boceprevir news

[Proactive]

Didn't see this posted


"74 percent of patients achieved SVR 12 with 48-week boceprevir-based combination therapy
High SVR 24 rate also reported for 28-week boceprevir arm"
http://biz.yahoo.com/prnews/080804/nym051b.html?.v=1

[willing]

congratulations! agreed that r7128 is one of the most promising prospects out there. Among its strengths is lack of  significant viral resistance (also a feature of r1626) , a big win over the NS3 inhibitors like the Vertex and Schering drugs. This will likely further reduce reliance of SOC  to "mop up" resistance mutations making the drug a good option for non/null responders, like yourself. Now that Roche is backing away from r1626 it presumably will start testing this more actively. I believe unavailability is the only reason you don't see much discussion of it here; there  is one at least one person (dragontamer?) on tx with it.

At least two other NS5B inhibitors  have gotten dropped along the way; let's hope this one makes it out the door.

[epiphiny]

Like Trin I am very impressed with how detailed your guys discussions about this stuff are.  I'm addicted to this site!!!

Anyway, I've been scouring these boards and have read a lot of threads like this one discussing the Telaprevir and the Boceprevir trials but I've only seen the trials for R7128 mentioned twice; once in this thread and once in an off-hand comment by HR.  I'm curious to know why there is not much discussion about this new drug, which has been given the fast track from the FDA.

I am interested because in June this year I took part in an 8 week study for RO5024048, which I believe is the same drug.  You can google it to get more info.  I had the study drug for 4 weeks in conjunction with SOC (with no lead in, all drugs started at the same time) and I was UND <15 at 4 weeks.

Being a previous non-responder to SOC treatment this was a huge development for me and as I wasn't treatment naive I was able to differentiate between the sides for each drug.  I can honestly say I experienced no adverse effects from the study drug, the only thing I noticed was a feeling of fullness in my belly after dosing.

I'd love to know what you all have heard about this drug and if there is anyone else who has been on this trial.

Many thanks
M

[willing]

thanks for the r7128 link  - those do seem very good numbers, as expected. Now if only Roche would license telaprevir or Schering would license r7128 we might start seeing some data on the combined effect rather than waiting 6 more years...

apologies if I seemed critical of your post above; the final results are indeed  speculation. There appears to be a  pro-telaprevir slant on this board, which may be of disservice to anyone with a shot at the BC phase 3 trial since even if Schering does come in 2nd place their SVR odds  still seem very good.  

Agreed that Vertex has  room to improve in Phase 3, whereas Schering's numbers are probably about as good as they're going to get.

I've read that description of the BC tx-experienced trial several times since it was first released and have never been able to make sense of exactly what they did.. However given the cross-over mess, am not surprised that unlike Vertex, Schering has never tried to use that data as a a basis for fast-tracking the drug for non-responders/relapsers.

[willing]

hope your tennis elbow improves, and many thanks  for your concern re my ailing logic. However, I regret to say, there has been very little  change (actually none, but that might seem rude) in my view on the topic: the only time sensitivity of VL tests matters is when the outcome guides tx decisions and yes, this is a changing landscape.

The importance of sensitive w12 tests has been long established. I haven't kept up on w4 tests (can 1s now safely make shorten/extend decisions based on their w4 test?).  Pretty much everything else is interesting but uninterpretable  and thus not worth stressing over (as evidenced by the number of posts trying to make sense of say a VL of 36 at w6).

Re the study you posted, I agree completely with the "not surprising" part, but not with the "more meaningful". Consider the following experiment: take 1000 patients on the same tx, doesn't matter which. At, say, day 10, extract not the usual paltry 2 or 3mL but a whole liter of blood and run 500 of the most sensitive 2IU limit tests on each 2mL sample. Declare a patient UND only if all 500 tests turn up UND. What outcomes would you expect? (1) very few, say 4 or 5, will show UND and (2) they'll all SVR since they had such strong response to tx. Does this have any "meaning" for the other 995? Does it help guide their tx?

Of course, I wouldn't go out of my way to get a low-sensitivity test, but the only time it seems worth worrying about is when you know before the test how it's going to affect what you do after the test.

(Must be the oats..)

