Telepravir failures. Do they get a second chance?

I was wondering if all those people who developed resistant virus strains during telepravir treatment eventually revert to 100% wild type virus strains, and if so, how long does it take?

It is understood that the resistant strains do not replicate as well or rapidly as the non-resistant type, and that after resistant strains become dominant, when treatment is stopped, that wild type eventually become predominant. If resisitant strain disappeared totally, or close enough, then a second bought with Inf-Riba-Telaprevir might have a chance at successful SVR ???

cheese

[susan400]

Are you a Prove 3/Group C'er as well?  I am.  I've been hitting a roadblock with being a Telaprevir failure myself.  I'm trying to investigate that trial listing on Clinicaltrials.gov where it is talking about a non-drug trial for former Telaprevir patients, to check for resistant strains.  So far, I don't have an answer on that.  Check it out on Clinicaltrials.gov.

Susan400

[nygirl7]

As I've said to Susan 100x before I think if they would just try and retreat you guys and succeed that would be such proof that the meds work it would help them SO MUCH............idiots.  SO not right to at least try and see what happens!

[Willy50]

It is speculative.  I think they have gone out of the way to not get the answer...at least not before approval.

Why? There is good reason.  They have proven in petrie dishes that there will be a resistance issue.  They have not tested it on people but there is a great likelihood of resistance.  The deal is....what would you use to beat the resistance?

They have theories that could apply but they are as yet unproven.

One might be that over time the viral load might revert back to the originating non-resistant virri.  If so after "X" amount of time one might stand a similar chance as a naive or somewhere in between that and a TVR resistant subject.

I don't think that they have shown that if you failed TVR You are immediately and permanently resistant and untreatable to PI's.  For instance.... might the newer (or more powerful) second generation PI from Shering Plough be enough to cure a TVR failure?  .....or a PI and some other adjunct (such as Sam-e or alinia) or some other procedure (such as predosing or initial surging)?

Or will it be possible to overcome the TVR resistance issue by sidestepping it; treating with a polymerase inhibitor?

As you may know, Vertex will soon start a trial of twin PI's (a polymerase and protease inhibitor).  It may be that dual inhibitors could provide the cure for the resistance issue.  

In general it may be that any new or different form of treatment that can trump the originating PI resistance issue could be sufficient to provide a response and an SVR.  Deal is...... that is unproven and it may be a while until it is proven.  I'd guess it may not be addressed until post approval of TVR and Boceprevir.

And yes, from what I've heard they are thinking that resistance to TVR will likely mean resistance to Boceprevire and vica versa and also to other PI's.

All I can say is that until they understand it better they shouldn't take half measures which could only serve to make matters worse.  You don't want to under-treat again.

Sorry, it's a measure of not great news but some hope.....

There are many ways being developed that could provide you a cure; not just the PI route.

best,
Willy

PS..... it is sad to say it but the next generation trials are going to create a series of next generation failures with comparable problems.  When they try dual PI trials and try to find out the if they can cut back on either IFN or RBV or both..... we may also see trial participants with resistance issues to BOTH protease and polymerase inhibitors.  What will those failures be looking to for a (re-) treatment?
Nuff said on that for now

[neptune235]

If you think of HCV viral replication as a series of events, a chain reaction, and note that specific viral proteases are involved in specific steps of the reaction, it may help to shed light on protease inhibitors and resistance/retreatment.

Telaprevir inhibits one protease at one step of viral replication, and Boceprevir inhibits a different protease at a different step.  Clearly, the PI that targets the earlier step is all that is required to inhibit viral replication.  This fact renders the PI that targets the later reaction as redundant.  Resistance to one protease inhibitor does not necessarily confer resistance to a different protease inhibitor.

This results in the idea that protease inhibitors will not be combined during treatment.  I would think that re-treatment with a different one for cases of treatment failure and/or viral resistance would yield good results.

[newleaf09]

I agree with neptune's reasoning.  You do not want to retreat with Teleprevir; it's not going to work for you. In some of the earlier work done on PI's and polymerase inhibitors they specified exactly which part of the molecule the drug was interferring with when they presented the Phase 1 info at conferences.  Look that up and look for a PI or Poly I that attacks a different site.

