Rats, boceprevir failed me

[foofighter]

Just got unblinded. I was in Arm 3, received Pegintron, Ribavirin and Boceprevir. Was 100% compliant (late on ribavirin by a couple of hours a few times).

Kinda freakin' out here. I was almost positive I got the placebo, since my labs didn't take a hit when the blue pills were added.

Willy or Willing what do you think? What does this mean for me? Does Telaprevir target the virus exactly the same way? My varicies had gotten bigger last scope and they are having me come back early for the next one so things are changing. Crap. CRAP!!!!

[child24angel]

I'm truly sorry
Elaine

[copyman]

so sorry foo.

I dont think you stopping early had anything to do with not clearing. I think it was apparent it was not going to work because you never fully cleared early (if i read the posts right?)

I think if a PI is going to work it works very quickly and the person should be unde within a few days and definitely by 4 weeks. I still think the way this virus replicates so fast that killing it quickly gives someone the best chance to clear.
This is one of the things I didn't like when I was deciding which studyl to participate in. I did not like the lead in and delay adding the study drug with Bocep. Also a shorter course of therapy with Telap.

Anyway I think I read somewhere that someone could try the other PI if they failed one. Hopefully this is true and you can try Telap next year.

Hang in there, it will all work out. To many good things happening with this disease for it not to.

[dointime]

The data for resistant mutations to both boceprevir and telaprevir is already published for both drugs, so you don't need to wait for drug approval to find this information.  As I remember it, most of the mutations for boc are also resistant to tela, and boc has one more all it's own.  Your mutation data will be a list looking like - v56k .....etc. which you can check off against the published data.

The percentage of mutant virus present does diminish over time to become wild type virus again.  However there is what is called an 'archival' memory within the quasispecies.  What that means is that the virus acts as if it remembers what it did to  evade the drug threat the last time and it does the same again next time only faster.  So you never completely revert to being 'naive' again with regards to the same type of drug threat to the virus, in this case the NS3-targeting PI's.  Anyway as Willing has said, not much is yet known about retreating with these PI's, so we can expect this info to be updated eventually.

Vertex stopped following me when my tx finished.  Currently the hepC medical world is not formally organised to collate resistance data and use it for retreating.  You have to do it yourself and encourage your doc to do it.  I have the luck that my doc is a virologist and has been fighting HIV for the last 20 years.  They are much more advanced in dealing with resistance to HIV, and maybe also HBV, so there is a precedent already set and I think it is just a matter of time for HCV.

dointime              

[spectda]

I flat lined in the 200's at week 6 and 8, but I had a reduction of pegintron from 150 mcg to 96 mcg that preempted it.

[Marcia2202]

No sweetie, I never got your pm. I wasn't even aware that you had to stop early. I was traveling for a few months in the summer and haven't been on so much lately either.

I pray that things will work out well for you, as well of for the others in a similar situation as yours.

Hugs, Marcia

[willing]

sorry about the bad news - but as you've noted, it's really not that bad. First, you're a very strong IFN responder and that stays with you for future tx. Secondly you did (weakly) respond  to the Boce - you dropped about 1 log with it. Your enemies were the sides,  a trial protocol that provided less flexibility in how to manage them and a suspicious flattening in the 2nd part of those 7 weeks. The one to be worried about in retrying with tela is the last one on the list. Lots of others have "flat-lined" for a while, spectda, most recently, but yours is a longish stretch that indicates there was virus capable of thumbing its nose at both boce and soc for about 5 weeks.

Retreat with Tela and you're likely to run into that gang again though this time you might overwhelm them with a full-length tx. Success rates in retreating with the protease, NS3-targeted PIs,  are really an unknown and will remain so until more experience builds up.  All that's really known to date is that (a) the resistant mutations are there all along and are selected for survival by the PI (b) they're generally less fit and  are replaced by wild-type once the drugs stop (though this can be a slow process) (c) cross-resistance between tela and boce is very high.

You got good advice above.  Robertbewell's and dointime's suggestions in particular.  Nag Merck about access to any sequence data available from your VL draws (with a lawyer's letter if necessary)  And check out the HEPCAT trial. They say "Non-responder to prior therapy with peginterferon alfa and ribavirin" and may exclude you because of the PI exposure  but it's worth checking. I suspect any Dr. you talk to is going to suggest trying a DAA that goes after another  viral target (r7128, bms790052, etc.) is a better strategy than  just trying an NS3 again.  However if nothing else is available trying to Tela can't hurt. In the worst case all you'll end up doing is making your NS3-resistant strains that much stronger, but there are so many other DAAs at this point that can clobber NS3-resistant virus that it's no huge loss. Burning a bridge behind you isn't that bad when you've got a couple more....