[Willy50]

Well...... first of all, I stated it was my opinion, not stated as FACT.  I see people try to sort thru trials and wonder which might be the best.  I offer my opinion (and reasons too) so that they can better understand the thought process.  It's an interesting subject and I'm really excited for all our future prospects.  By the way...... I may also be wrong about who is "best"; check out this trial result (preliminary as well)

http://www.hivandhepatitis.com/hep_c/news/2008/080808_a.html
Pharmasset Reports Preliminary Results of a 4-week Combination Study of R7128 for the Treatment of Chronic Hepatitis C
88% of patients achieve undetectable HCV RNA levels following 4 weeks of treatment with R7128 1000mg BID with Pegasys plus Copegus

(an earlier Vertex trial saw 12/12 hit undetectable in 4 weeks but the R7128 looks still looks very promising)- W.
---------------------------------------------------------------------------

Anyway....we were discussing my "forward looking statements"?       : )

Actually..... they aren't forward looking at all.  I offered my opinion based on current data.  Here's a bit of data.  I'm not sure what criteria you yourself would use but at least I hope you'll understand why I offered my opinion.  I think there's some basis for it and not merely my unbridled enthusiasm.  ; )
-----------------------------------------------------------------
(latest Boceprevir data for treatment naives;)
http://biz.yahoo.com/prnews/080804/nym051b.html?.v=1

    Treatment Arm                               All patients
    No P/R Lead-in 28 Weeks                     55% (59/107)
    P/R Lead-in 28 Weeks                        56% (58/103)
    No P/R Lead-in 48 Weeks                     66% (68/103)
    P/R Lead-in 48 Weeks                        74% (76/103)

The results of Prove 1 and Prove 2 were 61% and 68% SVR respectively for the "12 and 12"
This was done without a 4 week "lead in" and without rescue drugs which were used in the Boceprevir trial (according to reports).  Vertex seemed to provide higher efficacy without the 2 rather substantial aids used in the Shering-Plough trial.
----------------------------------------------------------------------------------------------------

Well..... what if you were to compare treatment failures; "non-responders?"

http://www.hivandhepatitis.com/hep_c/news/2008/061308_c.html

Vertex Reports 52% SVR 12 Rate for a 24-week Telaprevir-based Regimen in Genotype 1 Hepatitis C Patients Who Failed Prior Treatment


• 73% of prior relapsers achieved SVR12 with 24-week telaprevir-based treatment.

• 41% of prior non-responders achieved SVR12 with 24-week telaprevir-based regimen.

(this would be from Prove 3 preliminary trial results)

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

(Here are the Boceprevir results.  Once again, difficult to compare but you'll see that even without a 4 week lead in" or without the use of rescue drugs Vertex came out with a rather respectable lead over Boceprevir)

http://www.hivandhepatitis.com/hep_c/hepc_news_alter.html

Boceprevir in "Null" Nonresponder HCV Patients; oct 2007

Schering-Plough also reported top line results from a completed Phase II study evaluating boceprevir dose response and the need for ribavirin in patients chronically infected with HCV genotype 1 who were nonresponders to previous peginterferon and ribavirin combination therapy (i.e., patients who did not have undetectable HCV-RNA or who did not achieve a 2 log decline in viral load with a minimum of 12 weeks of peginterferon and ribavirin combination therapy). These "null" nonresponders to peginterferon and ribavirin combination therapy represent the most difficult-to-treat patient population. Patients who relapsed following previous HCV therapy (relapsers) were not included in this study.

This study was complex, involving seven different treatment arms. Patients were initially randomized to low doses of boceprevir (100, 200, 400 mg TID) before initiating an 800 mg TID boceprevir arm. Under the study protocol, patients received these boceprevir doses in combination with PEGINTRON (1.5 mcg/kg weekly) with or without REBETOL (800-1400 mg daily) for 24 or 48 weeks, or received PEGINTRON and REBETOL alone as a control. During the ongoing review of the study by the Data Safety Monitoring Board (DSMB), it was recommended that patients in the lower-dose boceprevir arms who demonstrated a substantial antiviral response during treatment cross over to boceprevir 800 mg TID in combination with PEGINTRON and REBETOL for an additional 24 weeks. Patients who did not demonstrate a substantial antiviral response during treatment were discontinued from the study. In addition, patients in the control arm who did not respond to PEGINTRON and REBETOL alone were allowed to cross over to boceprevir 800 mg TID in combination with PEGINTRON and REBETOL. Patients received a maximum of 24 weeks of the optimized regimen (boceprevir 800 mg TID in combination with PEGINTRON and REBETOL). In all, 357 patients were enrolled at centers in the United States and Europe, including 348 patients who received boceprevir at some point in the study.