[banarep]

Have not done a lot of recent research, but what I can remember from older articles is that the concern was from when telaprevir was being used by itself and not in connection with SOC.

[susan400]

My point is..., they do not know for a fact that I have resistance unless they check for these variants.  My doctor at Shands told me that I might not even have resistance since I only had the Telaprevir for 6 weeks tops and the Riba wasn't in the mix.  He said it's still only a theory and it's not been proven as of yet.  What do I care if I have resistance to Telaprevir and I want to see if I can treat with it or another PI...???  It's not like I'm going to be running around infecting other people with my resistant strain..., it's only going to hurt me, so if it's my body and I want to do it, it's not fair for them to exclude me from all clinical trials just because according to them, I'm considered a Telaprevir failure.  I didn't fail at anything.  Their trial setup has failed me..., not me failing.  I did everything that was required of me and even put up with the dumb rash and still continued on taking the Telaprevir and Peg...until they pulled me.  So, I ask you, who failed whom here?  Somebody owes us unlucky few people who have been kicked to the curb by the decision makers.  We signed up to be their guinea pigs and they don't take care of us afterwards....     Sorry, but, you said what you thought, Willy, and I'm saying how I feel as well.  Susan400

[nygirl7]

Their trial setup has failed me...,

Yup and had you had the riba you probably would have made it because you were SOCLOSEASITWAS!!!!!!!!

I agree - you should be able to try and see what happens it is your choice and your body.

[Willy50]

Hey, I was saying what I thought they would do; not what they should do.

I think that they should have been more proactive in seeking a cure for people who failed the first exposure to TVR.

I would also suggest that when exposing people to TVR or other PI's that could result in resistance issues that a more proactive stance in allowing rescue drugs might have been taken.

The deal is that they take the long view; no rescue drugs means a cleaner trial.  vertex can provide the FDA data and say; "Here is the results of our drug and SOC."

The more other drugs that they have to add to the mix (such as rescue drugs) the more complicated and less certain approval becomes.  IN being so conservative Vertex will have made approval more straight forward.  In theory they could submit a NDA and get it approved.  Likewise.....if they had allowed rescue drugs the FDA could tell them; we'd really like to see a cleaner trial in which rescue drugs were not allowed.  That would set things back another 18 months give or take....
So you can understand their hard line....

For me though...... after you "use" someone you become responsible for them.  I think that they need to work out a cure for people with the resistance issue.  I'm sure that they are working on that (the dual PI trial may also be part of that solution).

All I'm saying is that it probably won't be addressed until TVR is approved.  Potential solutions are being worked on.  I believe there will be several methods of clearing for you, but like many you'll have to stay well a bit longer to get them.

I also sense a separate issue.  I was addressing the issue of how resistance  *could* potentially be overcome.  Your issue is that Vertex *should* have a sort of parachute for those who have TVR resistant virii.  Maybe that should also come under compassionate (and or obligated) care.

best,
Willy

[mikesimon]

Hepatology. 2009 Aug 4.

    Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients.

"...Conclusion: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross-resistance to telaprevir. (HEPATOLOGY 2009.)."

[neptune235]

Interesting...  I wonder if they used modeling to show the cross-resistance.  Maybe this cross-resistance has a better chance to occur if the protease inhibitors target the same protein.  Are PIs being looked at for viral proteins

I'll be the first to admit my depth in o-chem and virology is, well...not so much.  

[Willy50]

Thank you for that.  I know that it will likely remain a question in peoples minds for some time.

I also liked seeing the "associated with reduced replicative fitness", meaning that perhaps the virus could over time in essence end up resetting to default and away from resistance.  That contains an element of hope for people.  Perhaps in time we will know if that is true, how long one must wait, and what it will take to overcome that issue.

best,
Willy

[neptune235]

Sorry...that sentence should read "Are PIs being looked at for viral proteins other than the NS3/4A?"

[mikesimon]

This stuff gets complicated. 1b resistance differs from 1a resistance.

