switching PIs in mid-stream?

[willing]

from posts it seems people are starting to make their triple tx plans for the summer. I'm seeing my Dr for a w24 half-way checkup in a bit and will be going over the upcoming  PI rx. Last time he indicated he was happy to write an rx for either tela or boce immediately after approval.

My latest thought is to start with Tela and switch to Boce if the rash is more than I can stand. The main reason is that I know what the anemia will be like but might get lucky with the rash and given that I'm starting late the shorter, 12w, tela duration seems a plus. From reviewing the data, the choice seems to come down to picking your sides. This type of switch was obviously not an option in the trials but should not be a problem now. The two drugs   target the same active site of the same viral protein in exactly the same way so given a couple  of days of overlap the switch should yield no reduction in  the selective pressure on WT virus.

Anyone ask their Drs' about this option or have thoughts on the topic?

[willing]

dointime: any credit is due to your honest posts about preferring to get thrown under a bus than face that rash again. Gives a reader  something to think about. I figure I can handle getting thrown under a golf cart but I'm going to draw the line at buses and cement trucks.

it'sallgood: I know I asked my derma before tx about whether there was anything I could do ahead of time to ward off psoriasis flares and his answer was no. But if you hear anything please post - this may soon be a popular topic.

[it'sallgood]

thank you so much for posting and also to all those who responded. i've wondered about switching PIs to deal with side effects, assuming both Boce and Tela are approved. the same question could be asked about the possibility of switching from Boce to Tela after anemia arises.

i've also wondered about adding a antihistamine or other drug to the regimen in order to head off the rash before it starts. does anyone know what the liver docs are prescribing to help with the tela rash form hell?

eric

[dointime]

I would have thought that the viral kinetics information for both tela and boce would be available by now.  That should be enough to tell you what the appropriate overlap should be.  

I think your idea of switching PI's is innovative and could be of use to anybody who develops a tela rash.  It is certainly worth pursuing, despite the challenge.  I think that this is the first acceptable response that anybody has suggested for what to do about a showstopper tela rash and you should give yourself a pat on the back,

dointime    

[willing]

all: first, many thanks for the good wishes. No idea whether it'll work.. but worth a try.

dointime/foofighter: you're quite right, it *is* a no brainer, but  at the moment that doesn't make it less of a challenge! The two main issues I see are (a) overlap period and (b) insco  approval. From the PI dosing requirements we know constant PI pressure is key. So stopping for a few days while switching PI would not be a good idea. But is 48-72h of overlap enough? Re the inscos I can see fighting to get approval for one and then having to call back to say no, never mind, I need the other...As lovebird noted, let's hope this just doesn't come up.

I'm less worried about resistance even if  vl will not be measurable. It seems reasonable that viral subspecies become extinct in order of fitness under the pressure of soc,  so there should be far fewer unfit but PI resistant virions left now than there were 6 months ago.

[foofighter]

As far as long lead-in, during initial visit for sprint 2 trial, when i asked about rollover for placebo arm, i asked if it would start immediately (24 or 28 weeks i think). Doc said he wasn't sure but thought right away.

It never happened for anyone as they ran out of bocep, only had drugs for study participants.Or so they said, who knows for sure. I think it was bill1028 who rolled many weeks later.

Anyway, I think your plan is gonna get you svr. Go for it.

[dointime]

Just a word about resistance.  I am sure that you have researched this yourself already.  Boca and tela produce more or less the same resistant variants except that boca has one more exclusive to it.  So by introducing the boca you would be running the risk of getting one extra resistant variant.  That has to be weighed against the increased odds of SVR by switching to the boca.  As you are a previous relapser you have a much increased  chance of SVR this time around by using a PI for the full length of time.

If you were not to succeed this time around then your planB would probably be the same whether you had switched to the boca or not, ie. you would be treating with 2 PI's next time, neither of which targeted the ns3.  So what I am saying is that I don't see that you have anything to lose by switching to the boca, even considering the consequences of resistance to retreatment.

dointime




  

[dointime]

Hi there willing,

The way I see it, you are already committed to the SOC and to a PI.  Your reasons for going this way and for choosing the tela are sound.

So supposing you get into the tela phase and you do develop a showstopper rash then what are you going to do?  If your choices at that point are to stop the PI or switch to boca then that seems like a no brainer to me.  Ofcourse you switch to the boca and you keep after those little b*ggers until you've dug all their graves 3 times over,

Just my 2 cents worth,
dointime    

[child24angel]

Thank you willing.
I have friends that are going to be treating in the
future and I appreciate your imput.