(focus on this paragraph)

In this study of well-documented null nonresponders, some patients achieved a sustained virologic response (SVR). Overall, 7-14 percent of patients in the boceprevir crossover arms achieved SVR compared to 2 percent in the control arm. SVR was associated with early virologic response and a longer course of therapy (more than 36 weeks). While potent antiviral activity with boceprevir was seen in the study, with viral loads in some patients decreasing below the limit of detection, viral loads for other patients decreased and then rebounded to baseline levels while on therapy and some patients relapsed following the end of treatment.  

(the long and short of it was for null/nonresponders responders only 2% on SOC got an SVR,

7-14% on Boceprevir got an SVR [while also allowed a 4 week lead in and use of rescue drugs according to reports],

and 41% of vertex non-responders achieved a 12 week SVR.  There will probably soon be "official" 24 week SVR data posted probably in the fall AASLD.  Until then we are flying on fuzzy data but I think there is enough evidence to make SOME assumptions, eh?

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

I'm delighted that any drug improves our current options for treatment.  I hold out hopes for all of them.  I just don't see that the drug trials allow easy comparison, but even in the existing forms they have taken I hope you can understand why I wrote what I did.  

I will note that this year Vertex will have started another geno 1 naives trial and will also try only 8 weeks of triple therapy followed by 16 weeks followup SOC.  We may see shorter TX times yet.  They will also start a treatment failures trial and I believe that it will use some form of the SOC lead in.  Since Sherring-Plough believes it works it may also improve the Vertex performance as well.  IF rescue drugs were to be used in either Vertex trial we would start seeing a better basis for comparing the 2 compounds.

I expressed my opinion.  I wonder...... what do you think?  

best,
willy

[Rockerforlife]

stem enhance worked for my tennis elbow


and i am not kidding

[jmjm530]

correct study link  http://www.medhelp.org/posts/show/605726?post_id=post_3312792

[jmjm530]

Willing As I've long quibbled with Jim, there's limited value to high-sensitivity VL tests
---------------------
No, I think you previously argued there was *no* clinical value in high-sensitivity testing, a position you have retreated from more and more and more (in face of study after study after study) to finally admitting you would take the most sensitive tests avail yourself should you retreat. And I don't blame your retreat in light of all the studies incld this recent one.
/show/605726?post_id=post_3312792\

Of course, the value is *limited* -- there simply isn't a magic test avail yet to predict SVR/relapse, but that never was in debate, was it? Writing this with one hand due to tennis elbow so this will probably be it from me for now. Hope this finds you better than your logic on this one particular issue :)

Jim

--

[Rockerforlife]

No rash with BOC drug

[willing]

willy:
>It will take about 1.5 years to get the complete results from the Vertex Phase 3 trial

indeed, and a comprehensive comparison of the Vertex and Schering alternatives may not be feasible for maybe 3 more years. However, with respect to:

>I believe that Vertex has the lead compound that will deliver the highest efficacy, cure rate, shortest treatment time, lowest relapse rate, highest success rate for past treatment failures.

that outlook would seem to fall squarely  into the category of 'forward looking statements'.

My objection is that people are choosing *now* between Phase III trials for the two drugs. This is a complicated decision with many factors (placebo risk, rescue drugs, resistance, etc. etc). However, the perception that telaprevir has been demonstrated to be the superior of the two drugs is unfounded, as far as I know.  Schering's last press release definitely was incomplete, as 3xtofar posted in another thread, but the numbers looked very encouraging. A 74% ITT, which may be  80% or better among those who actually completed tx, seems better than any other option currently available to 1s.

mre:
the point of that CD4+CD15+ T cell example was not to make any point about persistent/occult virus but simply to answer the question you raised :

"why would a direct acting antiviral (like telaprevir or boceprevir) enable SOC to "train" the immune system and improve it even more so in less than half the time?"

there are at least at dozen known pathways, of which this is just one example, whereby HCV blocks/impedes the immune response targeted against it. As virus is quickly eliminated by direct-acting STAT drugs the efficacy of the native immune response is restored.

However, I don't think elimination/decimation/eradication are synonymous. For example, elimination could describe the *slow* process by which CD8+ CTLs detect and kill off virus-infected cells, presumably the reason tx  is so excruciatingly long; decimation could describe the eye-popping drop in viral population when stat-C drugs or IFN first clamp down on HCV replication machinery in all infected cells to which the drugs have diffused. Eradication  would be the total absence of any viable virus, still a possible outcome, but one looking progressively more unlikely given the available data.

