Digested the AASLD news, I am bummed too

Hepatitis researcher wrote in a previous post:
"Not only would Protease +SOC for clear nonresponders not permanently eliminate the virus but something much worse will likely happen ( to quote as mremeet has properly pointed out some hundred posts ago:  " you will be saddled forever with resistance mutations against this treatment component").: This archived resistance mutations against telaprevir would make it impossible to clear the virus at that important future moment  when finally the next chance to treat with an inhibitor combo like Protease + Polymerase +maybe Nitazoxanide will become available that MIGHT, JUST MIGHT give a decent percentage chance to clear despite the preexisting IFN resistance. These are one way roads, just like you cannot normally shake  interferon resistance, you cannot shake off specific antiviral resistance, once it is established, EVEN IF A SEQUENCE TEST WILL SHOW THAT YOU HAVE RETURNED TO WILD TYPE AND NO MORE MUTATIONS CAN BE  "FOUND".

So this is the first authoritative confirmation of what we suspected, ie. that  telaprevir could be a one-time shot because of being left with drug resistance.  Not only that, but any other drug with the same resistance profile is off the menu once specific antiviral resistance is established.  Might that mean any other ns3 PI?    

I was in a Prove2 no-riba arm, failed tx with a breakout and now have VX-resistant mutations.  I was just coming to terms with failing tx.  Now I've got to get my head round waiting for some other drug beyond VX that can kill those mutations.  When I did the trial I knew that the tx could fail but I didn't bargain on f***ing up my future chances of a cure for years to come because of it.  That was definitely not explained and if it had been I wouldn't have done it.  

Well, too late to whine about it now, but I am really pissed and I want to highlight for others entering a trial what the consequences might be.      

dointime                

[meki]

Dointime...

I don't wish to sound like a ninny -- for I am beyond lucky... But a trial is exactly that... A trial.

They do NOT know what is going to happen.

Anything - including death can happen at a trial.

I do not believe in trials for me.

I do not think I would be in the first groups of humans to test out a product --- I'm sorry. I just don't have that much faith in human science... YET...

There will be a time in the future - that humans will understand how we are exactly created - and what substances will do... They will understand the chemical components and they will be able to see more clearly what future results will be.

Until that day - however - trials are shots in the dark.

No one knows what will happen ---- for good or for bad... and how far in the future.

When you do a trial - you should know that.

You might cure --- you might die --- you might never be able to cure --- you might become INF resistant - you might cure half way then get another disease.... and so on ad infinitum.

I'm glad you are warning others - but you should not be so angry for yourself.

Keep your chin up --- and your hopes out...

There will someday be a cure.

Meki

[ladywhy]

I was at Hep Dr. on Wed., I barely read about the conference before the appt. What I did ask was would I be considered interferon resistant?...He said NO...I am a slow responder. BTW, he was at AASLD. I don't know if he was playing golf, or downing shots at the bar..but. I am 35 weeks (or so) double dosing 2x a week...my last pcr showed a vl 1350...down from 45000 4 wks. b4. He gave the impression I should be happy....I asked about Alinia...he said maybe down the road..if necessary. So here i am double dosing...weight based should be taking 1000 mg. riba but an overdosing with 1400 mg.....and feelin' some rage today.
I feel like I'm between a rock and a hard place. I have just about had mor3e than I can take today...i can't seem to find a point for anything. Woe is me.

[jmjm530]

No disrespect to anyone, but I don't think things are necessarily as black and white as presented and the idea that you may have f*cked up future chances may not be correct. Please take your concerns to your doctor or another specialist and have them review your history against what is coming out of AASLD, including the resistance issue. I would think that if the repercussions of failed triple tx were that bad we'd be hearing more. At least don't give up hope without exploring things further.

-- Jim

[frijole]

would you mind giving me the address of the thread -- I can't find it
frijole

[spcecst2]

Did you say you've been double dosing for 35 weeks and you still have viral load of 1350?

[jmjm530]

Have you gotten another opinion on your treatment? I forgot your stats, but I believe most stop at week 24 if still detectible unless you're treating only to improve liver condition as opposed to having reasonable odds of SVR. Also, never heard of anyone double dosing that long.

-- Jim

[ladywhy]

No...I started DD at 26 weeks..@ 10 -11 weeks upped riba from 1000 to 1400mg.  I Have asked to stop tx....Hep Dr. (Director of Hep. Dept at a University Hosp) says...he cannot advise that at this time....

[ladywhy]

Be gentle with me fellows...I'm having a very rough day.

[zazza]

http://www.medhelp.org/posts/show/344760

[zazza]

My thoughts are with you. I can see you are having a difficult time.
Zazza

[zazza]

Trials are trials, yes, but the arms without ribavirin seemed to be a lost cause from start. I understand dointime's reaction. One would think it is not too much to ask to have the risk of resistance explained ahead of entering a trial.

[Andiamo1]

Dr D told me that one of the PIs in trial, I think the one from BI, goes after a different sequence in the RNA and would be effective with people resistant to Telaprevir.

[ladywhy]

Thank you..i appreciate

[Hepatitis Researcher]

dointime:
Not only that, but any other drug with the same resistance profile is off the menu once specific antiviral resistance is established.  Might that mean any other ns3 PI?  

A poster at the AASLD investigated the question of Telaprevir/Boceprevir crossresistance by testing replicons wihich had the known Telaprevir mutations engineered into the replicons exposed to boceprevir. Boceprevir was still mainly effective against those. My realistic guess is that in clinical use one would see mild crossresistance, not precluding the use of Boceprevir in Telaprevir resistant patients, but somewhat reducing their SVR results. It might also strongly depend on which exact TPV mutation a patient has developed.

To Jim :
Things of course are not black and white, we are always dealing with sliding scales and varying percentages. To allow for a clear communication of a critical aspect, it is often necessary to communicate that main aspect without burying it inside numerous side issues and additional influencing variables.The preclusion of future effectiveness of combotherapies by "premature" use a solo antiviral that will later fail to provide its role in the otherwise useful combo is a delicate but important aspect that has, certainly in HIV and HBV antiviral therapy, dramatically reduced/permanently eliminated  the chance of countless thousands to respond in a long term satisfactory supressive fashion to combos that are now on the table, with the realistic promise of lifelong viral supression and virtual elimination of disease sequelae. Thus treatment chances are to be carefully considered and your typical advice to approach a leading hepatologist that has a good knowledge base  and intuitive capacity to juggle/consolidate the available options with a patients personal situation is certainly a wise one, unless you are an expert yourself. But don't have any illusions about the possibility of any individual to fully perceive and evaluate all the critical information that is presented at such a huge conference. Weeks, not days would be necessary to fully absorb all the truly important new aspects and smaller  weigh-ins that are actually offered. Typically only the treatment aspects driven by larger pharmaceutical development can be paid attention to and these aspects are also the only ones for which there is enough money to persue the lasrge scale trials/proves that are typically required to cement at least a statistically sound result for any modality.

The industry sponsered "satellite meetings" are mostly the ones in which the practitioner receives his current education about progress and leading opinion by presentations/summaries from a handfull of hepatologists that certainly have their hands full in preparing for these extra meetings and dealing with elite patients that seek their advice. The disclosures that now are now mandatory before all presentations are also informative re driving forces behind the reshaping of strategic opinions.

[jmjm530]

Not having anything near your knowledge base, it's easier for me (and probably some others) to try and  look at this in terms of clinical applications.

Given a hypothetical geno 1, stage 3, treatment naive,  average pre-tx viral load, average bmi, etc, etc.  This person has made a decision, based on a number of factors to treat now.

