appreciated!

Trish

[lynda607]

http://pi.vrtx.com/files/uspi_telaprevir.pdf

[Bizzybee99]

Thanks Lynda for elaborating.  I just don't understand the "and/or" of the 4 and/or 12 weeks.   In other words, which is it.....4 or 12?  I'm assuming the measurement has to do with when the DAA is added to the mix, but not sure.  Please forgive my brain blur...I do appreciate learning from all you science minded folks.

Willy, I like your summation and feel it's quite accurate, at least for my situation.  I'm weighing several variables involved in the decision to tx or not at this.  Potential for resistance is only one of them.  Topping my list is the issue of how much the HCV actually has to do with my illness....it is the illness, not the threat of death that has always motivated my decisions to tx.  Another priority is determining to what degree it was the IFN that exacerbated certain aspects of my illness the last time around.  There is also no way to accurately calculate in my improved immune health for my odds of success....It's all best guesstimate type stuff.  I suppose a biopsy may be the final deciding factor, but nothing points to having progressed from my stage 1, six years ago.  

[lynda607]

BB,

I don't know how to further explain it other than to say it is not an "and or" situation.

Prescribing Information states:  detectable >1000 IU/mL at 4 weeks discontinue all treatment.  Detectable <1000 IU/mL at weeks 4 continue INCIVEK, pegylated interferon and ribavirin  If  detectable <1000 IU/mL at week 12 continue pegylated interferon and ribavirin but if detectable at wk 24 regardless of IU/mL discontinue all treatment.  

Additionally, those who are detectable at <1000 IU/mL at weeks 4 and 12 are advised to treat a total of 48 weeks.  Those who are UND at week 4 are considered RVR and a 24 week treatment regiment is advised.

[Trish77]

"Indeed achieving a 1 log drop vs viral suppression < 1000 by week 4, are two very different measurements.  I thought it was 2 log drop by week 4 and clear by week 12.  Are the stats getting tighter, or am I just learning new facts?   "

If you're referring to treatment guidelines in general without a PI, the official treatment guideline has been a 2 log drop by Week 12 and UND by Week 24 as guidelines to continue treatment. That's a very old guideline, however and I would think only those not staying current would be following those.  As more has become known, it has become generally more accepted that if you're not UND at Week 12, it means serious consideration for extending treatment to 72 weeks for a Genotype 1.  The introduction of PI's has changed all that.  There isn't a point in doing 72 weeks of PR - Peg/Ribavirin - if you can add a PI and do 48 weeks and have a strong hammer to hit the virus with on top of it.  The discussions then get even more granular and there are official guidelines vs accepted treatment practices.  The official documents take awhile to update - requiring a committee of specialists to hash out and agree as much as possible what they're willing to publish them as - and changes/improvements in actual treatment practices often are ahead of them.

[willbb]

As Beat the Beast  said  ...  I too very much appreciate this thread and the contributions . As someone waiting in the wings after failed triple it is helpful and informative to listen to others points of view. as well as reading any studies done that I have missed( or possibly don"t understand correctly)
Wiily.. yes ....lets hope as you say the  resistance issue  not as big a specter as in some people minds  .

  It is just when every time I talk to the knowlegable Hepa"s in my treatment team about resistance issues the blank stare  I get in return is somewhat disconcerting.


Undoubtedly.. much more info. will come out on this subject in the months and years to come  and in the meantime those that need to treat  the approx odds of 75% are a great improvement .. however I still maintain that for those with no or very little damage ..the landscape has changed  and the resistance issue should at least be factored into any desicion.

Best
Will

[Willy50]

(wrote) "Willy.. yes ....lets hope as you say the  resistance issue  not as big a specter as in some people minds."
==========================

I think that my point is that *simply* because one has resistance does not mean the are out of luck.

For instance waiting *could* get you back to wild type after a time,

Adding a 3rd or 4th component to the treatment could essentially "trump" the established resistance.

I believe that other improvements are being made even to current SOC (IFN and RBV) treatments, such as IR work, vitamin levels prior, such as Vit D. coffee etc.

Even the  work on the inoculation trial Hep vaccinations are showing some promise and may also be used as adjuncts with treatments.

The blank look you get from those in your treatment team just means that they are professional enough to not venture an unsupported opinion, although I'm sure they have one as well as hopes for us all.  

