Digested the AASLD news, I am bummed too

[dointime]

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                

[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!

[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.

[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.
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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.

[mikesimon]

Thanks for that. Mike

[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

[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.