Hi, Thanks for the great info from boston. I had a "hypothetical" question for you. I want to preface that i know you are not offering any medical advice here and is just your opinion as a person not a doctor.
If you were a stage 1 on biopsy report what would you do:
2 treat now with the present combo drugs?
3) try and get into a trial and with what drug?
4) what looks like the most promising drug in trials right now?
that is a loaded question. There are so many factors. Personally I waited till I was stage 2 to treat. I start next weekend. Four or more doctors told me to tx. When I was sent to a "top hepatologist" at U of M I was advised I could wait 3 years before treating. He told me this disease is very slow.
How long have you had HCV? You really need to do what your gut tells you to. That is my opinion.
For example when I was 30 years old I had a iopsy it showed inflammation only. I waited 22 years to have my current biopsy done which was recently it showed 2/2. Doc still said to wait. I decided to tx now.
I would probably wait until i could very substantially increase my odds with a promising combo, like Vertex plus Alinia ( if successful with Geno I as now tested in the US trials) plus SOC, with frequent monitoring. Furthermore I would consider Thymosin alpha as addition to SOC to improve the T cell response. Large scale trials with this are currently under way for treatment naive patients in Europe, I hear they are looking promising. The US trials were for IFN nonresponders and not unexpectedly by what we know now, the response rate was lousy for those. ( 3% vs 1% in the controls!)
Problem is you have to wait for availibility. So in the meantime monitoring fibrosis progression with 6monthly Fibroscans and Fibrosures might be an approach to keep the strategy under watchful readiness for revisions.
It will be a matter of historical luck, if and when real good ( low toxicity plus high effectiveness) new inhibitor drugs will be found. The search is on, most will fail, but a good polymerase inhibitor - nucleoside or nonnucleoside- will eventually be found. There is also a second HCV protease ( of the HCV virus), for which Achillion is currently developing a "nonprotease function but processing function" inhibiting compound. This is just an example. Roches Pol inhibitor 1626 is already followed by a new one, purchased by Roche from Pharmasset, less toxic and more potent, I hear. I saw at least 3 posters with new nonnucleoside Pol inhibitors at the conference as well, all with nanomolar inhibition constants. Those will always only be useful as add on drugs to prevent resistance to the rest of the mix, but could make the difference.
can you tell me why the push is on for the nonprotease approach vs. protease?
I've noticed myriad attempts at this. Why does the protease get the bad raps when it seems they worked better than the non....(at least in what little I read suggested they did)...I don't get that.
Is it just because they're cheaper to make? sorry if sounding uneducated here, it is the case.......
thanks for you opinion. i was asked to be in the pharmasset trial that will begin at the university of penn in the next few months with dr reddy. dr reddy was suppose to do a presentation on the pharmasset drug in boston but i can not find the abstract. dont think i will do it, still in a waiting mode but need more info before i make a final decision. i spoke with the trial nurse and she sounds like they really care about the patient. dr afdhal basically said the same thing as you about wait & monitor. but he did add that i watch my LFT's and if they go over 100 i should treat sooner.
Polymerase inhibitors will, in theory, be fully synergistic with protease inhibitors. That makes them attractive as add ons to someone else's Protease inhibitors. Because of the structure of the substrate, a small nucleoside compound can effectively inhibit the catalytic center of the Pol. while the protease requires a large peptidomimetic compound to block the functional groove, which in turn leads to a high immunogenicity of that compound, hence the rash. Furthermore, the rather large binding surface necessary makes it easier for the virus to develop a mutant that blocks binding by extending a new amino acid side chain in the binding area, thus effectively abolishing the binding and blocking effect.
Nucleoside pol inhibitors are very close to the natural substrate ( which also makes them easily toxic to the human Polymerases) eg 2Methylcytosine, attached to a valine for improved bioavailibility, turned out to be too toxic in the GI tract.
The currrent Roche pol inhibitor compound R 1626 is a prodrug to R1469 which is a cytosine with a N3 group attached as a side group to block the polymerase, that specific steric arrangement leaves not too many choices for the pol to reject binding of this compound, and often the respective binding resistant mutants are less fit and cannot easily compete.
Nonnucleoside pol blockers are potentially more numerous, but can quite easily rendered incapable of binding/blocking by changing the configuration of pol at its respective binding site, that is in this case not the catalytic center and therefore rejection of the blocker by mutation is possible with much less functional consequence to the pol enzyme. Since most single mutation already exists or is produced within one day inside the quasispecies, resistance develops with rapidity, eg HCV 796 that was fully resistant within 2 weeks in the monotrials.
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