[Bali05]

SVR rates were similar between tx arms of study C210
I doubt it will be pursuit.
Did you ever see any data on TCM435 and GT4 ?
It must exist. I read they did some preliminary studies and GT4 responded strongly
to it. TCM435 is currently in phase 3 with GT1 of course as usual....
Also would like to know if previous Tela exposure could be a problem for TCM435.

[lovebird99]

Thank you.  I hope neither of us will have to switch PIs.

[Bali05]

thanks willing , I am familiar with that study

[willing]

lovebird99: not sure whether that journal entry related to  your question, but here's another couple of thoughts. Uncertainty is hard to deal with but it helps to be clear about what to be uncertain about. Though it's common to see comments in journals along the lines of 'the mechanism of action of rbv is unclear' or 'of the hundreds of interferon-stimulated genes only a fraction are understood', one comment you'll never see is 'the mechanism of action of PIs in unclear'. The PI-virus interaction is now mapped   atom-by-atom - some gory details are in an article spectda linked recently:
http://natap.org/2010/HCV/022810_01.htm

So anytime you put tela/boce in proximity to wild-type virus you can expect a decline in their number, whether it's the first or last day of tx. Selection of  resistance is always an issue but should be less so later in tx - the resistant virions are less-fit and thus the most likely to die  off during months of soc-only lead-in.  

Your plan sounds right on target - tela definitely seems the right call. I think the main issue with switching if necessary would be the inscos - as long as there was enough overlap between the two PIs the selective pressure on the virus shouldn't change. From the virus' perspective it's basically the same drug.

Bali : here's what Pawlotsky had to say about g4s, tela "has modest activity on genotype 4 " citing :
Benhamou Y, Moussali J, Ratziu V, Lebray P, Gysen V, De Backer K, Ghys A,
et al. Results of a proof of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 4 HCV patients. J Hepatol 2009;50 (suppl. 1):S6.

[willing]

whoa .. this one sure went fubar. . I posted a journal entry :

http://www.medhelp.org/user_journals/show/281461/a-tale-of-two-winkies

that might help explain why I feel comfortable adding a PI later in tx and relying on  soc-enhancing adjuncts like ntz and higher dose rbv. This is not a last minute decision - I timed the start of my tx with planned PI availability by July and have worked through all this with my Dr. Obviously it's all a crap shoot,  but in my case I believe it made more sense to avoid further delay than to wait and get the full benefit of the PI (by adding it at the start).  I wouldn't recommend the approach  to anyone except others who expect to be on tx during PI approval (carmencita, uncledudeness, etc.). Apart from the sides and expense there's little to lose and potentially something to gain in way of reduced relapse risk.

However the question in this thread was not about adding a PI during tx, but about switching PIs. That issue may affect may more people - ie you plan on tela boce and then get hammered by the rash or the anemia - do you quit the PI or switch?

GD : sorry about infringing on your rebranding copyright. I hope it's a big, big, success.
Dora: what, no asterisks ?

[Bali05]

Tela and Boc overlap.If one does not work the other might not either. Has to do with
how they attack the virus the same way.
Willing is interested in switching "mid-stream" in case of of severe sx (rash,anemia...)

[lovebird99]

Maybe the question is too personal.  If not, I hope don't mind sharing what you do about the fear and uncertainty.  I need help with that part of it too, not just the science.  The science is important I know, but its the human, feet of clay aspect of it that is on my mind right now.  Thanks for any help you can offer.

[DoraExplora]

Boceprevir has a 4 week lead in and is administered until the end of treatment.

[jusjames]

bocep has a 12 wk lead in so why not add at the end, go for it

[nygirl7]

Nobody wants anybody left with  this cr-a-pp-y-a-ss disease. Cutting edge is one thing but it could cost a lot in the end. maybe play it safe in the middle if you have to.......?????

[lovebird99]

"One thing that never, ever, entered my mind was that the merits of their arguments, or their sincere desire to be of service, was tempered by the fact that it was my skin in the game and not theirs. If you feel that way, that's entirely your business - but to my thinking that's prbably where you should keep it. Speculating that someone's well-intentioned contributions should be discounted because of their more optimistic health status strikes me as going beyond cynical, touches upon defamation, and carries the taint of envy. It don't look good on you."

You seem to have missed my point.  Its not that anything should be discounted.  But if you go back and read the question I put to willing, I ask how he finds the courage within himself.  I say its an intellectual exercise for someone not having to make the decision for themself because they can't very well tell me how they found the courage.  Its not cynical, defamatory or envious, its just that willing is the one who had to drill down and find it within him to do this so I think his answer might help me.