If they treat with Telaprevir triple, what we know seems to suggest around a 65% chance of SVR with 24 weeks interferon/riba exposure.

If they treat SOC, around 40-50% chance of SVR with 48 weeks interferon/riba exposure.

Which of these treatment courses would you recommend this hypothetical patient to do, assuming again that they have made the decision to treat now? The question I am asking you may be the choice faced by many when Telaprevir hits the market, which is projected in the near future.

-- JIm

[jmjm530]

Same question for someone treatment experienced, who had a two-log drop by week 12 the first time, was UND by week 24 and then relapsed.

Same as above but without the two-log drop by week 12, although I think you already indicated they would not be a candidate for triple?

Lastly, I do understand that it takes time for things to filter out of AASLD, and do appreciate your 'heads ups' and analysis. But hopefully, this data will be assimilated into tx protocols/decisions by the better hepatologists and therefore my 'typical" recommendation. What other recommendation is there given the landscape? BTW I also recommended that this issue of viral resistance be brought to the hepatologist's attention as well as independently studied if the person is so motivated.

-- Jim

[dointime]

I suspect that we are just seeing the tip of the iceberg on the subject of drug resistance - a bit like the slowy unfolding subprime mortgages thing that's all over CNBC these days.  It's bad news, one drip at a time with a real doozie now and then.  

We're used to talking about retreating with SOC but the new drugs are going to be a whole different ball game.  The failed tx'ers are going to end up with treatment logs full of lists of their particular resistant mutants, and there are going to have to be tests developed (already called for by another poster here) to find out all the resistances that are in the mix before treating somebody.  I think there's a sea change happening here concerning retreatment that's got nothing to do with playing with the dosages or duration and all to do with finding favourable cross-resistance in the tx combo.  

Jim, I think there's not much been heard about it so far because nobody yet is in a position to go for retreating with VX.  I think there's going to be a few shocks if it really is not possible.  I asked my study Prof. about my retreatment options and he said he thought I'd be better off next time with 2 active agents in the mix.  HR's statement on resistance is the first decisive one I've seen anywhere.    

Andiamo - thanks for the information, and it's especially good to know that at least somebody is actively thinking about what to do about the potential hordes of people that will be made resistant to the new drugs, in addition to the hordes of people who already are resistant to SOC.          

[jmjm530]

Of course you understand that I was using the word "better" globally and not in comparison with yourself. Just wanted to clarify as communication has a tendency to go awry on the internet :)

[wyntre9]

Ladywhy,

I can't believe you're at 14oo riba and twice weekly peg at week 35 and still not UND.

Seems like something's amiss here.

And it's no WONDER you're having a rough time.  I'm amazed you still have the strength to type let alone string together a couple of coherent sentences.  I'm gonna email you something that happened to me today which might, at least, make you laugh at just how far riba rage can go.

Dointime,

Again, I'm so sorry for your predicament.

To all,

Just a hypothetical question/observation;

I have had multiple allergies for decades which ended in infections, sinus surgeries, etc., but no Dr. gave me much relief until 10 or 15 years into the process when i was lucky enough to find an allergist who THOROUGHLY tested me multiple times and then put me on a completely indiviualized series of injections.  He's now the head of the State Board of Allergies and Immunology.

I'm wondering if, as has been mentioned on Forum and in a number of recent hep-c studies, future treatment might be headed to a much more individually tailoroed approach.

Thoughts?

wyntre

[dointime]

"you cannot shake off specific antiviral resistance, once it is established,"

HR - Just to say thank you for this very important information which I have not been able to obtain anywhere else.  I do wonder why not, considering it is such an essential consideration for anyone planning to treat with the direct antivirals.

          

[Susie2007]

Just my 2 cents and believe me, it isn't worth any more than that. LOL! I agree with Jim that it isn't all black and white as he and HR have pointed out. Some of us don't know if we are null or partial responders.

HR, thanks for explaining how AASLD happens. Another thing to point out is that there are multiple sessions going on at one time so you really have to pick and choose. We were lucky enough to attend a satellite symposium which allowed us to get the resistance info from some pros who I have already mentioned. We also attended a Meet the Professor luncheon and got 1 hour of Drs. Zezeum and Sulkowski. There were 50 attendees, not very many when there are, I believe, over 4000 people at the conference. There were at least 3 other luncheons that we believe we would have benefited from going to. So just from the way the conference is set up, practitioners cannot get to hear everyone.

NIH Claims that there were 11,300 gastrodocs in the USA in 2003. Tht doesn't count the other docs who take care of hep patients such as infectious disease doctors and a few other specialties. So while 4000 at the conference seems a pretty helfty number, it also includes anyone who is involved in working with hep C patients. I don't know how long it takes all this news to become common knowledge for the hometown doctor.

[mremeet]

I'm sorry you're feeling so bummed out about what happened, I don't blame you. But really, I think you have good reason to be hopeful, especially considering you do have minimal fibrosis. Telaprevir sure ain't the only game in town, there's new stuff popping up all the time. It really seems like we're entering a golden era of HCV antiviral research and development, every year seems to bring more news and more hope. I think HCV will go the way of polio within ten years, there just seems to be a frenzy of development now that the drug co's really see the possibilities, both pharmacological and in the enormous potential for profit.

Anyway, as far as your particular situation is concerned, take a look at alinia. Sure, we don't really know it'll work effectively for geno 1's, but it probably will offer at least a reasonable amount of performance. And it might simply kick a$$, don't write it off or assume it's a dud just because the data hasn't been produced for geno 1's yet. Plus it has absolutely nothing to do with any protease inhibitors (including telaprevir), so you certainly don't have any alinia resistant strains. And look how alinia just seemed to pop out of nowhere (at least for me it did). I always hear about all these vague references about "promising" prelim anti-HCV test results for certain unfamiliar drugs, and then I forget about them because no one is talking about them anymore. Either they prove disappointing later or they're discovered to have toxicities etc and then they fall off the map. But once in a while one of those quasi-obscure drugs you heard about once or twice in the background noise unexpectedly steps forward and says "HELLO". Right now alinia seems to fit that bill and to a lesser extent SCH503034 (boceprevir). And it's just a matter of time before a polymerase inhibitor makes it's way to the front of the line too. Sooner or later they'll be able to kludge together some kind of combination of drugs that will kick your virus' a$$, and kick it for GOOD this time. You just wait and see. And yes I know that you had a real tough time with the riba, I did too. And yes it looks like riba is going to be with us for some time now. But I also think at least some of what you went through riba-wise was as a consequence of the after-effects of your time on telaprevir too (I know the telaprevir skin effects lasted throughout my treatment, long after I stopped taking it). And some people have a very dermatolgically troublesome initial tx, but their subsequent tx(s) are not as bad. That's a possible scenario for you too, just because you got hammered the first time around that does not mean by definition that the exact same thing will happen again. Also, getting back to telaprevir for a moment, even if you do retain a certain percentage of the telaprevir resistant virus, the longer you stay off any tx drugs, the more your viral population will return to wild type. Yes there will probably always be a vestige of the telaprevir resistant virus within you, but its exclusive numbers will probably fade very significantly over time. Eventually the ratio between telaprevir resistant types and wild types (that are telaprevir sensitive) will shift so that the resistant types will be in a small minority (and as far as I know a very small minority if you've been off treatment for a long time). Telaprevir might still be used (along with other drugs) to help wipe out the non-resistant strains, serving to get your VL down sooner rather than later. It may not have the same coup de grace quality it would have in a naive patient, but it may turn out to still serve a useful, (albeit muted), purpose (assuming the other drugs are effective in the absence of telaprevir as well).