[foofighter]

Do you have your mutation info? Does that mean as soon as Bocep is approved you will know whether or not you will respond to it? I didn't realize you were in the no riba like Susan. So sorry for both of you.

I called and left a message saying I want to pick up every record they have for me and hopefully the mutation info is there. At least I was told when they were recruiting that any mutations would be revealed to us. I just got a letter today inviting me to participate in the follow-up study (that ended with the unblinding info). I suppose there is something valueable to learn from people that don't respond to PI's. I wonder if the mutant virus might go away or change back after a while? Are they following you any longer?

Anybody else invited into follow-up that was in a Boceprevir trial?

[Willy50]

I agree, Foo did have a good response to SOC, if a 4 log drop was attained.  OTOH, if there was less than a 1 log drop, or "not a blip when the blue pills were added", it almost seems as though it was a null response to Boceprevir.  I wasn't really clear on why the trial was halted but if the labs were unchanged w/ the addition of Boceprevir I was just guessing that it was due to trial design criteria.  

My impression is that the 2 drugs (Boc and TVR) are very similar and so that response and resistance issues/profiles will also probably be very similar.

My reference to null responders in my first paragraph was to contrast the null responders in the two trials; I felt that if Vertex had a better response rate, then it may have made a difference, not because Foo was a null responder, but that the efficacy might be better demonstrated by comparing the hardest to treat groups.  (It has been a struggle to compare the 2 drugs since trial design has defied an apples to apples comparison between Telaprevir and Boceprevir))

Different drug combos and different drugs like the afore mentioned BMS, or polymerase inhibitors, or stat C drug combinations may be the next thing to try.

One may also experience more latitude outside of a trial if you want to walk off the beaten path, with a doctors cooperation.

I would also mention to Foo that Magnum has been conversing with representatives from Vertex,and it may also be possible to ask that same rep some pointed questions about what can be done for people who have failed a PI trial.  Is Vertex planning any FDA Phase 4 (post approval) trials with any strategies for combating the issue of resistance to PI's, or will that population have to wait for new approved drug treatment plans such as Stat-C' combinations? (that may be around 2015)

One of the first populations that will be pushed to treat will be past TX failures or advanced staging groups.  These will have the most problems clearing/ achieving SVR and therefore the future triple therapy treatments are going to produce a large population with potential PI resistant virii.  What are the plans of the two companies for *that* treatment failure group? (as well as the population that has failed in either the Boceprevir or Telaprevir trials up to date).

Willy

[foofighter]

I am a partial responder, super responsive to interferon (more than 4-log drop to SOC at week four: 9,920,000 down to 226). Then from 226 to <25 after two weeks of bocep.

So I was wrong Trin, bocep knocked out 200-some virons possibly. Then stuck there for the remaining 7 weeks. So 9 weeks of trial drug and an additional 1-log drop, right?

Yes, if I had been able to continue maybe I would have cleared. It was a moot point. They were kicking me out at my week 14 visit if my nausea had not cleared. It hadn't and I was so upset I called and quit before they could fire me.

Anyway, I pray that my liver can hang on a bit longer, that I can get the support I need from my doc to deal with sx that the trial doc did not AND that Pegasys will be easier for me to tolerate than Peg-Intron.

[can-do-man]

If you would have been able to complete the trial your odds would have been fairly good as you would have had the boceprevir the remainder of the trial.

Arm 3: Experimental
PEG 1.5 μg/kg + RBV (WBD) for 4 weeks followed by boceprevir + PEG 1.5 μg/kg + RBV (WBD) for 44 weeks with 24 weeks post-treatment follow-up.

[Trinity4]

In my opinion, I don't think foo had a poor response to the Boce and she's not a null responder.  <25 IU/mL is very impressive at week 6 even with a detectable level at wk 12.   We like to see UND but when treatment is stopped at week 13 there are too many variables to consider.  We're not dealing with a completed treatment here as in relapse. Who's to say if had she gone forward with the additonial 33 wks of inf & riba that she wouldn't have SVR'd?

Trinity

[dointime]

"When so many people are going to be treating with PI's it is going to become VERY important to have a "Plan B" for people who have failed triple therapy."

It is likely that you have viral mutations resistant to boceprevir.  Ask your study doc to find out from Merck which resistant mutations you have.  This information will be vital to choosing the drugs for your next tx.  For example, the mutations you have may also be resistant to telaprevir.

