stopping telaprevir at 4wks if VL >1000

[his3707]

I am in the telaprevir dosing trial.  becuase of a recent post about having to stop trial because the viral load was over 1000 prompted me to call my study doc and get an explaination and a possible back up plan.   This was the reply

That is a long explanation.
The short answer is that even when the drugs are available on the market, the guidelines will be to stop VX950 if viral count high at week 4 (FDA has not given those guidelines out yet, but expected to be either >1000 Iu/mL or >100 IU/mL).  The issue is that VX950 has done its job but the interferon and ribavirin has not been able to eliminate the mutations.  The fear is there will be further mutations of virus.  We don’t’ know the impact of those mutations down the road with newer treatments that will be coming.  We don’t want to set patients for mutations that will prevent future therapy from being effective.

So no, we would not be continuing VX950 after a week 4 viral count >1000.  You could continue Peg/RBV to see if it could finish the job.

[spectda]

In the boceprevir trials they consider more then 1 log drop in the 4 week SOC lead in period to be predicative of higher SVR rates.

http://hepatitiscnewdrugs.blogspot.com/2011/04/boceprevir-four-week-lead-in-response.html
"HCV-RNA decline after 4-week PR lead-in period helped predict
likelihood of SVR
In pre-specified analyses [Poster #481], researchers evaluated
the relationship between decline in levels of virus (HCV-RNA) after
the 4-week PR lead-in period to overall SVR.
In the HCV SPRINT-2 treatment-naïve study, patients
receiving VICTRELIS who had good response after the 4-week lead-in
period, defined by a greater than or equal to 1.0-log10
decline in HCV-RNA , achieved SVR rates of 81 percent (203/252) in
the RGT arm and 79 percent (200/254) in the 48-week treatment arm
compared to 51 percent (133/260) in the PR control arm. Patients
with poor response after the 4-week lead-in, defined by a less than
1.0-log10 decline in HCV-RNA, achieved SVR rates of 28
percent (27/97) in the RGT arm and 38 percent (36/95) in the
48-week treatment arm compared to 4 percent (3/83) in the PR
control arm."

[evangelin]

If you do the lead in, how much of a drop would you need to see to warrant adding the PI?


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For the anemia sufferers:

At Joe's last appointment, I brought up the problem of the anemia.  Joe had to take so much Procrit to stay out of trouble last time.  Because of the warnings on this drug, I am just as uneasy risking more Procrit as I am more interferon.  The P.A. told me that D alpha tocopherol ( type of vit E) helped with the anemia as shown in a trial.  She said it was necessary to take a high dose and start it quite a while before starting TX.  She didn't know the particulars.  I haven't for sure been able to find the trial she is speaking of.  I called today and asked for a more specific recommendation because his next appt. is in July.  On the outside chance that Joe does decide to try the PI, I want to have the right  D alpha tocopherol dose in place.  The word I got was to have him take 400 IU's for a month and then up it to 800 IU's for the approx, month remaining before she sees us.  I just thought I would pass this along for anyone else with big anemia issues.  Because of cirrhosis, Joe's hgb is below normal even when not on TX so I guess this is why it hits him so hard.  I don't know how much this might help but it should be safe to try. Couldn't be worse than al that procrit, not to mention a blood tranfusion.

We are still on the see-saw on whether to try or wait for the next generation.
Ev

[Trish77]

"I personally wouldn't want to risk stopping tx after 4 weeks of using boceprevir or telaprevir on the premise that the resistance variants will return to wildtype promptly and allow for successful re-treatment with other DAAs unless I had a medically urgent need to take that risk. "

I don't believe that's quite the premise for stopping after 4 weeks if <1000. Resistant variants don't return to wild type promptly, which is the issue - well, I don't consider two years promptly.  It takes, from what I understand, 2 years in most cases with regards to Telaprevir and your data suggests it's longer for some. What I've read on Boceprevir so far is that it's been studied at 3 years past exposure and resistant variants still remained. So, the way I understand it, I think the premise is to prevent too many resistant mutations from being created rather than the thinking that they return to wild-type promptly.  Other DAA's with a different resistance profile would actually be able to deal with Telaprevir's resistant variants so it's not that it's they need to return to wild-type either.  However, you still want to avoid creating any kind of resistant variants as much as possible to keep options open rather than narrow them.  That's the way I understand it.

"My question would be less about continuing with a PI past 4 weeks, and more about why introduce the PI to begin with if a person has poor response to soc and they can afford to wait for a better combo of drugs with less possibility of resistance and and a better chance of success. "

I sort of see that the other way around.  You might not need to introduce a PI if you are a treatment naive Geno 1 and early stage liver damage and you do a 4 week lead-in and you achieve RVR or eRVR even.  You've suddenly increased your chances to similar as if you added a PI - minus the cost and the resistance issues.  If you have a poor response to SOC, you need the extra firepower of a PI more.  Then you will want to see how you make out once you add a PI and when you go UND.  Throw in the different variables and what the response to that 4 week lead-in means differs per scenario.