Lastly, I agree with you about what you said about the informed consent issues. We all should have been informed of the possibility of being stuck with a resistant strain, especially depending on what group we were put into (i.e. the 12 weeks with and especially without riba). I mean, I know in the beginning no one knew if VX would work without the riba, and it was not known just how long it would take to work its magic. But still I think enough was known by the time prove 1 and certainly prove 2 commenced that we should have been warned about that possibility. I've never seen the consent form for the earlier phase 1 monotherapy trials, but I would suspect they say nothing about anti-virologically "shooting your wad" by enrolling in those trials either. And even if it were spelled out in doctoresque techno-speak, how many ordinary people would really get it anyway? I sometimes think of those people who stepped up for the early monotherapy trials, and I'm sure many continue to do so for the newer drugs in development. Their doctors probably tell them something like "Oh this is an exciting new drug, very promising possibility of a new cure". Probably parsing their words carefully so that technically they're not saying anything untrue, but effectively leading an immunological lamb to the slaughter (especially in the case of those with advanced fibrosis). On the other hand, where would any of us be if someone didn't either knowingly or unknowingly be the first over the trenches? I'd be lying if I said I didn't deliberately wait until I thought my own chances were "sporting" before signing up for prove 1. I take cold comfort in the knowledge that someone did take those earliest steps, not just for myself but for all of us. To a lesser extent both you and me carried the flag a bit further at our own risk and personal sacrifice, but at what price? I'm just sorry things worked out the way they did for people like you and nick and travelmom and amanda - SUCKS.

[zazza]

Jim pinpointed some very interesting issues above with his questions about treating with or without telepravir in the future.

[Hepatitis Researcher]

The concept of the "archived antiviral resistance mutation" was introduced by Doug Richman, a researcher/doctor whot was in charge of several HIV combo trials. It is well known among good hepatologists, but not a pleasant topic to bring up with a patient on a limited time frame.That the price for using a current chance is to possibly foul up great future chances  is not something a practitioner will wish to discuss with a patient - and many are actually not really aware of this.

The true issue is furthermore complicated by the fact that resistance mutations are in themselves of variable consequence to the immediate viral fitness and to the crossresistance effects on similar yet somewhat different drugs.
But as a general rule there is a development of ever increasing "multidrug resistance " when monotherapies are added sequentially with an eventual burnout of options and a monster of a virus that resists everything, which is an outcome that  the rules of evolution unfortunately clearly predict, if you do not block that evolution at an early point in that particular swarm of virus in patient X by rapidly reducing replication/genomic power using second and even third antivirals to stop the proliferation/de novo development of that very small original popluation that carries that critical resistance mutation/s.

So it is well established wisdom in therapeutic virology that a potent combo should be used first line that crossprotects each of its members from resistance developments and not to play around with sequential monotherapies. The fact that drugs are developed according to their pipeline and come out one at a time , while necessitated by the prudent precautions in drug development, fosters sequential monotherapy/pseudomonotherapy for the unfortunate that are in need for therapy at such historical times before the full cocktails are in place.

[spcecst2]

With "antiviral resistance mutation" would it be reasonable to think that “the” resistant mutation would be able to replicate during the rest of your treatment and show some amount of viral load on your test? If your test did not show replicating viral load would it truly be resistant to the treatment you are on?

[Hepatitis Researcher]

If you are UND with a very senstive test under treatment with an antiviral, it can be assumed that you do not have a clinically relevant resistance mutation against that antiviral..

However, when it comes to relapse after long UND during SOC, we must consider a more refined, subtle form of resistance to the immunological pressure that existed all this time on the small amount remaining virus. Some clever subtype of the quasispecies either existent even before treatment started or was developed from close precursors of such a form. Such tough SOC resistant remnants might be wiped out at the next attempt when relapsers are retreated with higher dose and/or longer duration. It is certainly not the same as having an IFN nonresponse, or partial response, meaning retreating has a very decent chance and surely better if an antiviral is added to SOC.

[spcecst2]

thanks for the reply!

[meki]

Isn't this maybe just the human body adapting to serious input of nasty medicines? (chemicals, etc.?)

I mean like The resistance to Staph meds and stuff.

I am not a scientist - but I would think it logical that over the past couple of decades we're already resistant to mutant strains --- that our bodies have developed resistance to anitbacterials to some degree already - and the strains have mutated.

So maybe it is logical that perhaps humans are becoming resistant to the medicines?

Meki

[dointime]

"But as a general rule there is a development of ever increasing "multidrug resistance " when monotherapies are added sequentially with an eventual burnout of options and a monster of a virus that resists everything, which is an outcome that  the rules of evolution unfortunately clearly predict,"

This is information that should be given NOW to every person considering treating with the new antivirals.  It changes the whole debate between patient and doctor about whether to wait or treat.  Previous to this, the downside for naive patients for treating sooner was 'only' the dismal success rate with SOC.  But the downside of multidrug resistance changes that landscape forever and seems to me to be the elephant in the room that is not getting talked about.  Your better choice is not actually to wait for the first direct antiviral that becomes available.  If your liver can wait, you should clearly be advised to wait for the combo that will do the job once and for all.  

Unfortunately, doctors are human like the rest of us and HCV doctors desperately need to up their cure rates, so it's not hard to see how they, like their patients will want to grab at the first hope available.    

dointime  

  

[wyntre9]

I see you're in the UK, dointime, so perhaps you didn't see the recent US coverage of the 'monster' staph infection, MRSH, that is so lethal due to resistance developed from years of over prescribing antibiotics it has closed dozens of schools in dozens of states and led to the death of a large number of HEALTHY teenage athletes.

Wonder if the same is true of any/all viruses/infections?

you're absolutely right that the possibility of long term mult-drug resistance should be disclosed to all patients starting on a round of hep-c tx.

Hang in tere,

wyntre

[Willy50]

The principle may be sound.....but I feel that the key is what percentage of people will develop this resistance; the null response.  Are we talking about 100%, 10% or 1%?  In cases where it does occur how can it be overcome?  Do we need to tailor our response this news differently for each of those percentages?

I keep getting the message more implied than spoken that everyone who treats and fails is thereafter saddled with the resistance.  Is that the case?  If it isn't .......what percentage of those who treat will become the null responders?

Yes...... the same dynamic occurs in HIV but it doesn't prevent people from treating.  Look at how many people have been treated and lives saved with HIV cocktails.

One difference....and I think it's a big-un between HIV and HCV is that our virus can be CURED.  We currently see a 40-50% CURE rate and it's moving to 70 + percent quite soon.  A virus like HIV that cannot be "cured" but just treated is likely to have far more resistance issues (some people have been doing drugs for 15-20ish years) than HCV where the newer treatments may provide cures in 24 weeks.  I know that HCV mutates quickly but the question remains what percentage of us will face the result of being null responders?    

Should this not impact on the way we are reacting to this news?

Other new methods of treating the virus should also both increase the SVR rate, provide treating methods which will not cause mutations, and provide treatments which could "trump" the resistance.  Is it possible that the resistant group will keep getting smaller and smaller and smaller with each successive advance?  HCV is somewhat self limiting; we won't spread this thru coughing or spitting.  Is the resistance issue as great a consequence as it is being conveyed?  

I'm just asking....... not arguing.  I would genuinely like to get a sense of the scope of this.    I know that I am looking at the glass as if it may be more full than it is..... but I ask.... are we looking at a half full glass responding to it as though it were empty?  Am I that far out of touch?

