Tx combos - dealing with resistance

[dointime]

Hi All,
I'd like to follow up on some very interesting points made in this thread:
http://www.medhelp.org/posts/show/554160

When telaprevir first started trials there was a belief that the best way to beat the virus was to hit it hard and fast up front with everything in the tool box.  RVR (UND in 4 weeks) was - and still is to an extent - the holy grail).  I understood the science to be that of closing as many doors as possible at the same time so that none of the viral mutations present could escape.  

The above thread discusses a different approach.  Forget for the moment the idea of pre-dosing alinia and SOC in order to bring the drug saturation in the body up to full potency.  I am interested in the the idea of using some of the combo drugs to get to UND before using the big guns (new drugs) to finish the job off.  It is a new one on me - but it makes sense - that with a smaller breeding pool there will be less chance of a viable resistant mutant being present.  There's also the idea of weakening the virus first and then hitting it hard, ie. saving one of the big guns for the coup de grace on the stragglers, even late into tx.  Ofcourse in my case that would have to be before my houdini-type virus staged it's customary breakthrough.

I know the drugs are not here quite yet but naturally I am thinking of my next tx attempt and how best to play it, ie. hit it hard up front or stage the drugs?  These 2 approaches seem to be conflicting but both make sense to me.  From the point of view of killing the virus but not myself in the process it would be nice if the drugs could be staged while not losing efficacy.  I am one of those who had a weak SOC response, probably due to low riba absorption.  I also get a rash from just looking at the drugs.  So I find the up front shock-and-awe approach that some brave souls here are currently undergoing, daunting to say the least.

Comments welcome please,

dointime                  

      

[susan400]

It would all depend on the trial site and the doctor running the trial.  Since the Debio people are paying for the SOC as well as all the labwork involved as long as I'm on the SOC, anything that I would do like that, would have to be authorized by them as being okay, otherwise I wouldn't be allowed to do it and still remain in the trial and having everything covered by them.  Susan400

[dointime]

Susan - wow, feet and leg cramps, sounds kinda fun - NOT.  Is there no end to the tribulations we have to go through.  I am so hoping to hear that you get the 2-log drop and can continue, also that you can get alinia at the first possible time the trial will allow.  

Orleans - I'm no expert on this stuff but I found this link on cell lines:
http://www.pnas.org/cgi/content/full/102/28/9739  

What I make of it is that the tizoxanide resistance occurs from changes that it makes to a part of the liver cells, and those changes are permanent and carry over to subsequent treatments.  The best news is that this study is saying that the changes make subsequent interferon tx more effective, so you get the benefit of the nitazoxanide forever although you only dose it once - a bit like a vaccine.  

That's just my interpretation, maybe others will understand more.  If this is true then we could all go dose up on alinia now and get that bit out of the way before our next tx!  It might keep our VL down by making our own immune system interferon more effective.  But before I get really excited about this I'd like to read the complete study.  Do you have a link for it please?

dointime  

[orleans]

I was hoping someone (dointime?) might comment on this. What do they mean "resistance is conferred by changes in the cell line, not by mutations in the HCV replicon" Are they saying that SOME of the virons are already resistant and come forward as the non-resistant die off?
"Resistance

Researchers also reported results from a laboratory study of the potential for development of resistance to nitazoxanide and its primary metabolite, tizoxanide. Huh-7 cells harboring HCV replicons were exposed to increasing concentrations of nitazoxanide and tizoxanide.

Based on their findings, they concluded that tizoxanide resistance can be generated in HCV replicon-containing cell lines, but that development of resistance to nitazoxanide or tizoxanide did not induce resistance to interferon or ribavirin. In fact, treatment of HCV replicon cells with tizoxanide heightened the antiviral effect of subsequent interferon treatment. They added that tizoxanide resistance is conferred by changes in the cell line, not by mutations in the HCV replicon."

[susan400]

I certainly can relate to what you are saying.  And yes, I got the horrendous VX rash myself.  It came out for me, early on in the treatment.  And YES, I know that it was the VX because I wasn't taken any Riba at that time.  The interferon has NEVER EVER given me that type of rash that I had w/VX.  So, for me, it's just another reason why I hesitate going down the VX road again.  It honest was like hives, blisters, raised welts and my sister who is a nurse said that it looked like I'd emmersed my arms in a pot of boiling water, that's how bad it looked.  And that was only 2 weeks into the treatment!  This time around on the Debio-025/Riba/Pegasys, I haven't had any rash yet and my day 29 is next Wed.  I've had a huge amount of fatigue but I've had no throwing up this time, just nausea.  The only different side effect that's come up for me this time, other than the normal SOC sides, it's a lot of feet cramps and leg cramps.  I've been drinking some Gatorade in between my water and my Dr. has started me on Zinc as a supplement.  I am not sure if this is unique to the Debio, or if it's the Hep C or what.  It's definitely cramps in the muscles and nothing like neuropathy.   Because it's not constant.  Anyhow, I take my last dose of the Debio-025 next Wed. and then, it's just SOC until I get the Day 29 lab results back.  When those results are up, if I have made my 2 log drop, I go on, or if I don't I stop it all.  If I get the 2 log, I continue on with SOC.

I didn't mean to make this so long of a post, but sometimes when I finally get started it's hard to stop until I get my thoughts out.