How long periods of serum-UND during tx support a hypothesis of eradication is not at all clear to me. The explanation seems much simpler. As I've long quibbled with Jim, there's limited value to high-sensitivity VL tests because they measure the wrong thing: they tell you next to nothing about the location and extent of your infected cells. During the short period that VL remain detectable in serum, the  rate  of reduction gives good information about response to meds. Once VL drops off the radar however, nothing short of extracting and testing tissue (ie cells) provides information about infection.

[deputydad]

Well I have put aside my gun and have decided to fight this one with the power of my body. 52 years and counting. I have served and protected this city and have been given this HCV for it.
Contracted it during and bad crime scene that most would not have walked into. Always wear saftey glasses if your cutting down bloody wall boards for evidence.
I kinda didn't want to hear the initial effects but now I can look forward to them and know why they are here.

Deputy DAD

[DoubleDose]

I do believe that the 'poorly thought out rationales' comment swings evenly in both directions.  I, personally, am still trying to keep an open mind, and in spite of your protests to the contrary I seem to see you 'validating' your favored articles and research, while dismissing the awkward, 'nerdy' "lab" stuff as not real world enough.  I guess we just need some 'lab' researchers who are ready to just proclaim the virus 'still there', as some of your 'research article' writers seem to boldly "proclaim" that it is eradicated.

I still don't hear much from you in the way of even-handed consideration of both sides of the argument. (as you glibly describe Willing's and my approach to be)   And just because you 'hear' us as leaning heavily toward the persistence theory, does not mean that this is our only, and irrevocable belief.  Your sensitivities frequently seem overly attuned  to the points of view that you seek to discount as not valid.

I still assert that the vast majority of true scientific "research studies" completed in the past five years, by viral research labs, have concluded with a finding of low level replicating virus.  And, all independently of one and other.  I don't believe that this MUST indicate that their findings are the ultimate truth, but I also don't feel that your discounting and dismissing them, without having any proof of error or mis-interpretation  on their part, is a legitimate position either.  I will wait to see how both sides obviously contradictory findings are ultimately reconciled, or explained.  
Being 'too certain, too soon' opens you to the opportunity to eventually find yourself  'hoist on your own petard'!  I'll remain on the ground with both eyes open, until further data arrives.

DD

[Trinity4]

I just want to add to all the ladies that I did not mean you are any less intelligent. There are so many smart, funny female contributors to this forum.  It just seems most of the discussions like this one are between the guys.  Whew, I hope I cleared that up!!
Trin

[Trinity4]

I read posts like this and it's so intriguing -  a bit beyond me but very interesting.  And then I get to Mre's statement "  So it probably has the capacity to give you a case of the nuclear sh!ts (whereas telaprevir has the leprosy rash).
Well the whole concentration thing is immediately replaced with uncontrollable laughter.
I don't know how you guys do it - seems like the gals stick with more of the basic kind of stuff - even snit back and forth a bit but you guys get into the really really deep heady stuff.  Amazing how the different sexes communicate.  Good job guys.
Trin

[mremeet]

DD - The only reason I decided to take issue with you guys on this matter (on this post and previous ones) is because it appeared to me as if you had become overly invested in the persistence theory. I thought when you guys discussed it, it was as if it was a foregone conclusion that low lying persistence was an irrefutable fact and all that was left to do is a little clean up work. You seem to give the persistence data overwhelming weight, and don't seem to doubt its veracity in the slightest. In many previous posts, you guys do not seem to acknowledge that this data either (1) may be wrong due to experimental error, (2) may be conditionally correct, but has detected something other than truly active replicative virus, or (3) have not given equal time to the overwhelming evidence supporting eradication and how it possibly ties into these seemingly contradictive persistence findings.

My only point is to delve into the oft ignored (on this forum) counter-case for eradication, which based on what I've learned so far, I believe is very substantial (albeit not yet conclusive). And attempt to reconcile these two apparently contradictive bodies of evidence. But due to limitations in my education on this matter, I can't reconcile them. They appear contradictory to me for a whole host of reasons (as we have discussed at length previously). Because they do appear contradictory, and based on the sheer bulk and reliability of the evidence in seeming support for eradication, I’m suspicious that the persistence findings may not be what they appear to be.