[spectda]

"I personally wouldn't want to risk stopping tx after 4 weeks of using boceprevir or telaprevir on the premise that the resistance variants will return to wildtype"

I meant to say:
I personally wouldn't want to risk stopping tx after 4 weeks of using boceprevir or telaprevir on the premise that the resistance variants will return to wildtype promptly and allow for successful re-treatment with other DAAs unless I had a medically urgent need to take that risk.
-Dave

[spectda]

Although it makes sense to my unscientific mind that the longer you unsuccessfully continue treatment with boeprevir or telaprevir the greater the chance for creating more durable variants. I personally wouldn't want to risk stopping tx after 4 weeks of using boceprevir or telaprevir on the premise that the resistance variants will return to wildtype

Unless I had a medically urgent need to take that risk. My question would be less about continuing with a PI past 4 weeks, and more about why introduce the PI to begin with if a person has poor response to soc and they can afford to wait for a better combo of drugs with less possibility of resistance and and a better chance of success.

Willing made many good points about using a lead-in before adding a PI. I hope you don't mind me quoting you Willing, but your comments were so well put as usual and they really convinced me of the benefit of understanding interferon response before adding a PI, especially since the data seems to show that the ILB28 test does not necessarily correlate with success.

http://www.medhelp.org/posts/Hepatitis-C/Telaprevir---18-yes-0-no/show/1510853
"The benefit of lead in is not a significant improvement in outcome - but critical information about what your personal SVR odds are with triple tx before the first PI pill.  Relapsers don't need to bother,  but anyone with a weak past response who is uncertain about whether it's worth trying  will benefit."

[spectda]

http://www.natap.org/2010/AASLD/AASLD_66.htm

"Some comments from several noted researchers/clinicians regarding drug resistance:

"Since there is no long term repository in HCV, the implications of "hidden" resistance are not the same. Even if resistance is present at 0.5%, repeat treatment with TVR would quickly knock out 99.5% of virus. Whether the residual resistant virus is 0.5% or 0.00005%, if you don't have another set of drugs (IFN,RBV, DAA) that can wipe out the residual population, it will grow up."

"these patients are still likely enriched for PI resistant variants, so they may still be at risk for breakthroughs with future treatment containing PIs, but would the mutations now emerge more strongly and quickly? It's hard to tell, only time and further clinical testing will tell. At the very least, the findings suggest that there will be a relatively sizable lag period for recovery of original repertoire."

"Good to see the result, but we still don't know whether enough resistance remains to affect re-treatment response. So, the really important clinical question is unresolved, and the result we have isnt surprising. Its good the result wasn't worse. I think we have an encouraging result. Clinicians and patients NEED to be thinking about resistance (to motivate best practices).... .....Next-generation sequencing ("deep sequencing", e.g. with a 454 machine) would probably be more sensitive - detect resistant variants at a lower frequency - but clonal sequencing is probably enough for this purpose. Next steps are (a) study larger numbers of people in the same way, but more frequently and for longer follow-up, to determine the range of decay rates of the resistant forms, and (b) re-treat with close follow-up to determine whether resistance will re-emerge at a high rate. Coupling (a) with (b) will guide the use (or uselessness) of resistance testing in the future. My sense is that the risk of resistance is never zero, so all we're asking is whether the risk returns to pre-treatment levels. Reasons that might not happen (i.e. enhanced risk) include (i) levels of resistant virus are higher, to a clinically significant degree, after unsuccessful treatment, and (ii) resistance mutations return to baseline but compensatory mutations, which make resistant virus more fit, are at a higher level and contribute to emergence of resistance with retreatment." "

[spectda]

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252561.pdf

page 13 and 14:

"Persistence of Telaprevir Resistant Variants/Follow-up Analysis
Study 112 is an on-going, 3-year, virology follow-up study in subjects previously treated with telaprevir from Phase 2 clinical trials. In this study, changes in telaprevir resistance- associated HCV variants over time are evaluated in subjects who did not achieve an SVR24 and had developed one or more telaprevir resistance-associated substitutions. In this interim analysis, follow-up periods in Study 112 range from 5 - 40 months with a median of 25 months. A total of 56 subjects were used for the analysis of persistence of resistant variants V36A/M/L, T54S/A, R155T/K/I, and A156S/T in the absence of telaprevir selection. Figure 4 shows the percentage of variants (V36M, T54A and S, R155K, and A156S or T or N) that were no longer detectable by population nucleotide sequencing at 6, 18, 24 and 36 months with the caveat that the follow-up data were limited and incomplete. Variants expressing one or more telaprevir substitutions remained detectable (i.e., present at >25% of the viral population) in some subjects at 24 months. By 36 months, V36M, T54S or A, and A156S/T/N variants had fallen below the level of detection in all subjects.