I think that the easiest to treat group, in theory would be the best responding group from the Vertex trials that were in a no riba arm.  I would think that they would start with this group and try to cure them.  If you can't successfully use a PI again on this group it would not bode well for other groups unless you could add other components to essentially provide a stronger treatment than the prior.

I also wonder how Taribavirin (viramidine) may be used to augment these new PI's,  It may be that anemia and dose reductions with riba will be less when combined with this trial drug, if so the SVR/success rate could improve.  It would remain to be side how the rash would be affected, but riba dose reductions could be further reduced thereby increasing the success rate.

Lots of good things are coming and as they get approved things are more likely to be able to be combined.  Don't lose hope....

willy

willy

[willbb]

Willy..I have certainly not lost hope in the least... possibly you interpreted my post  as a bit pessimistic.   That is not the case at all ..I am an eternal optimist and there is no doubt in my mind that I will treat succesfully in the future  :)   My concern was actually for others that are thinking of entering treatment  with  again no liver damage.... just to be  as aware as one can be in todays landscape..

Thx for the concern tho   :)

Will

[Willy50]

Nawww....I just meant it generically for everybody, not you specifically.  

Now that approval has happened they can look into this further.  Maybe the theories will be put to a test soon.  The sample group of people with potential resistance is going to get bigger and it is a question which may be answered soon.  

I hope so.

willy

[willbb]

I believe you are right on with that....by Pharma"s own data aprrox 1 in every 4 will be unsuccessful at triple.....  the sample group will unfortunately be huge  and they can"t have everyone wondering around with this issue ... thx again for all your input

Will

[Trish77]

" There is also no way to accurately calculate in my improved immune health for my odds of success....It's all best guesstimate type stuff.  I suppose a biopsy may be the final deciding factor, but nothing points to having progressed from my stage 1, six years ago.  "

I'm not sure what evidence you expect to see or experience?  Many many people have no idea of the extent of their liver damage until a biopsy.  There are some biological markers that might indicate but are incomplete taken on their own.  If you haven't had a biopsy in six years, I'd like to strongly suggest you go for one, hoping you have no physical reason why you can't be doing this.

[Trish77]

"Thanks Lynda for elaborating.  I just don't understand the "and/or" of the 4 and/or 12 weeks.   In other words, which is it.....4 or 12?  I'm assuming the measurement has to do with when the DAA is added to the mix, but not sure. "

To echo Lynda's comments - you can be detectable but <1000IU/ml at 4 weeks and still be there at 12 weeks.  Some people hit a plateau of sorts and viral load drops very slowly.  So I believe what they're doing is indicating treatment direction based on viral load at the 4 week and 12 week markers.

[Bizzybee99]

Got it, thanks!

[Trish77]

"From my posts though I think that you can infer that I believe that the resistance issue is not as great a specter as it may loom in some minds.  The fact that it isn't being addressed before many people are being treated w/ PI's is a little disconcerting to me. "

Willy, that nutshells some of my own perspective on this.  

I don't think it's as scary as it seems in some regards - I think there is more to know about which DAA's are able to knock resistant virons from other DAA's right out of the ballpark and there are a whole crop of them coming along and targeting different mechanisms of the virus.  And while the threshold of testing for resistant virons isn't low enough as yet to be as accurate as we'd like, that doesn't necessarily mean resistant virons are lurking below the non-detectable limit.  However, until more is known, it's prudent to be cautious for sure.  It's a balance of risks, depending on each individual situation.

I think in some regards also, they're being overly cautious and people are being pulled from treatment too soon but that's a personal opinion only.  Experienced hepatologists treating with the new approved PI's may be more willing to extend past the guideline on an individual basis but those GI's who are less comfortable and less experienced will perhaps go more strictly by the book, for better or worse, and I'm not convinced that enough is known yet to know where to draw that line.  

I also share your concern that not enough is being shared about resistance with those going into the trials with the DAA's and particularly the double-DAA's.  That concerns me probably the most, actually, whether people going into the trials fully understand the risks involved with regards to resistance.

On the whole, It's like new anything....it can take awhile to get it right once it's out there.  However, that's the only real way to perfect it.  Those who are early stage liver damage also need to realize that they don't necessarily need to treat with a PI.  An RVR with PR has pretty comparable SVR rates.  