I'm so sorry this happened to you.  I failed with telaprevir and I know how scared I felt.  As Willy said, the wait for approved drugs is long, so I hope you can find another study appropriate for you before then,

dointime        

[foofighter]

I sent a PM to you a while ago, but I am worried it didn't go. I wanted to say, my thoughts exactly! Your post made me feel better (although it seems to have been edited to the PG version somehow).

thanks for the caring, Miss Red Shoes. The rest of us will get there, maybe wearing something with no heel, so we don't break a hip!

[foofighter]

Robert, thanks for the suggestion and Mr. Bill, Hector, Willy, Can-do for the kind words and encouragement.

Willy, thanks for the long-winded advice. I appreciated every single word of it and took it to heart. I have to say I think I have been cirrhotic or close to it for a very long time and have been just fine, more or less until the last year. I had planned on hanging on till Teleprevir was approved, we will see if my liver has the same plan : )

And really there is no other choice than successful treatment for all us. So we have to keep trying.

Thanks everyone.

[Willy50]

Hi kiddo, I'm really sorry to read this thread.  It sounds as though you got really really close, but w/ HCV, that just doesn't get it.  It's kinda late to also wonder what would the difference have been if it had been Telaprevir.  I'd respond to that though; for people who were proven past null or non-responders it appears that Telaprevir may be a more potent drug.  This is worth a read on that subject; (particularly page 2)

http://www.thestreet.com/story/10853923/1/vertex-cures-hard-to-treat-hep-c-patients.html

          Today however, you have to look at things as how they now stand.  I don't think that it is well understood how well people with past exposure to PI's will deal with resistance issues.  Most of the evidence is that it will play a factor, and so...... I doubt that you will be able to get any PI trials in combination w/ SOC before they are approved.
           IF you were to look at a post approval strategy it may be worth one more swing at TX with a PI, but you would have to try various tactics to reduce viral load before TX and you might also augment (for instance, TVR, IFN and RBV) with other drugs (alinia), strategies (preloading, higher dose RBV), supplements (Vit D, milk thistle), and or even some experimental and less documented methods of attempting to lower viral load before TX, or improve the immune response (such as treating insulin resistance issues) Yes, I know that there is not a large body of proof that any of these, much less in combination would help, but would it hurt?
          In your case, you have very poor immune response, and given that PI's are known to create resistance, that is a bad cocktail.  To succeed with the current drugs in the arsenal, so to speak you may have to seek out little areas which could afford you a 5% increase here and there.  If one is able to do so, or rather, had one been able to have done so you may have cleared in stead of a stalled response just above detectable.  To be fair even doing everything known and experimental using the current tools at your disposal (at least after TVR is approved), it may mean that the rate of success for null responders with TVR may creep up only 10 or 20%.  There will likely remain a population which the new triple therapy cannot cure, but I believe that there are possible ways to improve the current and established triple therapy success rates.  Obviously, they cannot do any of these shotgun approach methods in a clinical trial.  
        I close this section by mentioning that a friend of mine treated a 3rd time with SOC after 2 failed relapses in the past.  Statistics suggest that you could sensibly predict failure a third time, but they went again, but THIS time lost weight, did lots of pre-TX cardio, and did a lot of Vit D this TX.  They RVR'ed this time and have maintained that for over 3/4 of their current TX.  They have a few months to go but the prospects look very good this time.  My point...... ya never can tell, never give up.
Don't overlook some of the *possible* but UNproven methods that you may read on the boards.  We hope that all you need is a slightly improved response rate, enough to clear EARLY and stay clear.

The final thing or things I'd say is that it is reasonable to assume that you may have some waiting in store for you.  The newest of the new drugs and combos are a few years off yet.  If you can undertake as many things that you can to improve your status you may be able to improve your health or even decrease your movement towards decompensation.  Without knowing your specifics, things I'd at least look at might be weight loss, diet improvements, potential insulin resistance issues, improvements in exercise/cardio issues.  IF you can stay put damage wise, I believe that the new stat-c treatments, in which IFN will play a much smaller part will greatly improve the success rate.  I think we will see if the stat-c combos will even need IFN or RBV by about the time Telaprevir is approved, but we may hear sooner on the boards.

Sorry for being long winded.  Now the disclaimer; I have no medical credentials or licenses, but I *do* have a drivers license.  : )    
It's just my opinion and I admit, there isn't a lot of hard proof to support the suppositions.  When so many people are going to be treating with PI's it is going to become VERY important to have a "Plan B" for people who have failed triple therapy.  And so.... whereas it may feel very lonely now, believe me the ranks will be growing and I know that the best and brightest minds are formulating new methods to treat those who have failed.  Once approval happens you may also see some post approval trials in which the issue is addressed.