Three percent of the subject isolates that had the R155K variant still had detectable R155K variants by population sequencing at 36 months. Lack of detection of a substitution based on a population-based assay does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment.

[willbb]

provided we proceed with an appropriate measure of circumspection."

I think they always measure you when this procedure is done :) Ouch

[researchmonkey326]

That's what I meant I surely don't want to discontinue tx with as well as I am doing. I was playing devil's advocate regarding being yanked at 4 wks particularly as close as I was. Thankfully my trial's protocol does not call for that.

[Trish77]

Aside from PI's, I would not stop at 4 weeks as a general rule either.  Only 20% or so of Gen 1 RVR but just under 50% SVR on the first round.  It matters when you go UND.  RVR is the best indicator but not the only indicator of SVR.

With the PI's, it introduces a whole other layer of complexity.  The concern with the PI is that mutated virus will be created that will not be eliminated if there is no SVR.  So the longer you go with a PI compared with a lower chance of SVR makes for the increased environment for mutated virus.  Generally, the mutations are not as strong as wild-type.  So it's not so much that the SOC hasn't eliminated the mutation but that the PI and SOC have not eliminated the wild, allowing for mutations to continue occuring.  

I'm not sure I agree with a hard and fast rule of stopping at 4 weeks if not <1000, I would continue to test for UND at 6 and 8 and see where the decline is.  It would be a balance between the probability of eliminating the virus entirely within the weeks after week 4 or the probability of virus and mutations remaining.

Having said that, mutations get weaker over time and Telaprevir mutations seem to disappear after about two years.  Just the same, the concern is the unknown and that mutations may have the ability to become as strong as wild-type virus.  This is all new territory so there may be more caution than necessary and it's a whole new world with regards to treatment and PI's.  I'm sure it will evolve over time as more is known.

http://www.natap.org/2011/HCV/021611_05.htm

"Great care will be necessary to counsel against unnecessary therapy in persons who have low likelihood of responding to PEG/RBV and a PI, including those persons with prior null response to PEG/RBV, and limited hepatic fibrosis. We will therefore likely require a substantial re-education campaign for providers in the coming years. The future appears bright, provided we proceed with an appropriate measure of circumspection."

Seems a hopeful note to me.

[Diane12855]

I disagree. My VL at 4 weeks was 1200 (down from 6 mil). By 12 weeks I was UND and I am still UND at 2 months post tx.

We need to be careful when we are telling someone to stop tx before the guidelines say we should with SOC. All that I read said that with SOC we stop at 12 weeks if not UND.

Diane

[researchmonkey326]

I understand what you are saying and I have been concerned that because I was not und at four weeks that my tx would not be successful and jeopardize future treatment.  But where does one draw the line?  My vl at four weeks was <25 detected.  Do I stop treatment at that point when it is so close that I feel like I could have been und had the test been done the next day?  Maybe treatment should be stopped at that point regardless of vl if it is not und.  What I have to remind myself is that I am in a trial and the primary goal is not to cure me but to study the drugs.  What my body is going through due to treatment is not the main concern of the phamaceutical company.  Anyway, those of us in trials might benefit from being in them but we know going in that we might not.  Of course, we do have the option of dropping out at any time for any reason if we so choose.

[copyman]

Makes perfect sense to me. People that do not have cirrhosis should stop treating if not Und at 4 weeks. With or without one of the new PI's.
Why put your body through excessive TX for nothing, with a good chance pf permanent side effects!

Quit if not und at 4 weeks, recover (shouldn't take long with only 4 weeks of tx), regroup, and re-treat with a different new drug.

Just a thought.......

[spectda]

I don't get it, why not use a lead in then to determine interferon response before allowing a PI?  Is there data that stopping at 4 weeks will create less resistance then stopping at more then 4 weeks?  
-Dave

[his3707]

I also asked if it didnt work, how long would I have to wait to retreat.  This is the second part of the reply

we are still learning.  The interferon and ribavirin are both critical (only a few people would respond without them).  High viral load has not been identified as a variable that makes a difference in the response.  Even the IL28B SNP type does not seem to make a difference (at least not in the studies to date).    Remember the VX950 works by interfering with an enzyme that the virus needs to make copies.  So the VX950 works very well by itself, just needs a little help