Lots to know and understand.

[willing]

>Futility rules state discontinue Incivek if vl is 1000 IU/mL or above at week 4.  Vertex
> had to base that on trial information which we are not privileged to.

lynda607: IMO any trust placed in Vertex or Merck making decisions on the basis of undisclosed data that reflect the best interests of patients as opposed to those of stockholders is misplaced.  As far as I know you will find no reference to that 1000 IU cutoff in any of the phase III trial data submitted as part of FDA approval, Where did that number come from? What is known is that among those not reaching eRVR (where eRVR is defined as UND25 at w4 and w12, ie RVR and no breakthrough) SVR still reached 60-66%. However it's  likely, based on SOC data, that those odds drop very quickly depending on how high your w4 VL is, and are much lower for a w4 VL of 900 than 30.

Are  pts going  to be told their odds ? Not bloody likely.

Another example is failure to disclose the effect of less than a log drop from the tela arm that measured lead-in effect. Disclosing this might have helped pts avoid pointless triple tx, but less drugs would be sold.


>people really need these resistance tests before they can make intelligent choices about >retreating with the DAAs.  So where are Quest, Labcorp, et.al with that?

dointime: it might be hard to build a business case for developing these tests : there are at least a dozen  resistance substitutions to look for, they are specific to the approved  NS3/4A PIs and the window of opportunity for those drugs is fairly short (3 years?). The issue of detecting shifts in enrichment of minority populations gets far more complicated. Classical Sanger sequencing is not usable and newer population-based sequencing approaches like Roche's 454 pyrosequencing give shorter reads with higher error rates. Getting approval of such tests as diagnostic, as opposed to research, tools would be a huge hurdle.

A case like foo's is unusual insofar as it seems a reversal of the usual pattern: inadequate PI response rather than inadequate IFN response. Even a research-only type sequencing test that checked for the presence of PI resistant variants among her dominant strains might be helpful. However, from published data this is only expected in a very small minority of pts.

[lynda607]

I agree, there is no conclusive data regarding vl cut off and futility rates.  I don't necessarily agree with the established perimeters but it's out there for interpretation by inexperienced GI's who tend to explicitly follow published guidelines as mentioned by Trish.  In my opinion, if response to triple therapy is not stellar early on then tailoring the PI treatment could be a consideration and potentially increase the odds of SVR.

Unfortunately, there are many with hepc who do not have extensive knowledge of the disease and treatment options and rely solely on their unknowledgeable doctors.  In the end, we can only hope logic and viable options meet in the middle.

[dointime]

"The blank look you get from those in your treatment team just means that they are professional enough to not venture an unsupported opinion, although I'm sure they have one as well as hopes for us all."

willbb, Willy50
I'd say that this blank look is open to interpretation.  My own interpretation would not be that it is so benign.  I'd say it was a poker face to cover the guilt they feel from knowing all along about the resistance risk and not telling you.  I'd say shame on them.  I'd say that any hepa who returns no more than a blank look to a question about resistance should be avoided.      

willing:  Very interesting about the difficulty of the business case.  I get that - don't like it but get it.  Thanks.

dointime    

[dointime]

"It concerns me is the threshold being used by treating doctors using the PI's in deciding to stop treatment with the PI if still detectable at >1000 at 4 weeks."

As we are getting into the nitty gritty about this I just have a small niggle to add.  As far as I know, PCR results still take 1 - 2 weeks to arrive.  In the waiting time you still continue to take the pills.  So while the decision comes out of the situation at 4 weeks, you don't actually stop taking the pills until later.  That gives the resistant mutations, if there are any, possibly up to 6 weeks to run, not 4 weeks.  I'm not sure how much difference that makes but I wanted to highlight the misnomer that the mutations only get 4 weeks to run if there is a discontinuation of tx.

dointime    

[Trish77]

"That gives the resistant mutations, if there are any, possibly up to 6 weeks to run, not 4 weeks.  I'm not sure how much difference that makes but I wanted to highlight the misnomer that the mutations only get 4 weeks to run if there is a discontinuation of tx. "

That's one way to look at it.  The other way, I suppose, is that the resistant mutations are not as fit as wild type.  So it also potentially gives a little more time for them to be killed off as well.  The thing is, you have no idea if the virons that are left are resistant virons or wild type.  None.  They don't know and they don't want to take the chance, I presume.  