More explicitly, if you’re collecting a large body of data, it's normal to sometimes get "outliers". By outliers I mean data that just doesn't fit, or otherwise defies what the common understanding of what's really going on. Once a trend is established and a basic understanding is thought to be established, outlying data (that falls well outside of normal experimental error) is often dismissed as being experimentally erroneous. If the data is believed to be erroneous, it's left out and excluded in the analysis. But sometimes outlying data is not erroneous, and it warrants a closer look. And if nothing can be found wrong with it, the other larger body of data must then be re-examined for legitimacy. And if nothing can be found wrong with that data, then the entire functioning rationale that had been previously accepted must be re-examined. This process must iteratively continue until the issue is resolved, and/or a unified theory is developed that accommodates all sets of seemingly contradictive data. *This* point of fact, I don’t see you and willing struggling with very much. You seem to not be bothered very much at all by these apparently starkly contradictive datasets. You seem to feel favorably about one set of data and basically ignore the other. Or when pressed, present awkward and obviously poorly thought out rationales in an attempt to get back to your “favored data.” Well, there ain’t no favorite data. And if willing is a lab tech and likes lab tests, that’s fine. But just because you’re a lab tech and you work with lab tests and like lab tests, that doesn’t mean that the lab test data is “betterer.” It reminds me of the old adage “When the only tool you have is a hammer, everything looks like a nail". ;-)

MOA – From memory boceprevir had a similar discontinuance rate as telaprevir does. If I remember correctly, gastrointestinal issues were the biggest reason for people quitting. So it probably has the capacity to give you a case of the nuclear sh!ts (whereas telaprevir has the leprosy rash).

And the reason it would be important to treat for 4 weeks prior to introducing the PI is because the PI needs a reasonably good SOC response in the patient in order for it to work. If the SOC response is very slow or lackluster, the PI usually won’t work. And not only will it not work, the person can end up with a PI resistant strain afterwards. So it would be advantageous for the patient to take SOC first for 4 weeks to see how well he/she responds to it. If the patient did not respond well to SOC, then the treatment could be discontinued to prevent a wasted tx and to preclude being left with a PI resistant strain. Or if the patient was responding to SOC, except slowly, the SOC tx (i.e. without the PI) could be extended further (i.e, for 8 or even 12 weeks etc) until an UND status is achieved and then the PI could be introduced. Which theoretically could quickly drive home an SVR with much greater reliability at that point. And do so without the development of PI resistance. Lastly, as you can see from the data posted above, the SVR rates were better for those that did not get the PI for the first 4 weeks (all total tx times being equal). What this means is that you can actually be more likely to SVR by taking *less* medicine. And these PI’s really have significant side effect profiles, so that’s a big win-win right there.

[moahunter]

Now, how does this drug compare side effect wise with Vertex? Also - are we going to see a scenario arise, where patients will try SOC, and if not RVR at 4 weeks, then add an extra drug to the mix? I mean, for a lot of people, why would you go 48 weeks with 3 drugs, when you could go 48 weeks with 2 (or course, a more complicated equation if possible to go 24 weeks with 3).

[DoubleDose]

I agree with you.  Your comments regarding relapse after long periods of undetected are indeed supportive of the eradication scenario.  I also have considered this situation as the other side of the coin, as far as the persistence vs. eradication debate.  Were it not for the numerous research studies that have found replicating low level HCV after SVR, in various places, I would be a 100% supporter of eradication as the obvious answer.  This is whi I remain open minded, to both sides of the debate.

  You make a very good point, and I have also been unable to explain this contradictory viral behavior.  So on the one hand we have an obviously 'blue sky' when you look at the known viral behaviors, and it all seems very clear.  On the other hand, when you put on some glasses and look at the sky (researchers using high amplification tools) it now arppears gray and rainy.  

There are good arguments for both sides, but a lack of explanations for the contradictory findings and behaviors on both sides.  That's why I am waiting for scientists to figure it out, and explain the different study findings so that we all can understand why there is such confusion and disparity in the final conclusions.

Willing:  I will try to find a link to the Egyptian studies later today.  Thanks for your input as well.

DoubleDose

[mremeet]

DD – It is not me making assumptions, or claiming to have absolute proof of eradication, or any of the other red herrings, straw men and false canards you’ve claimed I’ve asserted in your post. All I did was simply point out, yet ANOTHER simple and easily observable treatment/SVR scenario that breezily fits into the eradicative case. And simultaneously appears to contradict the improvement/quarantine theory put forth by you and willing. I’m not claiming absolute proof of anything, simply pointing out yet another small tile in an ever growing mosaic of evidence that eventually will lead to a final proof (one way or another).

Willing: “in brief, unchecked HCV infection overwhelms the ability of the immune system to eliminate the virus.”