I am not a technician.  Keep it simple for me.  : )

best,
Willy

[Willy50]

"( to quote as mremeet has properly pointed out some hundred posts ago:  " you will be saddled forever with resistance mutations against this treatment component").: "
-----------------------------------------------------------------------------------------------------------------------

We have been treating with interferon since the 90's....... so we would assume that the resistance issue should apply here.  The principle may have proven itself to some degree since many people who having failed TX were not able to clear after re-treating.  We have also seen many people who were able to retreat and clear given other advances made in the drugs coupled with interferon or thru basic improvements in treating; better doctoring or use of rescue drugs.  Do you know anyone who re-treated and cleared?  I do......

Monotherapy; approx 10% SVR rate
INF-RBV     approx 30-35% SVR rate
Peg INF-RBV approx 40-45% SVR rate

The new rate will soon go to 70 plus percent.  Other compounds are coming which can bring it higher.  The period of time between the improvements is going to be coming very, very fast.  Each time an improvement is made it will reduce the number of infected people and take more "resistant" people off the rolls, no?

Andiamo has treated 6 times and failed 6 times.  In taking a new (7th) treatment he was able to clear the virus in his FIRST WEEK and has maintained it thru 24 weeks.  In only about 12 weeks we should see the SVR12 rates for the Prove 3 "12 and 12'".  I remain hopeful for THEIR and OUR prospects.

I'm just saying.....have some HOPE people.

best,
Willy

[jmjm530]

I like your thinking. Let's not get down on things when in fact there is so much more to be optimistic about treatment wise, today than yesterday. Hopefully, the whole resistance issue will be put in perspective when the doctors/researchers return from AASLD and have time to assimilate everything.

-- Jim

[mremeet]

I think you've missed the point on a few issues:

willyquote: "I keep getting the message more implied than spoken that everyone who treats and fails is thereafter saddled with the resistance. Is that the case? "

The message that is being discussed (and has been discussed previously) is that of viral resistance. And viral resistance not for "everyone" who treats and fails, but for some under certain circumstances that treat using the newer drugs and fail. In dointime's case, specifically telaprevir resistance. Dointime was in the prove 2 trial and she was randomly assigned to the riba-less group. She only took IFN and telaprevir and like all the others within the riba-less group, her virus waned initially, but then came back. Telaprevir has a window of efficacy in monotherapy and when dosed with IFN alone. It works for a while, as monotherapy it works for a few weeks, with IFN that time is stretched to maybe a a month or two. But the virus figures a way around it in that time, and once it learns its new game plan - it sticks with it. Dointime is now and will probably continue to be "saddled" with a telaprevir resistant strain, and as HR pointed out there may be partial cross resistance to other protease inhibitors too (due to their similar modes of efficacy). If dointime had been given riba, there's a very good chance she'd be amongst the SVR's right now. And no mention was made to her (or any of us) that something like this could happen (i.e. being stuck with a PI resistant strain). She knows that, and she's understandably pissed. That's what this is about.

willyquote: "Yes...... the same dynamic occurs in HIV but it doesn't prevent people from treating.  Look at how many people have been treated and lives saved with HIV cocktails...We currently see a 40-50% CURE rate and it's moving to 70 + percent quite soon.  A virus like HIV that cannot be "cured" but just treated is likely to have far more resistance issues (some people have been doing drugs for 15-20ish years) than HCV where the newer treatments may provide cures in 24 weeks.  I know that HCV mutates quickly but the question remains what percentage of us will face the result of being null responders?"

You're comparing apples to oranges by comparing HCV to HIV. Yes they're both viruses, and yes they both can develop drug resistance. But the comparison stops there for the following reasons:

1. HIV is an imminently deadly disease. HCV takes time to debilitate and kill, usually decades and even decades (and sometimes never). Once you are infected with HIV it most certainly will not take decades for you to start going downhill and for you to die an awful death. And left untreated, death will come to nearly all who have it, unlike HCV. If you're infected with HIV, you will probably get sick and die within a coupla-five years (there are rare exceptions, but for most this holds true). This is rarely the case for HCV. And even in the case of those with HCV borne ESLD and/or even HCC, there's even a last chance "out" in the form of transplant. There is no last chance exit for HIV patients, other than treatment with existing drugs.

2. Since HIV is an imminently deadly disease, HIV patients have little choice in the matter when it comes to treatment. Taking various antiviral cocktails that will not cure their HIV is their only choice other than to stand by and wait for death. And yes depending on the specifics of what strain of HIV they have, and what drugs they're taking and how compliant they are in taking them, they will develop resistance to some, most or all of the drugs they take over time. But that's the way it has to be, they can't afford to do otherwise. Conversely, HCV patients more often than not, can usually afford to wait out newer more effective drugs. They don't have an imminent death sentence and they usually aren't overly burdened with side effects from the disease itself. This affords most HCV patients the luxury to fully consider the downside of developing possible drug resistance by taking a mixture of drugs that may not be that effective and may leave them with resistant strains after their failed tx attempt.

3. The side effect profile of the drug treatment regimens for HIV and HCV are quite different. A typical HIV patient that takes their daily drug cocktails are almost always in much better shape than your typical HCV patient that's knee deep in SOC treatment and especially those knee deep in SOC+PI tx. I met a few HIV patients at the clinic I was enrolled for my own treatment. Let me tell you, they were the portrait of fitness and normalcy, whereas I was a slovenly, rashy, itchy, anemic, hairless spaced out nut job. I think they actually pitied and perhaps even feared me somewhat when they were talking to me. They said they were happy as clams and living life to its fullest. I know I certainly wasn't, and the comparison between us was stark and unmistakable. And although there are many HIV drugs with bad side effect profiles (including GI issues and rash), and many HIV patients do endure bad side effects from them, usually some kind of combination can be worked out so that these HIV patients live normal lives with a high level of functionality (and minimal sides in comparison to HCV tx). So this is yet another factor that goes in favor of HIV patients taking treatment and HCV patients perhaps holding off.

4. The existing treatments for HIV are very effective at controlling the disease. HIV cannot yet be cured, but it can be controlled in the vast majority of those who receive treatment. HIV has more or less been downgraded in the last 10-15 years to a chronic non-lethal disease that must be continuously treated. If HIV patients are dutifully compliant with taking their drugs, most will probably continue to survive for decades, and if a cure is eventually found within those decades, they'll never die from HIV. In contrast HCV can be cured, but for geno 1's the cure is unreliable. Anyone undergoing treatment today using SOC is rolling the dice for a year (or more) with a very unpleasant treatment and perhaps ending up not only not being cured but also with long term negative side effects stemming from the prolonged use of SOC. Add into the equation a PI, you have even more bad side effects and the possibility of squandering a good shot of being cured should the treatment not work out (for a host of reasons, not the least of which is early discontinuance due to sides and/or due to IFN insensitivity). All of these factors are once again major differences between HIV and HCV tx which factor into why HIV patients treat and why HCV may not treat (even considering that HCV can be cured).

[mremeet]

(cont...)  5. Lastly is the wide array of drugs that are available for HIV treatment when compared to HCV treatment. While sitting in the examination room waiting for my doctor to come in there was a poster on the wall showing many (but not all) of the anti-viral drugs that could be used against HIV. I was stunned, they have what amounts to a huge arsenal of various drugs to pick and choose from. That's in very stark contrast to the paltry few and highly imperfect drugs that are currently available to HCV patients. The HIV community has really done their job since the emergence of HIV in the mid-80's to attract attention ot their disease, to change public perceptions about who gets HIV and why, and to pressure politicians into dumping money into its research. When I fully realized how many truly effective drugs are available for HIV, I simultaneously realized just how successful they were - especially considering that a hell of lot more people have HCV than HIV and a hell of a lot more people die either directly or indirectly from HCV than from HIV. But getting back to the array of available drugs for HIV, that variety makes successful treatment (suppression in this case) with minimal side effects much more likely than what would be possible with the very few tx options currently available to HCV patients.