"....Reported telaprevir resistance substitutions, by order of increasing resistance, include: V36A/M, T54A, R155K/T, V36A/M+R155K/T, A156V/T, and V36A/M+A156V/T.[52,53] The very early selection of resistant viral populations in patients receiving telaprevir is in keeping with the notion that these variants preexist in the majority of HCV-infected patients at the time of treatment initiation. Their rapid outgrowth during single-agent therapy suggests that the fitness of these natural polymorphic variants is relatively high, albeit lower than that of wild-type virus, explaining why they are rarely detected before therapy.[54-56] Differences in resistance profiles between HCV subtypes 1a and 1b have been reported. For instance, variants with changes at amino acid position R155 often preexist and are selected by telaprevir in most patients infected with subtype 1a, whereas telaprevir resistance is less frequent in patients infected with HCV subtype 1b and variants bearing substitutions at position R155 are rarely selected. Therefore, accurate determination of the HCV subtype will be needed for inclusion in clinical trials of new HCV drugs and in clinical practice when telaprevir becomes available. Methods based on the sole analysis of the 5’UTR region should be avoided, and the most appropriate method currently is the second-generation line probe assay.[57]..."

"Less is known regarding resistance to boceprevir compared with telaprevir. Selection of boceprevir-resistant variants associated with virologic breakthrough is reportedly frequent in prior peginterferon/ribavirin nonresponders treated with the triple combination of peginterferon alfa-2b, ribavirin, and a relatively low dose of boceprevir (Capsule Summary).[62] The reported substitutions included those found in telaprevir resistance as well as V170A.[63] In the SPRINT-1 trial, 3 groups of amino acid substitutions conferring resistance to boceprevir were observed in patients who failed to eradicate infection: major substitutions (detected in > 25% of resistant cases): V36M, T54S, and R155K; less common substitutions (detected in 5% to 25% of resistant cases): T54A, V55S, R155T, A156S, V158I, and V170A; and infrequent substitutions (detected in < 5% of resistant cases): V36A/L, I170T.[62]

The triple combination of boceprevir, peginterferon alfa-2b, and ribavirin is currently being assessed in a phase III trial in treatment-naive patients infected with HCV genotype 1.[64]"

See:  http://tinyurl.com/yk5gx68

Mike

[epiphiny]

I'm not a pointy head and can't give you indepth scientific answers as those posts above have but I can tell you what my Doctor told me 2 days ago when I was discharged from the Hep C Clinic.  My Doctor is right up there with trials and new treatments and has given several presentations regarding new treatments at Liver Conferences worldwide.  As you all know I was on a polymerase inhibitor trial for R7128 originally developed by Pharmasset now owned by Roche.

As discussed above resistance to protease inhibitors can develop within 2 weeks.  However with the new polymerase inhibitor as above and the next generation polymerase inhibitor have so far shown that NO resistance develops to these drugs.  Therefore this drug will be the go to drug for those people that have no success with a protease inhibitor.

He also said that trials that are based entirely on polymerase ihibitors and Riba (no interferon!) are happening and the first results for those trials should show in November this year.  As you may or may not know the FDA has fast tracked R7128 as it recognises that there is a huge gap in treatment options for relapsers and non responders.

Susan, if I was you I would start looking for any Roche trials with these drugs.  I'm only guessing here but it would seem to me that you would be a great candidate for such a trial as you fit the exact criteria that these new drugs are aimed at.

I hope this will give you some hope!

Epi :)

[susan400]

I am just so incredibly frustrated with this whole thing!!!!  Not with you all and I hope you know that...   Sometimes I just get so angry about it and frustrated about it, that I feel like bursting out into tears.  Yes, I have other things in my life to think about besides Hep C..., don't get me wrong there.   It's just that I have had bridging fibrosis for over 5 yrs and I really don't know how long it will be until it will progress..., as does nobody else who is currently not SVR...  I don't want to get worse, I want to get over it!  I'll probably be needing to have my 5th biopsy next spring and that gets old, too.  To the best of my knowledge, there aren't any fibroscanner's in my county and since I'm on an HMO, I have to get my medical care here.  Anyplace else isn't covered by my plan.  So, for me it's ultrasounds and biopsies every 3 yrs.  I just want to be done with this so bad!  When am I going to be able to post... SVR!!!  ????      I was just told by my insurance plan last week that my drug coverage is going to be limited to only Tier 1 and Tier 2 drugs so, even if one of these new drugs get approved, I'm not going to have a way to pay for them.  That's why I NEED a trial of something to help me here!  Susan400

[Willy50]

In such a case there may be programs in use such as commitment to care where drugs may be provided for people whop cannot otherwise get them.