Yes, but what about people who are treating with SOC and achieve UND status (using a sensitive PCR) and maintain that status for months and months during their treatment, only to relapse later? This happens all the time and is very common with SOC tx (especially for geno 1). The point being is that the virus is massively subdued (or “eliminated” in your words) for many months while the immune system is ramped up to all get out (presumably being “improved”). It certainly should have the chance to become fully improved during this timeframe, shouldn’t it? And yet when these PI’s are thrown in, suddenly SVR-ing becomes much more likely in half the time. Your explanation certainly doesn’t explain that, whereas simple, brute eradicative power *does.*

“If you can somehow decimate the virus, eg via a PI which only allows variants with a particular mutation to survive, you re-enable the immune response.”

Firstly, I’m a little confused with your choice of words here. “Eliminate” and “decimate?” Do you have something against the word “eradicate?” ;-)  Secondly, your argument here simply ties into a case for eradication, and you even explain it in a way that would lead many readers to interpret it that way. So not sure I’m getting your point in terms of supporting the case for improvement vs eradication. And once again, why wouldn’t an SOC patient who remains UND for months and months during treatment (only to relapse later) have a “re-enabled” immune system as soon as 99.9% of their virus is expunged? But that’s not what we see at all in SOC tx alone, is it? Why is that?

“Here's some detail on one example of this (there are others) which focuses on CD8+ T cells, the ones responsible for killing infected cells:”

Yes thank you for that. But I still don’t see how this supports the improvement theory any more so than a case for simple eradication. Basically all it’s suggesting (indirectly) is that if the viral load is lower, the immune response is likely to be more efficacious and more able to subdue the virus. Apparently you’re under the impression that *that* is not strongly suggestive of an eradicative process when an HCV patient achieves SVR? That’s a non-sequitur if I ever read one.

“Reduce the amount of HCV peptides floating around, the officers come to their senses and the infantry starts doing its job again.”

Once again, you seem to be making a case for eradication, not lasting improvement/quarantine afterwards. And once again you’ll have to explain how SOC tx failures who achieve and maintain an UND status for many months so commonly relapse afterwards when most of their equivalent PI dosed brethren *do not* - even with half the tx duration (as the BCVR and TPVR data has clearly demonstrated).

[Willy50]

"As best I can tell, at this point, the two leading NS3 PIs, seem to yield very similar results.  If anyone knows of any evidence for VX being the more effective of the two it would be interesting to hear about it; given the absence of  rash sx, boceprevir would seem the default choice." -  Willing
=========================================================

It will take about 1.5 years to get the complete results from the Vertex Phase 3 trial for all arms (SOC is 48 weeks + 24 week PCR's),.  According to Vertex (perhaps a half year ago) the trial was to be kept blinded the entire time.

I believe that Vertex has the lead compound that will deliver the highest efficacy, cure rate, shortest treatment time, lowest relapse rate, highest success rate for past treatment failures.  It's weakest point could be the rash issue.  The discontinuation rate is very similar between the two compounds....and yet the boceprevir used rescue drugs while the Vertex trial did not allow them.  One could infer that the discontinuation rate would have been higher with boceprevir if they were not allowed.  Equally. the success rate would have been lower.  Should Vertex use these drugs in the phase 3 trials one could also infer they would see a higher yet SVR rate and a lower discontinuation rate.

Vertex has a 8 week triple therapy arm in Phase 3.  Since the rash doesn't usually become an issue until later in treatment the 8 week triple therapy arms could well have a lower rate of rashes AND anemia.  I don't think there is much question that the Vertex treatment is a tougher regimen..... since they tend to have a similar discontinuation rate in 24 weeks as Boceprevir does with the (4+ 24 week) treatment and (4+48 week) longer treatment.

Personally, I think that the Vertex efficacy has been proven both in treatment failure trials, in their shorter treatment times and their higher success rate in spite of not using the 4 week lead ins or the use of rescue drugs.

On the subject of the range of results.....these trials are still small enough that a few patients can skew results.  It has also been said that the Boceprevir trials had more harder to treat patients and so this could also make comparison harder.  

It has been said by Vertex that for Phase 3 trials...... the FDA wants to see cures.  That suggests that we may see the use of rescue drug(s) allowed in the trials.  Vertex has also had sufficient time to improve their means of treating the sides.  They have said that IF they could keep everybody on full treatment they could see 90% SVR rates.  I would not be surprised if we may continue to see further improved trial results..... that is....IF it weren't for the fact that they maintain that they will keep results blinded.