Willyquote: “"( to quote as mremeet has properly pointed out some hundred posts ago:  " you will be saddled forever with resistance mutations against this treatment component").: "
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We have been treating with interferon since the 90's....... so we would assume that the resistance issue should apply here.”

The quote that was attributed to me was specifically pertaining to (1) treatment with a protease inhibitor (in this case telaprevir), (2) within the context of those who were treated with PI monotherapy or with a PI and IFN alone (without ribavirin, as occurred with dointime), and (3) for those who for whatever reason either have a low response or a “null” response to IFN. It was NOT generically applied towards all who treat, especially with SOC alone. The issue of SOC resistant strains (leaving out PI resistance for the moment) is a much more complicated one, and I certainly don’t pretend to fully understand it. On the one hand patients who fail one treatment with SOC can and do treat again successfully – that much is absolutely true (as evidenced by several successful “frequent-flyers” on this forum alone). And the virus cannot easily change itself so that it is truly and specifically “resistant” to either ribavirin or IFN. Ribavirin and IFN stimulate complex referred immunological responses from the body itself that make it very difficult for the virus to evolve a defense against, whilst ribavirin (apparently) constantly gives the virus unhealthy birth defects (by sending it to “club dead” mutating it into unfitness) - and THAT’S why the virus usually cannot come up with a mutative workaround even when allowed to survive in the body for several weeks or even months while the SOC drugs work their magic (unlike PI’s which alone will allow the rise of resistant strains within a mere 2 weeks or so). It’s not uncommon for an HCV patient to take up to 3 months (or even more in some cases) to become UND, and then they eventually wrap up their treatment at 48 weeks (or whatever) and go on to SVR. That would never ever happen with a PI alone, at least in the form we know them today.

On the other hand, getting back to SOC “resistance” after failed SOC tx(s): I’ve often wondered if those who treat unsuccessfully with SOC don’t end up with SOC resistant viral strains, but end up with an SOC resistant immune system instead. As Einstein correctly pointed out, what’s observed to be going on is relative to the observer. In other words, from our perspective we think of a virus as always becoming the thing that is resistant. And in many cases we know that’s absolutely true. But in some cases it may possibly mean that the immune system itself has been changed or altered in a negative way by taking interferon and ribavirin, especially over a prolonged period of time and/or with multiple (failed) attempts. I recall once when HR stated that the immune system can be modeled and described using mathematical polynomials or differential equations, and within those diff eqs there are an array of constants or coefficients that define the characteristics of each person’s immune system (and these coefficients are unique to each person). If I recall what he said properly (please correct me if I’m wrong HR), these coefficients are permanently altered or changed when a person takes IFN and perhaps ribavirin too. If that’s true, then it would seem possible to me that the immune system *may* be altered in an undesirable way in some people when viewed within the context of (1) its ability to fight HCV alone, and (2) its ability to be as responsive to IFN and/or riba as it was during earlier course(s) of (failed) treatment.

So it is my layman’s guess that when we see someone who fails treatment multiple times with SOC, it may not necessarily be because they have an HCV SOC resistant super-bug. In some cases, the resistance to clear may be because their immune system has been altered and has become desensitized in some way to the SOC treatment drugs. Pure speculation on my behalf, but that might be playing at least a partial role in some of the toughest to treat.

[jmjm530]

Re SOC only -- don't the numerous cases of treatment experienced SVR's argue against resistance to the SOC drugs. As long as the person responded the first time, they seem able to respond the second time and often SVR if tx is extended. Further, and just a personal theory here, I think the opposite of inteferon resistance may take place. In other words, the first treatment 'primes' the immune system so to speak and the second tx finishes the job.

Re Dointime and 3Xtx and resistance -- I think the numbers still have to be developed, crunched and anaylzed before we understand the clinical implications of interferon null (or partial) response for future treatments. Certainly something, however, I would ask my doctor about if in Dointim's (or similar) shoes, not to mention doing independent research. We're very fortunate to have HR here to give us a heads up.

-- Jim

-- Jim

[mikesimon]

Thanks for that. Mike

[gauf]

So it is my layman’s guess that when we see someone who fails treatment multiple times with SOC, it may not necessarily be because they have an HCV SOC resistant super-bug. In some cases, the resistance to clear may be because their immune system has been altered and has become desensitized in some way to the SOC treatment drugs. Pure speculation on my behalf, but that might be playing at least a partial role in some of the toughest to treat.
--------------------------------------------------------------------------------------------------------------------------------
Well, that is a disturbing hypothesis. We may may well clear the Hep, only to leave ourselves wide open to other diseases like cancer etc. Seems like a bit of bad news lately but what choice do we have? I myself feel terrible for those who were not aware of consequences of being in the Riba-less PI trials. It is a heartbreaker.

[mremeet]

jimquote: "Re SOC only -- don't the numerous cases of treatment experienced SVR's argue against resistance to the SOC drugs. As long as the person responded the first time, they seem able to respond the second time and often SVR if tx is extended."

Absolutely, and that's why I stated above "...patients who fail one treatment with SOC can and do treat again successfully – that much is absolutely true (as evidenced by several successful “frequent-flyers” on this forum alone)." And if you actually read my previous post, you'll see I wasn't discussing nor promoting/advocating the notion/probability of SOC resistant strains of HCV. I was primarily discussing the *possibility* of an SOC resistant immune system instead, and specifically the possibility of an SOC resistant immune system being produced or otherwise invoked in some (small) percentage of those that have been exposed to multiple failed rounds of SOC. And once again it was a speculative look at *possibilities* in *some* people (i.e. a small minority) - not a sweeping generalization applying to all who fail their first time around (for whatever reason).

jimquote: "Re Dointime and 3Xtx and resistance -- I think the numbers still have to be developed, crunched and anaylzed before we understand the clinical implications of interferon null (or partial) response for future treatments."

Sure, the numbers do need to be further collated, crunched, and counted before we understand the full and complete implications of IFN null (or partial) response in regards to the use of protease inhibitors. Who suggested anything to the contrary? But no matter how much we crunch and calculate and ascertain, there will always be a certain amount of uncertainty. Heisenberg reigns supreme and always will. The perfectly knowable will always be unknowable, and that will always apply to this situation. In the meantime, I certainly think there's enough actionable intelligence at this point in time in regards to both riba-less performance and/or to the strongly IFN resistant patient to say with good certainty that the odds are not good for them should they decide to use telaprevir (or probably any known protease inhibitor at this point). Not only are they not good for SVR-ing, they're not good in the sense of developing a PI resistant strain of HCV as well. This is important to know for any patient pondering enrollment in a trial and/or planning treatment in the future when one of these PI's become commercially available. And since it is important, it's worth talking about it NOW, not later. I think the verdict is nearly in, in regards to ribaless and/or IFN resistant performance in conjunction with a PI - if your mileage varies on that count, then by all means feel free to let it vary.

jimquote: "Certainly something, however, I would ask my doctor about if in Dointim's (or similar) shoes, not to mention doing independent research. We're very fortunate to have HR here to give us a heads up."