Susan400

[dointime]

I am lucky in that I have the liver time to wait and that's what I'm gonna do.  My one and only tx took a year to organize and get done, and looks like it will take another year at least to get over.  That's 2 years of my life, and I ain't getting any younger.  So next time I tx I want to be d@mn sure it is with drugs that will finish the job.

As to your question on doing multiple studies, each study has it's own exclusion and inclusion criteria.  However currently it seems that treatment-naive are more in demand for trials, so by definition you can only fit that bill once.  

I sense you are nervous about starting tx, and rightly so as any rational person would be knowing about the possible sides.  I was scared to death of the unknown when I started tx.  Now I am just as scared to do it again because I know I'm the type that gets a rash.  But lots of people don't have anything very bad happen, so I'll keep my fingers crossed that you are one of them :))    

dointime  

[fretboard]

Joy, I guess I just wanted to hear that again, I don't know why.  LOL  Oh well, I will find out what is in store for me personally as I get closer and closer to pushing my boat.  On another note here, when you are weak as far as the SOC goes, is there a chance that infergen may work or are you done with trying anything for awhile?  I hear they have this new once a month interferon and a new form of ribavirin still in testing.  At least the Taribavirin is still in testing, I'm not sure where the once a month interferon is as far as testing goes.  Oh, when you are dropped from a telaprevir study, can you go on another study, or are you exemt?  Seems like a protease inhibitor would be an option.  Hope I didn't just mix up my PI's.  Anyone?    

[dointime]

CS - very good point CS.  I was thinking that null responders are still left out because of not being able to reduce their VL using SOC.  However as you point out there is also an advantage in it, ie. it lets them keep their powder dry till their killer combo comes around.

fretboard - I think that when you rattle the virus's cage and your body by txing then anything can happen.  That you might set off faster disease progression is just one of many consequences that you take your chances with, to be weighed up against the equally uncertain consequences of doing nothing.

I am struggling with fatigue but at this point don't have any answers.  You are doing the best you can by getting yourself informed and asking questions.  After that you just have to push your boat out there into the water and hope for a good journey and SVR on the far shore,

Good luck
dointime                

[fretboard]

How is your HepC going?  I've seen other threads where ppl have thought that their disease was progressing faster because they had tried tx.  How do you feel about that?  Do you take anything at all for fatigue or anything else?  Since I will tx soon, I want to know as much as I can about this disease.  Good luck to you with any future tx.  God Bless

[CockSparrow]

What i like about the approach is if you have a null/flat response then you can avoid taking vx and thus becoming even more resistant that you already are.

By you i dont mean you personally if you know what i mean.
CS

[dointime]

Mre- Thanks for posting that thread.  I think I must have dismissed it first time around because I thought it was about Vertex share price only, so I did not persevere to the nuggets further down - shoulda known better.:))

If the possibility of selection of drug resistant mutations really can be reduced by waiting to dose until VL has been knocked down then that would be a huge step forward in tx.  Finding a way to enable telaprevir to retain it's killer potency over more than one tx would be an enormous boon.  Ofcourse it is not totally one shot at the moment (as you know but others may not).  People like myself who already have resistance to telaprevir can still use it again to drive down wild-type virus.  It just won't be effective on that last pool of resistant variants, for which another active agent (hopefully in current development) will be needed. I am watching Vertex's VX500.  They have been very quiet about it so far but I have a wild hunch that they might have engineered it to nail those resistant variants which have emerged via telaprevir.  Well it makes financial sense, doesn't it.  In the event that telaprevir becomes widely used there's going to be a lot of people needing an antidote for those pesky resistant mutations.

Fretboard - thanks for posting   I am a geno 1b.

dointime
      

[fretboard]

Yes, now I remember your situation, are you a geno 1a?  Those links that were posted are very good, there’s quite a bit of education and fireworks to boot:)  Personally I haven't tx'ed yet so I am really responding to your post in the hopes that someone else with tx experience will chime in here.  I’m sure you know about this site, but others may not, good luck with your tx options and God Bless.  Oh the site, www.hcvdrugs.com, or hcvdrugs *******.  It has a nice graph set up to show you the currrent drugs in trials and their respective positions on the graph.  

[mremeet]

Here's an old link where we discussed this unique strategy some time ago (with a few reality tv-ish fireworks thrown in ;-) .

http://www.medhelp.org/posts/show/325762

I haven't read anything new on this "SOC preloading" strategy since then, but I did read (here on this forum) that Vertex is now going to try it as well. I dojn;t think they would be wasting time on it unless they thought it had merit. And they're ahead of everyone now (in the PI realm), so that says something. Plus, if memory serves, the original SP link of the boceprevir researcher has him sounding a bit like the cat that ate the canary. Sounding like he was on to something hot. Here's an excerpt from geterdone's shering plough's post (embedded within the last link provided):

"But right now I think it's fair to assume that we are feeling pretty confident about the design of our run-in phase, which is the utilized interferon plus [Ribavirin] for four weeks, before dosing with a protease inhibitor. There is couple of reasons for that. First reason is that it takes four weeks to get the study state with these molecules, which is important.

You had [hit] the prime immune system and we think that priming helps decrease the viral load, and that we think is important. Also based on our learnings because we would like to be able think this would result in a fewer mutations in that particular population, which is an important clinical parameter."

In my opinion, I can see where this might be a good strategy. And perhaps an astounding strategy for some. A strategy that especially helps those with marginal SOC performance get to the promised land.