I'm terrified I'm going to get this wrong and die a horrible death.  I'm looking for information, help, inspiration and instead I get judgment.  Thanks so much all of you.  Looks like you think its more important to pass out stars and best answers and be popular around here than to be supportive to someone who is sick.

Thanks very much.

[Bali05]

I looked into adding Tela at the tail end of tx myself . Only problem I am GT4
and the only trial that exists with only 20 something people did not improve SVR
and I am at 48wks now.
However I did think about this possibility for quite some time before results for GT4 were made public and spoke to my
hepatologist about it. He has a cirrhotic GT1 currently on tx and he is waiting
for Tela to become available so he can use it on him tail end.
Also a friend of mine was told by a different hepa that this could be done.
All I am saying is , it is not just Willing thinking of doing this the first time
there are most likely many others .
I can see a patient and hepatologist wanting to try this when  the patient had a previous
failed treatment and advanced stage disease.

[GoofyDad]

I'm going to get uncharacteristically serious for a second. When I treated, I was stage 4, had a 1st grader who needed a Dad, was going to be laid off in a little over a year, among other compelling reasons that made me want to clear the virus.

I had a rough treatment that took a physical toll. That's not unusual for cirrohtics who treat with SOC. I was lucky and had an RVR  (GT 3a). At 26 weeks my super hepatologist wanted me to stop - after signing  me up for 48 weeks originally. He left the decision up to me, but felt in my case the drug exposure risks outweighed the odds improvements of continuing.

This was a gut wrenching time for me. There was a dirth of data upon which to base this decision. I contacted a researcher who published a relevant work in Sweeden, and also purchased other studies that had relapse rates for GT3s, RVRs, and Cirrhotics. There were some really smart people here who debated and gave me council. Some were in the "Are you freakin' nutz, you have ccirrosis, you need to treat till the drugs kill you camp." Others were more forgiving. I will be forever be grateful for the time and energy these strangers gave me, and the emotional investments they made on by behalf.  

One thing that never, ever, entered my mind was that the merits of their arguments, or their sincere desire to be of service, was tempered by the fact that it was my skin in the game and not theirs. If you feel that way, that's entirely your business - but to my thinking that's prbably where you should keep it. Speculating that someone's well-intentioned contributions should be discounted because of their more optimistic health status strikes me as going beyond cynical, touches upon defamation, and carries the taint of envy. It don't look good on you.

OK - back to the fart jokes.

[lovebird99]

No need to put words in my mouth.  I don't suggest anybody comes here just for intellectual exercise.  I just said that if you're SVR you don't have to face these questions about your own health.  Debating possible outcomes is dead serious to me because I have to roll the dice again.  You already won your war with hep c, I still have the battle ahead of me.  See the difference?

As for gratitude for help received, nobody questioned your gratitude or your motives (or anybody else's).  I'm saying what I think - resistance to the PIs is not a risk you are going to have to take.  If you don't have to face the risk then it IS an intellectual exercise, something you can debate without exposing yourself to harm. I'm sure its easier to assure yourself that resistance is not an important factor because you don't have a dog in this fight.  

I think the risk of resistance is important.  You have said that you don't think its significant and for you its not, but you are already safe and I am not so its no wonder I see the risk differently.  I'm not sitting on the sidelines talking about interesting theories.  I'm trying to get the answer to some questions in hope that I will be able to make the decisions that will give me the best chance.  I want to get rid of this virus, that's why I am asking questions.  Its nothing to do with anything except I want to win this time around.  I got my butt kicked pretty bad last time and it turned out to be all for nothing.  I want better odds this time and I think the PIs are going to give me better odds but since there's still the possibility of failure I want to consider absolutely everything that could affect the outcome.  Even though you say its not all that risky I still plan to consider anything that COULD lessen my chance to get SVR someday.  My liver is in worse shape now than it was in 2006 when I first started treatment. I don't have nearly as good insurance coverage this time and I spent all my money on the last treatment.  Since then I have been trying to play catch up and these are lousy economic times to be doing that.  I don't have much room for error either financially or medically.  

I'm not here to pick a fight, I want information. Its not a zero sum game.   I'm just asking willing about his process, and that's a question only willing can answer.

[eureka254]

It may be that in the future the hcv community can actually thank willing for being a part of retrospective research data on adding PIs during tx.

Goofy Dad:
In the immortal words of Dirty Harry, "So what about you, do you feel lucky?"
-----------------
In the immortal thoughts of Dirty Goofy, if you feel lucky, do you get lucky?  
Or is that outside the box thinking?