Aa
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
"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
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
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
MEDICAL PROFESSIONAL
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.
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.
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?
MEDICAL PROFESSIONAL
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.
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.
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