My condolences and best wishes.....

Willy

[RobertBeWell]

You might want to check out this trial:

Study of the Anti-HCV Drug (BMS-790052) Combined With Peginterferon and Ribavirin in Patients Who Failed Prior Treatment (HEPCAT)
http://clinicaltrials.gov/ct2/show/NCT01170962?term=bms-790052&rank=5

It's for people who failed treatment. It's an NS5A inhibitor, the first in class. Research describes it as "the most powerful anti-HCV drug yet developed".

This study is recruiting even as I type.

Best of luck,

Robert

[HectorSF]

I am very sorry to hear about the setback. It has got to be a big disappointment and very upsetting. This disease is a real roller-coaster. Just when you think you've found the answer and your hopes are high...

Definitely check out possibility of trying telaprevir.

Keep trying to stay as healthy as possible for as long as possible. When these meds hit the market, new knowledge will be gained through experience with a wider array of patients and may lead to optimizing treatment protocols that may be advantageous to yourself and others.

Take time to grieve. Then hang in there. We all pulling for you.
HectorSF

[can-do-man]

I was a relapser, first tx just did have a 2 log drop at 12 weeks and didn't become und until week 24, went 86 weeks but relapsed after 4 weeks post. Was dx with cirrhosis over 5 years ago........ Hang in there

[foofighter]

I guess I should have said I/my body failed to respond to a PI. Kind of a sensational headline I guess. Sorry about that. I'm totally not knocking Bocep, I am just shocked/bummed.

I don't think anyone can "blame" any of the drugs available when it comes to response. It is all the goofy types of virus, damage, etc., etc. and how interferon works with your system. Percentages say some of us will fail with the new drugs and I am the first on the other side of those percentages in our group it appears.

Yes Trin, I got down to <25 detectable with SOC and then sat there. Not a blip when the blue pills were added. That is why I thought for sure it was placebo. Especially after everyone here responded so quickly. I think Spectda was the guy that waited the longest to clear after adding the Bocep. Whatever my remaining bugs were, they didn't care about the PI.

As I said I am going to contact to HR to see if it is even makes sense to try with Telep. I had been working toward getting things in place at work to be able to stay home the next go-round so I could complete tx. But who knows. We'll see what he thinks.

CanDo. Yay Bocep and Telap. It is and will be a miracle for so many people. Also were you a relapser, partial or null responder?

[Bill1954]

Aw, Fooo…

You really need to consult with a hepatologist before you panic, but I agree, what a stinking drag. Do you mind quickly recapping the highlights of your trial participation here so that others can comment with more accuracy?

I believe that Telaprevir and Boceprevir target the same region, but I’m not certain if there are enough wrinkles among them to warrant treating with Telaprevir. This does change the playing field, huh? I haven’t looked around much lately; what is going on with the *polymerase* inhibitors that target NS5B region? You should discuss this with the doctor, and see what, if any, bearing your last trial participation will have on you in terms of inclusion/exclusion with other products.

We have a gal in our local HV support group that’s had frank cirrhosis for many years now, and seems to be managing fairly well; but of course, she has to keep on top of EGD’s and the like.

Do you have an appointment scheduled with a hepatologist yet to discuss this? If not, that’s on the list for Monday, huh?

All the best to you, Foo—keep in touch,

Bill

[foofighter]

Thanks Marcia. I am scared. Haven't felt like this for a long time.

Seeing how tough things have been for Hector lately, I just kept thinking we will both be able to hang on till next spring/FDA approval. Now I don't know if it will make any difference for me. I am gonna give H.R. a shout. I guess I need to know what will happen next.

Thanks again.

[can-do-man]

Sorry to hear that but being able to do only 13 weeks, thats only 9 weeks of boceprevir and being a geno 1 not sure any drug out there right now will cure you. i think its a bad rap to blame boceprevir though............. Best to you

cando

[Trinity4]

I re-read your profile and looks like you were <25 at weeks 6-12 but detectable.  Given that info you may very well have cleared if you had been able to continue the SOC.  Inf & riba will still be used in conjunction with telaprevir so that's something to think about if you're considering re-treating with it.

Trinity

[Trinity4]

Foo, you didnt do a full 48 weeks of inf & riba correct? You had to stop after 13 weeks? Not sure you can say the Boceprevir failed you if you didn't finish the course.  

Telaprevir targets the virus like Boceprevir does but it may be worth a go because you went UND first go round.

Good luck,
Trinity