It's a weird deal.  I know people who have committed crimes who get swooped up and cared for by the government.  Other people; middle class blokes may not be qualified for that kind of care.

What's wrong with this picture?

Susan, even treatments like chron-vac the innoculation could end up working..... even for people who cannot tolerate IFN or don't have the platelets for RBV.  

I don't even come close to knowing what all you've been through and how much more you have to face.  I'm pulling for ya though.... (and the other TVR people who didn't clear)

Willy

[dointime]

Mikesimon's post just about covers it for the resistant variants.  I'd just like to add that HR wrote here about the 'archival' capability of the virus.  Even though the virus does revert more or less back to wild type eventally after tx, it has 'archived' a memory of the threat that it met, ie. the telaprevir.  In practice, this means that if it meets telaprevir again it 'remembers' what it did last time to mutate round it and it can do it faster the 2nd time.  So nobody reverts back exactly to the same as before their first tx.

dointime        

[dointime]

My hepC doc is a virologist who has done a lot of work with HIV.  He was telling me that they now do a sequence analysis on the full length of the particular gene being targeted because they keep learning of the clinical significance of mutations which they previously did not think were significant.  So there may be a lot more resistant variants in the mix for hepC than currently recognised.  It is very much still work in progress.

The other thing he speculated about is the possibility that for some people it may not be possible to achieve SVR, but that a constant state of UND might be achieved with a drug combo, much like HIV is now controlled.  This would not have to include the use of riba or inf.  I didn't like this idea at first but it is growing on me.  I stress that the idea is pure speculation currently but it could point the way to a realistic solution for some non-responders.  If it can be done for HIV then why not eventually for HCV.  

dointime            

[Cheesegrater]

I would like to see more facts on the "archival" capabilities of the HCV virus.
Do you have any links?

Cheese

[dointime]

Doug Richman wrote about the archival capability of a virus while researching resistance and HIV.  You could look for his original research.  

Here's the link where I learned about it.  Read Hepatitis Researcher's posts.
http://www.medhelp.org/posts/show/344760

dointime

[Cheesegrater]

I read the post by HR.
I have read a few posts by HR and find that he does seem to be quite knowledgeable. However, I would hold off on accepting what is posted on a public site, regardless of who posts it, until I see some concrete data from properly conducted experiments. (And one has to be careful in interpreting experiments as well, as poor experiment design can give ambiguous results).

Since reading your reply, I have done a quick search through HIV resistance, and have found one site that indicates that even the HIV virus can revert back to wild type if the resistant form has poor reprocuction and if drug pressure is removed.

One must remember that HIV is a DNA virus, it uses an integrase enzyme to insert it's DNA into the DNA of the host cell, according to a few sources I came across. Having the instructions for HIV hardwired into the cell's DNA probably makes the instructions a bit more long lived than what may be possible with a RNA virus, which does NOT integrate into the Host DNA.

What I am saying is that the "archiveability" of resistance is by 2 different mechanisms, if such a thing does occur in RNA viruses, and therefore the lifetime of the archive may be radically different.

Resistant HCV reversion to wildtype MAY be faster and more complete than seen in HIV resistance.

cheese

[dointime]

I completely agree with you.  The trouble is that to my knowedge there is nobody in the world at the moment who has treated more than once with telaprevir or any other PI.  I'm also not sure if it would even be possible to conduct an in vitro experiment to test the archivability of the hcv virus.  So we are left with the old chestnut - that there are many things about hcv that are as yet unproven and this is one of them.  So the best be can do is conjecture and keep an open mind, as you seem to be doing.  

dointime