That's very thoughtful of you to suggest to dointime she should do "independent research". I'm glad you said that, otherwise she might not have known to have done so. Sounds like code for, "if you don't like the answers you're getting here, look elsewhere." Did it occur to you that she's doing some of her independent research right now? And it's also very thoughtful of you to suggest to dointime that she should ask her doctor about it too. But if you think that dointime is going to receive some kind of magical data from her doctor about the issue of telaprevir resistance as pertaining to ribaless treatment that will fly in the face of what we now know about it, think again. Especially since we already have an extremely experienced, extremely smart, thoroughly versed "hepatitis researcher" doctor here who's on the cutting edge and is specifically weighing in on the situation. I just don't understand what your point is here, and it's a common point you bring up all the time when you're even partially contradicted. "See your doctor and get a consult, everything here is speculation etc etc".  Of course everyone should get a consult with their doctor jim, who's suggesting otherwise? Who *ever* suggests otherwise? You say this all the time as if someone is trying to dissuade the person who's asking questions or opening a discussion to somehow not see their doctor or to not discuss it with their doctor. Dointime is a grownup jim, she's smart and she's an experienced HCV patient, she already knows to "see her doctor". She IS seeing a doctor and has been seeing a doctor. And since discussing it with a doctor is her best option, why have you weighed in on the situation with your own advice/thoughts? Why do you always weigh in with advice of your own? Don't you think keeping it simple and simply advising the person to "see their doctor" is the most appropriate response? Isn't it irresponsible for non-doctors to weigh in on situations like this? Or is that advice only appropriate when someone other than you weighs in on the situation? (including an acual doctor, incredibly) Jim, this is a PATIENT TO PATIENT forum. Everyone here knows it's a patient to patient forum. It says in multiple places that it is a patient to patient forum. Dointime is a regular here and has been here a long time. She knows full well it's a patient to patient forum. Furthermore, even though this is primarily a patient to patient forum, we are fortunate to have HR step in and pay us a visit once in awhile, as he has here. HR is not a patient jim, he's a real doctor - a real hepatologist who knows all about what we're talking about. And guess what? He's knows a lot more about it than we do and there's a very good possibility that he knows more about it than probably 99.9% of other GI's and probably near that same amount of actual hepatologists.

[mremeet]

gauf: "Well, that is a disturbing hypothesis. We may may well clear the Hep, only to leave ourselves wide open to other diseases like cancer etc. Seems like a bit of bad news lately but what choice do we have?”

Dude, what I said was a speculative rant, nothing more. And even if it the notion that the immune system can be altered in a negative fashion (in regards to its responsiveness to SOC), it will probably be in a small minority. As previously stated, this is obviously borne out in what we see in several here who have treated successfully in multiple attempts (with SOC). Like yourself for instance, you responded both times with your treatment, there were just various extenuating circumstances that snagged victory from your grasp that had nothing to do with insensitivity to SOC (i.e. with the initial early discontinuance due to infection, the sub-optimal riba and not prolonging treatment to 48 wks etc). You responded once, you responded twice and I’m confident you’ll respond again, and god willing for the final time. Please don’t let what I said discourage you in any way!

[jmjm530]

You seem to take my statements as argumentative when I'm just expressing my overall take. I only put you in the "to" line because you brought the subject up, but my comments were to the group as well. And how I express my opinions to "Dointime" is "code" for nothing and frankly none of your business. Once again, your ad hominem response is not welcome, not that you seem to care.

[gauf]

No, I understand completely that it was "food for thought", and I know full well that the jury is out on the long term effects of these drugs. But like I said, what choice do we have? It is possible I may or may not develop some immune problems down the road, but all I can do now is try and get down that road!  I always appreciate your posts my friend.

[Willy50]

: o      Now I'll never get my work done.  : )

Hey guys.....we're all on the same side; keep it light.

Mre.......your original quote, which HR quotes you and then I quoted HR using your quote to which you replied to me, quoting me quoting HR using your quote is not being used to put you on the spot.  : o

You made that quote some time ago but it is being used here today.  Our understanding of things may change and so it may not be fair to use that quote...... but on the other hand it will increase your google ranking.  : )

Thank you for the reply.  I take it as a kind response to my question.  I just stopped in for a work break and will digest this later...and try to answer it.  Some of it I have no answer for since we agree.

My main premise stands; what percentage will bcome null responders?  IF it is indeed a small number I think that our reaction to the viral resistance question may be over the top.  This is nothing new really is it?  I mean..... I've read the pharms say that it can't happen with interferon but I never quite understood/believed that virii couldn't mutate into more resistant versions.

I think the main thing that is unstated here is that we all want to know how it affects specific members.  We are talking about the principles generally but I think we all really want to know specifally in this thread for Dointime.  There are others here who have failed a Vertex trial and we all want to see them clear.  I still have hope that it can be done but perhaps I need to sit down and read the AASLD studies....which I haven't due to being out of town.

I'll be back later to respond but I still encourage people top remain positive.

thanks  and best,
Willy

[gauf]

Mind if I quote you on that?

[Whrose]

i do enjoy your posts!

one comment i have a problem with.

"I've often wondered if those treated unsuccessfully with SOC don't end up with SOC resistant viral strains but end up with SOC resistant immune system instead."

this is most interesting when considering the virus ability to modulate the host immune response on multiple pathways, however this alteration is not provoked by SOC but by the nature of viral evolution to survive and protect its genome.  maybe this is why with some individuals after repeated and or altered treatments may eventually have successful outcomes.  i also have hope that perhaps the development of meds that stimulate the Th1 immune response will be a useful adjunct to SOC for these people.

however exploring the drug resistant varients of treatment meds may be also a key reason (and one we may be able to prevent) for many of the response issues. would be nice to have improved diagnostics of this form of resistance and some stats on the numbers of this occuring.  this is where my interest becomes acute as drug resistance in any infection not only leads to evolution of superbugs but limits the effectiveness in what is already a limited arsenal of therapeutic alternatives with hcv or any pathogen.
i am thinking that viruses in particular over other micro organisms because of their replication and mutation rate will be a much more difficult organism to combat drug resistance issues. for sure we need more research in this area so as to provide the best and proper treamtnent regime and not create more difficult organisms.

thanks for always providing interesting insights.
Whrose

[geterdone]

from your post… What I would like to know and if there is an answer, at what point dose the INF and Riba start doing more damage to our immune system than helping it fight the virus?

jasper

But in some cases it may possibly mean that the immune system itself has been changed or altered in a negative way by taking interferon and ribavirin, especially over a prolonged period of time and/or with multiple (failed) attempts. I recall once when HR stated that the immune system can be modeled and described using mathematical polynomials or differential equations, and within those diff eqs there are an array of constants or coefficients that define the characteristics of each person’s immune system (and these coefficients are unique to each person). If I recall what he said properly (please correct me if I’m wrong HR), these coefficients are permanently altered or changed when a person takes IFN and perhaps ribavirin too. If that’s true, then it would seem possible to me that the immune system *may* be altered in an undesirable way in some people when viewed within the context of (1) its ability to fight HCV alone, and (2) its ability to be as responsive to IFN and/or riba as it was during earlier course(s) of (failed) treatment.

[Whrose]

oh dear. i am just now really get the gist of what you and Hr meant by SOC resistance.
i think i will take a while and digest this. it is surely a large plate of information to consider.
again thanks mre....