I am not "up" on the issue of occult HCV but I have wondered if a stronger form of treatment could serve to eliminate.... or neuter the virus more than basic SOC.  Just one more idea to throw into the mix.  IF "occult viral infections" do persist after SVR.... but do so beneath the radar....is it possible that a different form of treatment could render a cleaner form of SVR?  I'd be interested to see if there are differences in the quality of life post TX comparing the groups who do SOC, Boceprevir triple therapy and Telaprevir triple therapy.

I'm still betting on Vertex but I am delighted that the boceprevir is also doing well.

best,
willy

[willing]

vx vs bc : agreed that it's still too early to make any call other than they seem to be very close. And yes, vx may have a small lead (which may or may not grow with data from the  phase III arms)  The closest oranges to oranges comparison that can be made is vx's prove-2  "24-week arm: TVR 750 mg q8h with P/R for 12-weeks, P/R a further 12 weeks" for which results were "24-Week 69%+ 73%+ 65%" at w4, w12 and eot+12, against bc's sprint-1 28 week no lead in "boceprevir in combination with PEGINTRON and REBETOL at the doses described above for 28" for which w4 was 38%, w12 was 69% (from the easl abstracts) and eot+24 was 56% (from the above release).

Still, comparing those arms is neither strictly the same (vx administered for 12, bc for 28, total vx tx was 24 to bc's 28)  nor does it represent the best outcome : bc's w4 rvr jumps from 38% to 62% with 4w lead-in. Total discontinuation rates due to adverse effects for both hover around 10%, but from anecdotal feedback on this forum it seems the vx rash is a bigger threat than bc's "AEs leading to discontinuation in boceprevir-containing arms were fatigue (2%), nausea (2%), depression, neutropenia and anemia (<1% each)".  bc's 74% with lead-in +48 may be as good as it gets, whereas vx's numbers may improve as the phaseIII results come in (disclaimer - I own neither vertex nor schering stock but had a really hard time with psoriasis during my tx)

mremeet: "why would a direct acting antiviral (like telaprevir or boceprevir) enable SOC to "train" the immune system and improve it even more so in less than half the time??"

in brief, unchecked HCV infection overwhelms the ability of the immune system to eliminate the virus. If you can somehow decimate the virus, eg via a PI which only allows variants with a particular mutation to survive, you re-enable the immune response. Here's some detail on one example of this (there are others) which focuses on CD8+ T cells, the ones responsible for killing infected cells:

"Growing evidence suggests that regulatory T-cells play a significant role in the suppression of virus-specific Tcells. For example, in chronically HCV-infected patients, CD4qCD25q T-cells have been found at a higher frequency compared to individuals with resolved HCV infection or healthy controls (Sugimoto et al., 2003; Cabrera et al., 2004; Boettler et al., 2005). These regulatory T-cells
suppress the proliferation and IFN-g secretion of virus-specific CD8q T-cells in vitro. Suppression by
CD4qCD25q T-cells was shown to depend on cell-cell contact (Cabrera et al., 2004; Boettler et al., 2005) and was independent of suppressive cytokines such as IL-10 and TGF-b in some (Boettler et al., 2005; Rushbrook et al., 2005) but not all studies (Cabrera et al., 2004). Interestingly, the suppression was not restricted to HCV-specific CD8q T-cells, but included CD8q T-cells specific for other viruses, such as Epstein-Barr virus and influenza (Boettler et al., 2005; Rushbrook et al., 2005). However,
specificity in vivo might be mediated by the enrichment of CD4qCD25q T-cells in the liver (Ward et al., 2007), where they might limit immunopathology in the chronic phase of HCV infection. The mechanisms responsible for the induction of CD4qCD25q regulatory T-cells are still poorly understood, however. It has been shown that they can be induced by certain HCV peptides in peripheral blood mononuclear cells (PBMCs) from HCV-infected, but not healthy, individuals in vitro (Li et al., 2007)."

from  http://www.ncbi.nlm.nih.gov/pubmed/18321220

in English, immune (infantry) CD8+ T cells are susceptible to the effects of other, regulatory,  CD4+CD25+ T cells  (officers). However these officers  can be influenced by the presence of HCV peptides. Reduce the amount of HCV peptides floating around, the officers come to their senses and the infantry starts doing its job again.

DD: do you have a link to that Egyptian study on familial transmission based on flow-cytometry data ? I can't remember the authors - thanks.