The difficulty I have with cutting off at >1000IU/mil , depending how much greater you are, is that under SOC/PR treatment, nobody would stop at that point.  You'd keep going aiming for an EVR, as the SVR rates are still quite good for EVR.  Best for RVR, but still good for EVR.  So my concern with stopping at that point, across the board for anyone with a viral load of >1000IU/mil, is that my personal opinion is that a certain number of those people could have potentially achieved SVR and not have been left with potential resistant virons.  Some hepatologists may proceed beyond that on an individual basis but my concern is that a number of GI's will not and will stay strictly with that stopping rule and I'm not even sure where that stopping rule comes from.  Anyone?

Trish

[cheesenrice]

http://www.clinicaloptions.com - register with them ( free ) - from there you can select hep hiv oncology - they keep you posted with email updates - sorry i took so long

[spectda]

Although they may not be including and providing personal sequencing data in the decision making process to the patients as they should and we all wish they would, my impression is that they are quite clear from trial data that failure with triple tx is associated with resistant vairants, not wildtype. Maybe I am misinterpreting the information but this is what I understood.

Personally I believe that the 1000 iu/ml threshold after 4 weeks of a pi is quite liberal and in the absence of personal sequencing information the only exception for continuing would be altering/tayloring treatment as Lynda607 suggested and/or if the patient is out of time because of their disease progression. To me this still all points to using a lead in with all but relapsers.  

As other's mentioned, we need qualified specialists to be treating people with these powerful drugs who are able to offer individualized therapy and make these decisions which  have much more serious implications then with soc alone. We don't have PCPs prescribing chemo to my knowledge, why are they treating people in the first place?

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
"In a regimen of telaprevir, Peg-IFN, and RBV, the primary role of telaprevir is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The primary and complementary role of Peg-IFN and RBV is to clear any remaining telaprevir-resistant variants.
Clinical virology results from clinical studies of telaprevir in combination with Peg-IFN and RBV have shown a clear and consistent resistance profile across HCV genotype 1 patient populations (treatment-naive and prior Peg-IFN/RBV treatment-failure). Sequence analyses in patients not achieving an SVR with a telaprevir-based regimen consistently identified amino acid substitutions at 4 positions in the NS3•4A protease region that were associated with decreased sensitivity to telaprevir, consistent with the mechanism of action for telaprevir: V36A/M, T54A/S, R155K/T, A156S/T/V, and V36M+R155K. Phenotypic characterization of these HCV NS3 variants determined that lower-level resistance to telaprevir (3- to 25-fold decrease in IC50 to telaprevir in a replicon-based assay) was conferred by V36A/M, T54A/S, R155K/T, and A156S, and higher-level resistance to telaprevir (>25-fold decrease in replicon IC50) was conferred by A156T/V and V36M+R155K. Telaprevir-resistant variants are less fit than wild-type virus and are sensitive to Peg-IFN, RBV, and polymerase inhibitors in vitro.
Predominant baseline resistance to telaprevir is rare (< 1% to 2.7%) and does not necessarily preclude achieving an SVR with a T/PR regimen. On-treatment virologic failure during telaprevir treatment is associated with higher-level telaprevir-resistant variants, and occurs more frequently in genotype 1a compared to 1b. On-treatment virologic failure rates on T/PR
Page 5 of 147
Telaprevir NDA 201-917 FDA Advisory Committee Briefing Document Vertex Pharmaceuticals
are low in treatment-naive patients, and prior relapser patients, but are higher for prior nonresponders patients. Relapse is generally associated with wild-type or lower-level resistant variants. Overall, TVR-resistant variants were observed in 12% of treatment-naïve patients (Study 108; T12/PR arm) and 22% of treatment-experienced patients, after therapy with a telaprevir-containing regimen. Resistant variants were observed in the majority of subjects who did not achieve an SVR. Resistant variants tend to be replaced by wild-type virus over time in the absence of telaprevir selective pressure."

[dointime]

I think that it is invalid to compare the SOC timing with the triple therapy timing for stopping.  If we are talking about telaprevir for example, it is just so much faster at cutting down the wild type virus, so it is not reasonable to have the same expectations as for SOC.

