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
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
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
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
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
MEDICAL PROFESSIONAL
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.
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.
Thank you..i appreciate
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.
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.
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