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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.
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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.
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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.  

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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
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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?  
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"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
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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.
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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?

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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

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

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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
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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
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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
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" 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.
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"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.
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Got it, thanks!
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"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.
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>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.
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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.
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"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    
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"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    
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"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

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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
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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."
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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      


    
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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.
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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?
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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.
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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)
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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?  
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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.
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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.  
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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.
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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  
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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.  
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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

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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%.
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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.  
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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.
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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.



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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  


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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.  
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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.
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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.
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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
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