So if somebody has a viral load of >1000IU/mil at week 4 with the triple then that has a different implication for the success of the tx than if the tx were SOC alone.  What I think is missing in the recommended triple tx regime are PCR's at week1, 2, and 3.  It is quite possible to become UND in the first 4 weeks and already be having a breakthrough by the week4 PCR.  That is what happened to me.  In that case you would know that your viral population consists of a majority of  selected out resistant mutations which are on the rise despite the presence of SOC.  That would be valid grounds for stopping.  

" The thing is, you have no idea if the virons that are left are resistant virons or wild type.  None.  They don't know and they don't want to take the chance, I presume."  
I think that they do know from the monotherapy trials of VX950 that virions left by week 4 are mostly resistant mutations.  What is perhaps hard to appreciate when we are used to SOC is just how very fast a drug like telaprevir works.  It just decimates the wild type virus in a matter of days.  So before you are even near the 4 week mark the only question left to be answered is whether SOC and your ifn response can effectively do the mopping up of the resistant mutations.  If you are still >1000 at 4 weeks then the answer to that is probably no.  However if somebody wanted to hang in there and bet on SOC finishing the job then that's a debatable choice much like for SOC at the 12 week mark.  It just comes so much faster because adding the PI to the mix is like adding nitro.
  
dointime      


    

[Bizzybee99]

I have been weighing the need for a biopsy and do appreciate the advise on this.  The reasons I had tentatively decided to hold off on a biopsy are as follows:
-liver biopsies in 2000 and again in 2005 were both stage 1 indicating slow progressive disease (according to hep doc).
-my liver panel, and platelets are always in normal range (APRI 0.3 = likely minimal fibrosis)
-Recent abdominal CT showed mild hepatosplenomegaly (common with chronic viral infections), but it didn't show any liver fibrosis (although they weren't looking for fibrosis specifically).
-My hepatologist won't do a biopsy because they are not going to tx me having been a null responder with SOC in 2005.  They may only be treating the null responders who are now at stage 4.  They seem very concerned about the resistance issue.  Anyhow, they don't think I have progressed at all, and they are basing that on the above information, and palpation.  Of course I could, and very well may get a biopsy elsewhere.  It's my out of state internist who wants to do the Tx.
-I don't care to have another needle run through my liver unless absolutely necessary.  I think it can cause scaring as well.  I also know that the biopsy, although the most accurate of all tests,  can be invalid.    

In spite of the reasons for passing on a biopsy at this time, the reasons for having it done are quite obvious as well....if I'm over stage 2, I should have my out of state internist do the Tx even though I am a previous null responder with SOC....maybe.  I'm still not sure on this, and this is why I am appreciating the feedback.

[penn1023]

I wonder if I should even get another biopsy. Last one was 2005. There won't be any treatments for me due to autoimmune problems. I believe docs can see if you have cirrhosis based on blood tests?  My ALT AST PT PTT Fibrinogen, GGT ALK Platelets, Albumin are normal. I have a high VL. What do you think?

[Andiamo1]

Fibrosis progression is not linear.  It is certainly good news that you had little progression over five years, but that does not mean that you definitely won't progress over the next 5 years.  There are many variables such as age and lifestyle, just to mention a couple.

[spectda]

My last three biopsies

diagnosed 1998 and stopped drinking (didn't drink heavily prior)
1rst tx 2010

1999-stage 0 (about 20 years after infection)
2004-stage 0 (about 25 years after infection)
2010-stage 2/3 (very close to bridging) (about 31 years after infection)

[curiouslady1]

Thanks Spectda,  very sobering.  

To all on this thread:  Here is my dilemna.  I am treatment naive and have the choice of going into a trial (Pharmasset - PSI 7977 +BMS 79002 and Riba) or getting SOC with triple therapy right off the bat.
I must continue to work at a job which requires maximum alertness but is home based.  Little or no family support.  I cannot be taking time off but my morns are free for vomiting.  Research is being conducted at a major University hospital.  I am genotype 1a, blood tests normal with FLD.  I am over 60.  Signs look good for no cirrohsis but biopsy will tell the story.

The trial is randomly assigned but open.  The relevant arms are PSI 7977 add BMS after 7 days and both for 6 months; PSI 7977 and BMS for 6 months; PSI+BMS+Riba 1000mg for 6 months.  Once assigned you cannot switch.  