[DoubleDose]

So I see it is you making the assumptions throughout your replies above.  Just because an antiviral helps speed the viral load reduction process has very little bearing on whether or not the immune system 'takes over' after a low enough level of virus is reached.  I do not see how your comments offer any proof one way or the other that the immune system is not involved after ending tx, if indeed there turns out to be a 'secretive, or unseen' persistent viral mechanism at work...call it a virus in remission, or a 'controlled' virus.  Your rationale escapes me, but, again, I am not trying to offer 'proof' that viral persistence is a fact, as you seem to be trying to accomplish with the converse side of the issue...wishing to claim it a proven fact that the virus is totally and irrevocably eradicated.  

My position is that we must continue to study the issue, and ask these questions, if only because a great many HCV researchers (who probably know quite a bit more about this issue than you and I combined) seem to keep finding 'hard' clinical evidence of ongoing viral replication, years down the road after SVR, and also after spontaneous resolution.  I am not trying to debate with you, or win points for the debate, but to find the ultimate truth about the virus.  I am not nearly so concerned with trying to construct theoretical arguments, as you use above, to disprove your logic.  If the virus is really eradicated, that's wonderful news.  If its still lurking there, somewhere, under the radar, then I want to have some objective proof, and consensus among the leading world researchers, as well.  I have no axe to grind.  

Claiming that your opinions are in fact 'more valid' using this line of logic, and theory, does not even begin to trump all of the clinical evidence, and research to date demonstrating replicating HCV...by any stretch of the imagination.  Until the studies showing evidence of surviving HCV after SVR are refuted, proven wrong, or withdrawn by their authors due to some error, or mistaken conclusion, I will insist on keeping a very open mind.  You can come to whatever conclusions you wish to...its a free world.  If you want to insist that eradication is a proven fact...then you can state this belief all day long...and I am just fine with it.  Its your right, on this forum.  I am less certain of the realities.

DoubleDose

[frijole]

Ahh, so this is where the fun is.  Cando clued me in but I had to hunt the thread down, already dispatched to page 2.  Much more interesting than vegetables.

The one thing that stands out to me in these Boceprevir results is the 38% SVR for the control arm for 48 weeks - only 39 of 104 patients cleared.  Why so low?  I don't understand that but it sure makes the BOC arms look good.  Anyone seen any data on that?

Okay - so the Lead in arm is the best -- this is INF + RBV for 4 weeks, then add the BOC for the remaining 44 weeks - and the SVR rate is 74% after 12 weeks post treatment.  All these results are called SVR 12 as compared with the normal SVR 24 (6 months post treatment).

The results are very promising for what they call RVR.  If I read this right RVR is not 4 weeks but actually 8 weeks -- With the lead in arm, that means 4 weeks INF+RBV and 4 weeks of INF+RBV+BOC.  In those cases - if you have RVR at the end of the 8 week period, the SVR rate was 92% for 48 weeks and 82% for 28 weeks of total treatment.  Now that is exciting but it all hinges on what the BOC is able to do after the INF+RBV has lead the charge.  

I have been leaning heavily toward the Vertex trial, but the fact that Boceprevir allows rescue drugs is a mark in their column.  I appreciate this discussion as a method for decision making.  Willing, I appreciate your pointing out that, as a news article, the data is skewed, not mentioning the low dose RBV arm.

Thanks to all
frijole

[Mr Liver]

My first shot took about the same course yours did. I had blankets layered on me shaking uncontrollaby, and I could not get my teeth to quit chattering. This was almost 9 years ago and I knew virtually nothing about HCV at that time. I was surprised early on in tx to learn that the way you feel when you do actually have the flu is the result of the immune responses, and not through any direct action by the flu virus itself. That first shot and my reaction all made sense now.

I don't think there is any doubt that the immune stimulating properties of IFN start as soon as its reaches the bloodstream. There are quite a few studies done in the past that have shown that injected IFN starts a chemical signaling process within the first several hours after the injection.

Thanks for the post.
ML

[foofighter]

I got a call from a trial coodinator today for this next Boceprevir trial saying they will be screening in September (hoping to start people in Oct.-Dec.).

NCT00705432

She said that they will allow rescue drugs and that even though my platelets are below 100 that there's a 10% window there. Never have heard that before. And she was excited to talk to me. Happy with my knowledge and thought I would be a good candidate, so we will see what shakes out. My plan was to do SOC with Alinia in the fall, but maybe I should go for this one.

No Vertex trial near me, so I guess it's the next best thing!

Foo