Aa
hepatitisresearcher
Your opinion please? Lets say a patient went thru treatment (1b) pegasys/copegus 180/1200 for 48 weeks, starting VL was 10 mil, middle aged male, slight liver damage, still detectable at 600 week 12, clear week 16 (less than 50), relapsed, waited 3 months and started treatment over, VL 500,000, double dose pegasys 4 weeks, 1400 copegus, no VL detected at week 4 using heptimax, did shot every five days from week 4 thru week 12, did 1600 copegus for month and half, waited full seven days at week 12 and got negative heptimax, doing 180/1200 rest of treatment, ast/alt normal at week 12, does this person have the same chance with RVR statistics (as high as 85% SVR) with 48 weeks, or are those RVR statistics only good for someone who does treatment the first time using the SOC? I hope you can understand what I’m asking here?
I just read a post on the other side of this forum from someone who has relapsed and is now in their 36th week of vertex which I assume from the post ends at 48 weeks, what would be the difference from vertex after relapse and me doing high dose and stopping at 48 weeks with 4 week rvr? I am planning on doing the 72, but I wonder what exactly is the difference from vertex knocking it down hard and fast and myself high dosing SOC and knocking it down hard and fast?
Thanks,
Thanks,
all I meant by "couldn't make sense of the CMI measurements" was that I'm not familiar with IFN-gamma elispot assay - simple ignorance on my part, not skepticism. I'll make an attempt at correcting that and follow up some of their refs.
Any thoughts on the Egyptian study, that looked at Cellular Immune Responses? I guess the crux of the article for me is: what to make of this phenomenon, and whether the researchers' second 'possibility' might have some possibility for being valid. I also wonder how this 'mild infection' was transmitted, because they did not really pose any theories on why there would be a 'cellular' reaction, versus a full humoral reaction, which would have likely provoked HCV blood antibodies, or a full fledged HCV infection. Do either of you see any 'holes' in the research? From my perspective the study appears to be saying that a significant percentage of people living in close contact with HCV infected persons, in this study, came away from this association with some 'other' sort of either ' lasting immune reaction specific to HCV', or possibly some sort of 'controlled, compartmentalized inffection', not of the typical blood/liver variety. I am still very intrigued by this study, and this subject. I think there has to be some significance attached to it...even if the consequences of this cellular reaction are either still unknown, or presumed to be minimal, or absent.
DoubleDose
DoubleDose
OK, I'm working hard on extracting-foot-from-mouth; it's not easy. On re-read of that article they did in fact deposit sequences for the derived clones in genbak with accession numbers AM400248-AM400838 and AM401639-AM402384. This means anyone interested can rerun their stats along with whatever other tests they choose to determine whether there is or not evidence that riba accelerated the pre-tx rate of mutation in those two genes. Nevertheless...IMHO this is very much a rarity, most summaries of clinical trial results *do not* publish their original data
sorry, with regard to the Chang paper, the analysis is on a cell-based system, not in-vivo. But still: no mutagenic effect observed at 100microM.
it occurred to me that, if this theory is correct, continuing riba post eot is presumably of greater value than ifn. Cells infected with residual, "stealth" virus, ie virus missing recognizable CTL epitopes (BTW there is a nice databse of known epitopes at the lanl hcv database: http://hcv.lanl.gov/content/immuno/tables/ctl_summary.html ) might still be able to activate the ifn expression pathways, and thus partly compensate for absence of the dosed ifn, however there's no way they could make up for the missing riba.
However the larger question seems to be whether there is evidence that riba is an HCV mutagen at in-vivo concentrations. Understood that the level of mutation required to construct de novo recognizable CTL epitopes is much milder than that postulated by Crotty's original "error catastrophe" hypothesis. However my read of the Pawlotsky paper is that they could find no evidence of any mutagenic effect above the baseline induced by the HCV RNAP error rate in the NS3 and NS5A genes they sequenced. Their discussion section notes that their results in this regard are more reliable than either the preliminary ones based on vitro studies, since the concentrations used there, 50-100uM, could never be reached in-vivo (though some of the riba dosing used during the SARS epidemic is impressive), or the results of an earlier in-vivo study by Asahina in '05. They claim to be superior to the latter, in part, because their analysis explicitly accounted for quasispecies diversity as opposed to mutation-induced variation. I haven't yet been able to understand the paper in enough detail to decide if this claim is justified, but the challenge of separating the alleged riba-induced mutation from a noisy background generated by quasispecies differences, the ongoing RNAP error rate and the sequencing errors you mentioned seems to require some fine-tuned data analysis. In this regard, HCV patients everywhere would be enormously grateful if researchers would *release their damn data* and let others have a shot at analyzing it! (sorry, but this is one of my ongoing gripes).
Unfortunately, I can't get access to the full text of that Chang'07 paper, but from the abstract it appears they also support the no-mutagenic-effect-in-vivo position (here with a different virus, but presumably this is not relevant if mutations are based on riba as a generic guanosine analog) : "Sequencing analysis of the conserved polymerase regions of NV in the ribavirin-treated (100 microM) and nontreated groups showed that the mutation rates were similar and indicated that ribavirin did not induce catastrophic mutations."
As above, "similar" could possibly well be masking a mild mutagenic effect.
Are there other data that clearly support a role for riba an an HCV mutagen at in-vivo concentrations?
However the larger question seems to be whether there is evidence that riba is an HCV mutagen at in-vivo concentrations. Understood that the level of mutation required to construct de novo recognizable CTL epitopes is much milder than that postulated by Crotty's original "error catastrophe" hypothesis. However my read of the Pawlotsky paper is that they could find no evidence of any mutagenic effect above the baseline induced by the HCV RNAP error rate in the NS3 and NS5A genes they sequenced. Their discussion section notes that their results in this regard are more reliable than either the preliminary ones based on vitro studies, since the concentrations used there, 50-100uM, could never be reached in-vivo (though some of the riba dosing used during the SARS epidemic is impressive), or the results of an earlier in-vivo study by Asahina in '05. They claim to be superior to the latter, in part, because their analysis explicitly accounted for quasispecies diversity as opposed to mutation-induced variation. I haven't yet been able to understand the paper in enough detail to decide if this claim is justified, but the challenge of separating the alleged riba-induced mutation from a noisy background generated by quasispecies differences, the ongoing RNAP error rate and the sequencing errors you mentioned seems to require some fine-tuned data analysis. In this regard, HCV patients everywhere would be enormously grateful if researchers would *release their damn data* and let others have a shot at analyzing it! (sorry, but this is one of my ongoing gripes).
Unfortunately, I can't get access to the full text of that Chang'07 paper, but from the abstract it appears they also support the no-mutagenic-effect-in-vivo position (here with a different virus, but presumably this is not relevant if mutations are based on riba as a generic guanosine analog) : "Sequencing analysis of the conserved polymerase regions of NV in the ribavirin-treated (100 microM) and nontreated groups showed that the mutation rates were similar and indicated that ribavirin did not induce catastrophic mutations."
As above, "similar" could possibly well be masking a mild mutagenic effect.
Are there other data that clearly support a role for riba an an HCV mutagen at in-vivo concentrations?
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