The director of hepatology says they like that study.  There is no control arm so everyone gets meds.  But if I don't clear in one arm or if I have severe sides, I cannot then be reassigned to another.  

They will give me SOC if I fail (he is unconcerned about resistence).  

Which would you pick if you were in my shoes all things considered?  

[lynda607]

12 weeks only of daily Incivek -  RVR = 6 mo. total treatment time.  

You will have side effects with the PI's recently released or the Pharmasset trial drugs but with Incivek it is stopped after 12 weeks regardless.  An option might be a 4 week lead in with SOC and add either Victrelis or Incivek according to SOC response.  In my opinion a bird in the hand (Victrelis or Incivek) is worth two in the bush.

You will be effected by the drugs regardless of what drugs you choose and there is no way to gauge the degree it will effect you until you take the plunge.  You might be able to schedule throw up time but you can't schedule fatigue or anemia or the myriad of other side effects that can happen.  If you commit to treatment you take what comes a day at a time and the primary focus is beating  the virus.  Lifestyle changes may be necessary when trying to achieve that and if you absolutely cannot be flexible maybe it isn't a good time to treat now.

[curiouslady1]

There is no interferon on Pharmasset and the Riba is for 24 weeks if that is the arm you get randomized to.  It is the Polymerase agents that are emphasized.  

[lynda607]

I see, haven't really kept up with the most recent polymerase trials. There is no doubt in my mind future treatment will not include interferon and it may be so refined that ribavirin is no longer required either.  In this phase of the polymerase trials that exclude interferon it's a matter of risk vs reward and that's a tough call.

[dointime]

You could possibly make a more informed decision if you got an IL28B test.  Your likely ifn response is relevant to this decision.

Good luck
dointime  

[curiouslady1]

Wow.  Thanks for the suggestion about the added test.  I didn't know there was anything beyond finding out about the genotype.  I will ask about the IL28B.  Of course, it probably cost an arm and a leg if it is new and may not be considered standard with insurers.  

[coeric]

dointime - thank you for your informative posts. so if someone is tt they might be better off with the study curiouslady is considering?  and if cc curiouslady might be better served by triple therapy with teleprevir?

in study 108 the 12 week telaprevir study found that with the least favorable genotype, tt, 73% achieved SVR and in the most favorable genotype, cc, 90% got to svr.  

personally i would let the biopsy tell me what to do.  if i had little or no scarring i might take a chance on the study, assuming i really wanted to treat soon.  if i were a 3 or 4 i would take the bird in the hand any day.

blessings
eric

[coeric]

i went back and looked at the total number of subjects that had the il28 test in study 108 and also received 12 weeks of telaprevir. the number was 140 so there may not be a significant difference between the three il28 genotypes.  for all three genotypes combined the SVR was 78%.

[willing]

good point about the resistance clock running while  waiting, up to  a couple of weeks, for the w4 PCR to come in. This can be avoided by having a w2 test and, if this doesn't look on target, arranging a quick turn around w4. For those counting on quad therapy that includes Vic/Inci in case triple doesn't deliver, the sooner you stop the PI the  less resistance selection  you'll have to overcome in the future.

I also think we should be cutting our Drs some slack in making these decisions. How the h*ll are the poor guys supposed to predict the unknown? There is scant information available on the impact of resistance selection and none on triple re-tx. Asking them to roll the dice for us doesn't increase our odds of winning.  

[cheesenrice]

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.

[cheesenrice]

Graham R. Foster, FRCP, PhD:
Poordad and colleagues[7] conducted a retrospective analysis of the boceprevir phase III studies, SPRINT-2[8] and RESPOND-2,[9] investigating the potential correlation between IL28B genotype and SVR in patients with genotype 1 HCV infection treated with boceprevir plus peginterferon/ribavirin or peginterferon/ribavirin alone (Capsule Summary). The relative impact of IL28B genotype and treatment regimen on SVR rates differed between treatment-naive patients in SPRINT-2 and patients with previous treatment failure in RESPOND-2. Among treatment-naive patients with the IL28B CC genotype, SVR rates were high at 78% with peginterferon/ribavirin alone and 82% with boceprevir plus peginterferon/ribavirin. However, among treatment-naive patients with the IL28B CT or TT genotype, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone. In patients with the CT genotype, response rates were 65% with response-guided therapy and 71% with 48-week therapy including boceprevir vs 28% with peginterferon/ribavirin alone. In those with the TT genotype, corresponding rates were 55%, 59% and 27%. Therefore, an encouraging finding from this analysis was that the differences in SVR rates according to IL28B genotype observed in treatment-naive HCV genotype 1 patients treated with peginterferon/ribavirin alone were substantially, although not fully, mitigated by the use of triple therapy with boceprevir plus peginterferon/ribavirin.