[mremeet]

Guys what I said was speculation, please don't take it too seriously or over simplify what I posed as a limited scope *possibility* as a proven or well supported fact (cuz it ain't!). And jasper you ask "at what point dose the INF and Riba start doing more damage to our immune system than helping it fight the virus? " Again I'm not suggesting it does "damage" to the immune system, what I'm suggesting is that it alters our immune system. It certainly alters it while we're on the drugs and it appears to alter it in a lasting way after we stop taking these drugs. For some people that long term (and perhaps permanent) alteration involves automimmune issues (sometimes serious), for others it may mean more colds and flu bugs, for others it may mean skin issues (psoriasis etc). And perhaps for others it may mean a decreased sensitivity to IFN in the event there are any future attempts at using it again - PERHAPS! (i.e. that possibility is certainly in no way a done deal)  Please don't read too much into what is basically a speculative dining room table discussion amongst amateurs (aside from HR, obviously). And whrose thanks for the kind words, but when you say "i am just now really get the gist of what you and Hr meant by SOC resistance" please understand that I'm not speaking for HR when I postulated what I did above. I did reference what he said about the permanent alteration of our immune systems after taking IFN, but the rest of what I said he has not subscribed to nor agreed with (that I'm aware of). For all I know he thinks it's a buttload of tripe - so please don't be under the impression I'm speaking for him simply because this thread has a reference from him quoting me and then in one of my responses I quoted/referenced him. Sorry for any confusion, it was not intended.

[ladywhy]

My brain is functioning on a very low level presently. I have reread this beaucoup times...yet frustratingly enough, I 'aint gettin' it. Could someone explain this 'as if' they were talking to a 5 y.o? From the little I have digested, it seems more than likely I fit the category of 'interferon resistant,' yet my tx dr. says, "No" I am a very sloooowww responder with a vl of 1350 at 34 (or so) wks...double dosing the last 10 (or so). Please help. I've been in bed for the past three days...and the bills jus' won't pay themselves....
I don't want to give up...especially if my Hep. Dr. is against me stopping.....
After reading up on Lonestar's journey through tx., I feel like I may have a chance with infergen...again, Doc nixed this idea too. I feel desperate enough to try to get this Alinia from Mexico...i'm at my wits end. I wonder if it would do any good at this stage of the war. It seems I would have little to worry about reg. toxicity...but what the heck do i know.......it's not cheap either...

[Whrose]

actually in another post HR complimented you on your perspective regarding resistance.
i do agree with you that this view is speculative. i enjoy it though.

to throw a wrench into SOC influenced immune changes,. i also entertained this. however in my personal experience. i developed auto immune arthropathy first sx before SOC.
i have speculated that chronic hcv had altered my immune sytem that allowed this situation to present. no doctor will deny or confirm though. so in my case the virus altered my immune system that left me predisposed to this. again this is my theory. but i would bet based on 3 generations of family medical hx with no auto immune arthropathy present that my immune system was altered from the virus. luckily for me, SOC was successful and my immune sytem was not resistant to the SOC.
as my rheumy patiently tells me. the immune sytem is complex and although we have made great strides there is so much we don't know yet.
you are one heck of a layman though, and have very good reasoning in the realm of speculation and rational deduction.
kudos    

[Whrose]

i will give my one cent to your question. other's more expereinced will certainly have more insight.

according to Dr Shiffman in his article at CCO a slow response is described as undetected viral load between wk 12 to wk 24. if you are detected at week34, by this definiton you would not be a slow responder. he also describes a partial responder as one who has a 2 log drop by week 12, but still positive at week 24. so by this definition it appears you would fall under the category of partial responder.
as HR pointed out there are shades of response that should be individually evaluated.
perhaps he will come on and give a better answer to your situation.
i also read a summary by Dr Hassanein at CCO that stated if one is detected at week 24 there is no possibilty of SVR on that same treatment and it should be modified with goal to get to undetected.
however it was not clear what changes would be the best in this situation.
your doc appears confident of your response by what you write. this has alot of weight. i am not sure what changes you have made to your tx but i do wish you the very best and will keep you in my prayers. stay positive.
btw. if it were me, i like the idea of adding alinia since you are still detected at week 34. for me it would make sense if you are in the fight to have all the tools available to do the job. did you ask your hep doc what he thought about it? what length of time are you planning at this point on present regime?
hugs

[Willy50]

Sorry....I've been busy.  I actually wrote out a long reply detailing point by point.  I may PM it but the bottom line is that it just confuses things arguing about points likening or contrasting  HCV and HIV.  I also want to avoid strenuously arguing minutae especially since this is an area where the data is very sparse and theory, not fact and data rules.  My heart is just not into arguing the points.  I truely don't know the answers.

I care about how our relapsers are and I know you do too as well as HR and many others.  I know we have to prepare ourelves for bad news.  It will really smart IF it comes so close to the finish line.

I'd like to think I still presented my point, whether right or wrong.  Current trials will answer our questions soon enough.

I'd still encourage people to stay optimistic.  You can see strides being made every week on this board.  Think what has been accomplished in just this last year.  The years that come will be better still.

Be patient....we will all get there.

Best,
Willy

[ladywhy]

That was a help. Thanks so much for responding. I am going to have to sit down with dr. and not let his NP push me around anymore. I did mention Alinia...he said wait and see...
I have to be a better advocate for myself...
Good night and thanks again.
Yvonne

[Whrose]

i was reminded after consideration of mre's rant (affectionately said) regarding immune alteration from SOC of another interesting fact that liver disease from chronic hcv increases the risk for lymphoproliferative disease. hcv is not only hepatotrophic but also a lymphotrophic virus. although i remember the risk is low ~4-5% (correction requested), the point is that hcv may do more damage and immune sytem alteration in chronic time than SOC. i say this not to scare us but to cause us to consider that chronic infection may do more immune alteration than SOC presents which supports my theory. the incidence of cryoglobulinemia may also represent this link. our immune system may take a hit with this virus as our body mounts a viral defense. the added risk of stimulation of immunopatholgy with SOC or chronic infection represents valid concerns when we consider treatment risks vs chronic viral infection.  the thoughts that hcv has the ability to replicate in certain immune cells is proven. i wonder that in time these sequalae of chronic infection will be better understood.  in fact i look forward to this.

[Whrose]

my heart of support to you now. i feel for your present challenge. you are in a tremendous fight right now and under the effects of these powerful meds. i wish there was an easy answer but unfortunately there isn't. the best we can do sometimes is not enough in our fight and the best our hep docs can do likewise sometimes is not enough.
but i will always hold out for hope rather than despair, positive attitude over giving up, knowledge over speculation, a doc who cares and fights the fight with me over the quack selling me false hope, and bravery over a cowards closet.

you are all of the best in our community and i am awed by your true grit. sleep well and happy dreams to you.
hugs.....Whrose

[geterdone]

Thanks! I guess the word damage was an extreme expression and that the word “alteration” would have been a better fit. Yes, our immune system is chemically altered by taking these meds for a prolong period of time and the possibility of lasting effects after stopping treatment all the sudden. This is where my focus is and I am starting to think what would be the best course of action to possibly head off what may or may not be a permanent autoimmune system problem or problems at the end of tx and how I am going to wean my self off these meds and hopefully allow my own immune system to start repairing any chemical alteration that may have been caused by the prolong use of the meds. I know this may be forward thinking and am sure others are just trying to get through the treatment as I was in the earlier stages of tx but with 12 weeks left I do not want to end tx cold as many before me had and end up with the possibility of any lasting effects of the meds. See my journal as to why I had focused in on the reply to you about immune system problems. Mermeet, I had posted some time ago about small vain bleeds on the scrotum for which you had replied more or less little is known about it, It has since stopped after reducing the riba from 1200 to 1000mg it took about three weeks to completely subside.