By contrast, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone in treatment-experienced patients with the IL28B CC or CT genotype. In patients with the CC genotype, response rates were 79% with response-guided therapy and 77% with 48-week therapy including boceprevir vs 49% with peginterferon/ribavirin alone. In those with the CT genotype, corresponding rates were 61%, 73% and 17%. Among treatment-experienced patients with the IL28B TT genotype, there was a trend toward a lower SVR rate with response-guided boceprevir-based therapy vs 48-week boceprevir-based treatment: 55% with response-guided therapy and 72% with 48-week therapy including boceprevir vs 50% with peginterferon/ribavirin alone.



The IL28B CC genotype was determined to be predictive of SVR in both studies according to a multiple stepwise logistic regression model (P < .001 for SPRINT-2; P = .025 for RESPOND-2). However, when response to the 4-week peginterferon/ribavirin lead-in phase was added to the model, IL28B genotype was no longer a significant predictor of SVR.



It is important to assess the validity and applicability of these findings. The patient numbers in some of the subgroups are relatively low as not all of the patients in the trials were available for IL28B genotyping. The trials were designed before the predictive value of IL28B genotype had been discovered; therefore patients had to provide additional consent to be included, and IL28B genotyping data were available for only 63% of the population. However, despite this limitation, the trend is fairly clear: boceprevir improved SVR rates in nearly all of the IL28B genotype subgroups, with the exception of treatment-naive patients harboring the CC genotype (who exhibited high SVR rates regardless of regimen) and previously treated patients with the TT genotype who received response-guided boceprevir plus peginterferon/ribavirin. It still remains to be determined whether patients with the IL28B TT genotype can achieve SVR rates as high as patients with the CC genotype with boceprevir-based therapy. The suggestion from this analysis is the rates are not quite as high, but they are still a great deal higher with boceprevir-based treatment than with peginterferon/ribavirin alone.



Paul Y. Kwo, MD:
I would echo the point that IL28B genotype data from retrospective analyses such as this one must be interpreted with caution. The SVR rate of 78% among treatment-naive patients with the IL28B CC genotype receiving peginterferon/ribavirin alone is reasonably consistent with what has been observed in other studies, although somewhat higher than the rate observed in the large IDEAL analysis by Thompson and colleagues,[10] possibly due to the small sample size. The results showed that treatment-naive patients with the IL28B CC genotype did not derive substantial benefit from the addition of boceprevir to standard peginterferon/ribavirin, yet treatment-naive patients with the CT or TT genotype did derive a substantial benefit. This pattern was markedly different from that observed among patients with previous treatment failure where the addition of boceprevir improved SVR rates regardless of IL28B genotype.



Stefan Zeuzem, MD:
Regarding the limitations imparted by retrospectively assessing IL28B genotype, it is also possible that the results may be biased because patients who were lost to follow-up could not be queried for consent. As a result, the analysis may include a slight selection bias toward compliant patients and potentially toward patients with SVR. Future studies that include IL28B genotyping as an enrollment criterion will be much more informative.

Paul Y. Kwo, MD:
That is a legitimate question to ask in a country with limited resources because SVR rates are high with peginterferon/ribavirin alone among treatment-naive patients with the CC genotype. However, it is important to consider that patients with the CC genotype are much more likely to be able to undergo a shorter treatment duration if a DAA agent such as boceprevir is included in the regimen. In the current study, 89% of treatment-naive patients and 82% of treatment-experienced patients with the IL28B CC genotype were eligible for short-duration therapy with boceprevir plus peginterferon/ribavirin. That is a very encouraging take-home message from this presentation. Although it would be preferable not to withhold boceprevir, in a country where treatment is truly limited because of constrained resources, it would not appear to be an unreasonable strategy if the DAA agent is unaffordable. In regions such as Asia, where SVR rates are already very high due to the high prevalence of the IL28B CC genotype, it may be difficult to improve SVR rates further and if resources are limited, continuing to treat with peginterferon/ribavirin alone might be a strategy that is cost effective. It depends on the prevalence of the CC genotype.



Paul Y. Kwo, MD:
The data from the SPRINT-2 and RESPOND-2 analysis do convincingly suggest that knowing that a patient has the IL28B CC genotype will allow us to counsel him or her that there is a high likelihood that they will be receiving shorter-duration therapy.

Paul Y. Kwo, MD:
Regarding the relative predictive value of IL28B genotype and response to the 4-week peginterferon/ribavirin lead-in, IL28B genotype was no longer a significant predictor of SVR when the lead-in response was included in the analysis. That result is not surprising because IL28B genotype predicts peginterferon/ribavirin sensitivity; it is not perfect, but it is the first genetic tool in the era of personalized medicine that has allowed the prediction of a patient’s ability to clear HCV quickly during peginterferon/ribavirin-based therapy. The 4-week peginterferon/ribavirin lead-in, however, provides a real-time assessment of a patient’s peginterferon/ribavirin responsiveness, and therefore, it is not surprising that the impact of IL28B genotype is no longer evident when response to the 4-week lead-in is considered.

[dointime]

Here's my thinking on this.  The 4-week lead in is not useful in this case because if at that point your ifn response was found to be poor then the fact that you have started tx would disqualify you from the trial which is for tx naive only.  Same goes if you do incivek and you don't pass the futility rule at 4 weeks.  So while the IL28B test is not the holy grail, it is the only indicator you can get on your ifn response while keeping all your options open.

If the IL28B test were to show that you are a cc then you get lucky, as that would be a really good indicator of success with the triple therapy in 6 months.  The triple would then, in my opinion, be your best choice.  Other than that I would not say.      

All trials, by definition, are unknown quantities for which we have insufficient information to make informed choices.  They are all, to some extent, a leap in the dark.  I have tried to highlight in this thread some of the ramifications of failing a DAA trial, and advised that they be taken into account when deciding on whether to do it or not.  I don't think that speculating on the success of a phase2 trial is helpful.  If you do the trial then you should at least be clear in your own mind, no matter what you hope for, that the outcome is uncertain.        

Best,
dointime  

[curiouslady1]

I don't know that taking particular tests are the patients choice unless you want to pay out of pocket.  I did so when the genotyping first came out, it was $700.    You are right about the uncertainty dointime but if you are not inclined to interferon treatments, it seems a reasonable uncertainty, esp. if all arms get meds.   They do not do controlled, double blind studies on Hep C anymore.  That is, everyone gets something.  

[almawe]

If one 'fails' a 4 week trial of telaprevir, and as a result now has resistant issues, does that mean that it would be futile to attempt SOC in the near future?...whilst throwing all at  the body to get the uptake of interferon going, including things like alinia into the mix. Doctor seemed to think there was around a 10% chance. Am a stage 2, CT, la.

[willing]

what did your VL drop with tela look like? I'm not sure there's reason to assign a number like 10% but believe your Dr's point about it not being  a good bet sounds right.

In rough terms, when you started triple say 99% of your viral variants were susceptible to the PI and 1% wasn't. The PI took care of  stopping replication among  the 99%  "wild-type" (no such concept as PI non-response) but the ifn/rbv was incapable of eliminating the 1% and they multiplied and grew. By restarting soc you'd be betting that the improvement in ifn  response due to alinia,SamE or whatever now made it capable of dealing with the 1% it couldn't deal with before and the 99% handled by the PI. Could certainly happen but, as a stage 2, waiting for quad therapy sounds a better bet. Best wishes.

[coeric]

Recently I spoke with a PharmD professor that is doing research on the DAAs and asked her about the futility rule with telaprevir. The 1,000 copies ruled seems rather arbitrary. The answer was yes it is arbitrary. In the trials there were a few that had viral loads of 100 or 200 and they went on to SVR. 1,000 was chosen to ensure that all those that might have a chance to clear are given the opportunity. She seemed convinced that those with several hundred copies or more did not have an adequate INF response and would not clear.
Blessings
Eric