Thanks!

jasper

[mremeet]

geterquote: " Mermeet, I had posted some time ago about small vain bleeds on the scrotum for which you had replied more or less little is known about it..."

Wha??? Dude, I never commented on your scrote veins. Mremeet don't do no scrote veins. Please, see a properly qualified and licensed scrotologist to address your concerns.

[mremeet]

What I'm trying to say is that this particluar subject just ain't my bag. Nuff said.

[mremeet]

Oh yeah, I found a licensed specialist who can almost certainly "give you a hand."

http://youtube.com/watch?v=k61AN4fynDM

http://youtube.com/watch?v=3SCJLlSf21Y

[ladywhy]

Those were such kind and supportive words...thank you.
I definately believe, no matter the situation, it's always better
for everyone involved to not be negative...it only feeds on itself.
Thanks for the reminder.....this is why I keep coming back here,
for the advice...and the wonderful support.
It has been a great gift to me.
God Bless You
Love,
Yvonne

[geterdone]

ROTFLMAO, good clip tho, sorry if I embarrassed you. It seems that the male ego will not allow the discussions of such topics as told by the death rate among men as a gender and why there are ten women for every man. The subject was brought up back then as now because it was directly related to the drugs being taken and what had rendered the problem incase some other unfortunate male may encounter the same problem while taking these meds in the course of treatment fore which it was brought up in the first place. Again, sorry for the embarrassment and the subject will never be broached here again. Lol!

jasper

[dointime]

Hi mre - thank goodness you weighed in on this one.  I knew I had something important to say but I just couldn't have mustered either the energy or the eloquence to say it like you have.

You said:
"But if you think that dointime is going to receive some kind of magical data from her doctor about the issue of telaprevir resistance as pertaining to ribaless treatment that will fly in the face of what we now know about it, think again"

You got that one right!  I have asked about the problem of resistance and retreating several times to two doctors, both very experienced virologists, and all I have got is evasion.  With HCV it is so easy to just trot out 'oh well, so little is understood ...it's too early to really say, .... blah blah'.  Now I find out that the concept of the "archived antiviral resistance mutation" is well known among good hepatologists.  Those snakes!  

I just wouldn't like to see a whole new generation of multi-drug-resistant non-responders to be created in the next 10 years before a really effective drug combo comes along.  This news has removed any doubt from my mind that I will wait for as long as my liver has got before doing another tx.  HR's info has really made the difference.  

Well, great to see you are still hanging out here even though you're SVR.  How's the beer sampling going?

dointime                
  

[mremeet]

Thanks for the kind words, and I figured the docs you may have spoken with would provide vague non-commital answers or perhaps just shrug their shoulders. They're human beings too, and when confronted with treatment failures I think many of them take the evasive course to avoid unsettling conversations - for both their patients and themselves.

But with all of that said, you are not doomed to never be successfully treated again, far from it. And I do not necessarily think it will take years and years for you to access effective treatment that could very well give you your own SVR. It's very possible you could be cured using just SOC alone, especially with creative initial dosing and/or extented tx. Not a pleasant thought, I know, but again some of the hell that riba put you through may have been from the carryover effects of the telaprevir. A second round of SOC alone a year or so from now may turn out to be a lot more tolerable (skinwise) than you imagine it could be. No guarantees of course, but that is a possible outcome.

But outside of SOC, obviously there are already several fallow fields that very well may bear fruit for you in the near future too. Like alinia, obviously. Also boceprevir in a coupla years. And there may even be a shot at using telaprevir to help you too. Not all of your virus is telaprevir resistant, and the longer you stay off of treatment, the more telaprevir sensitivity will increase amongst the viral population. There will always be an archived tpvr resistant vestige remaining, but in my opinion that does not necessarily mean that telaprevir (or certainly another protease inhibitor) will not be able to be used to at least assist in some way during a creatively thought out treatment strategy.

I especially think it might be possible some of the newer dosing strategies that are being tested may turn out to be useful for some people (perhaps including yourself). For instance the way in which boceprevir has been dosed after 4 weeks of SOC in the SP trial. It's a matter of debate right now if this strategy is effective or not - but it might be effective in situations like yours. For instance, here's a hypothetical situation: lets say you decide to treat 2 years from now. By that time your virus should have mostly reverted to wild type, or types that are vulnerable to telaprevir (albeit the resistant vestige shall remain). And lets say you decide to predose with riba and perhaps procrit (depending on how anemic you were last time) for 3 weeks and then start out taking SOC+alinia for 4 weeks (perhaps doubledosing IFN for the first 2-4 weeks too). Assuming the predosed riba+SOC+alinia knocks out most of your virus within 4 weeks, and perhaps even to undetectability using a sensitive PCR (i.e. 10 IU/ml or better), it's likely that very little of the tpvr resistant virus will remain. It's even possible that virtually none of it will remain at that point. So perhaps adding telaprevir into the mix at that point could pay dividends and very quickly wipe out virtually all of the remaining virus. And even if there still is a tiny vestige of tpvr resistant bugs remaining, they'll still be vulnerable to the SOC and perhaps the alinia too. And by that time your immune system will have definitely been "turned on", and riba+IFN serum levels will have been fully saturated. So the usual "grace period" that the virus gets during the earliest phase of treatment with concurrent SOC+PI dosing will not be in the running. And I suspect it's that "monotherapish" grace period where the virus is mostly just confronted with the PI alone in the very beginning of concurrent PI+SOC tx (*especially* without riba!) that it gets just enough "liebensraum" to mutate up a resistance. But there won't be any liebensraum this time, the heat will be on and coming from all angles by the time the telaprevir is brought into the picture. Also, at that point the virus will have been swimming in ribavirin saturated blood for over a month. It is not completely understood how ribavirin works, but it is thought to cause the virus to mutate excessively and to cause unhealthy mutations in the virus. I can't know if the virus undergoing so many unhealthy mutations over the course of a month of strong antiviral therapy would be enough to mutate out any telaprevir resistance, but theoretically it seems plausible to me. Point being of course: combine the fact that VL is significanty cut down by week 4 (especially in regards to riba predosing), combined with the fact that SOC's referred immune responses are fully activated at 4 weeks (especially if IFN doubledosing occurs), combined with any role alinia may contribute (which I'm optimistic it will), combined with the mutative effects of riba perhaps diluting any remaining tpvr resistance, just *might* make the delayed introduction of telaprevir at that point a winning strategy. And in the unlikely event the telaprevir has minimal effect, I don't see any reason at all why it would disturb the effiicacy of the other drugs (i.e. you've got nothing to lose, side effects not withstanding).

Remember that you did respond to IFN in your previous treatment, and you also responded to ribavirin when it was latently introduced. You can respond again, with creative dosing and with the help of alinia and/or some new PI (perhaps even including telaprevir) you can get it done. And depending on how quickly you can squash your virus into UNDetectability, you might even be able to shorten your treatment to 24 weeks with reasonable safety (to help shorten the ordeal with the inevitable skin problems).

Hope you're feeling better soon and this isn't getting you too down. Hang in there, you'll make it out of this one way or another.

[dointime]

It's really good of you to spend the time drawing all this out for me.  I'm keeping a copy just in case but hoping I don't need to go this route.  

I decided to get myself out of the rut and got on a plane to Mexico.  It's given me lots of new things to see and think about instead of sitting around nursing my post traumatic stress from the trial and 2 breakthroughs.  I'm still keeping in touch with the forum but the change of climate is sure helping to get me out of the dumps, especially since I had to stay out of the sun all year because of the rash.  I'd like to stay here for the winter, just chill, get a life, you know...

dointime