get: yes , that's the "virus may be able to shut down ifn generation" effect I was referring to above which presumably leaves recognition & destruction of infected cells entirely dependent on externally activated CTLs.
"targets and cleaves IPS-1 early during infection thus ablating RIG-I signaling" does that sound like disabling the alarm when you first break in or what? Turns out that's only one of a slew of immune-evasion tricks hcv manages to pack into its tiny 9600 bp genome. From a recent review..."The ability of HCV to antagonize the TLR3 and RIG-I pathways is remarkable and revealing, but this is probably only the tip of the iceberg in terms of interactions that this clever RNA virus uses to outwit its supposedly sophisticated host". (from PMID: 17522203 )
hr: a couple of unrelated comments (and a thanks for contributing so much to this board!).
- my criticisms about the Shiffman'96 paper were only directed at that study as inadequate evidence of the benefits of tapering. I agree the approach seems very reasonable and it would be good to see it validated. However it raises a larger question that both goofydad and mremeet have brought up recently regarding mixing strategies for combo tx. (how to best combine vx,soc,ntz,r1626, etc.) Tapering is effectively a recognition that the prescribed ifn duration may not have been sufficient for eradication but that, with some help, the stimulated adaptive response can do the rest of the job on its own (sort of a pulling-out of Baghdad..). Optimally combining drugs would seem to require knowledge about each drug's likely survivors. Whereas Schering and Vertex know a lot about the survivors of their respective 796 and 950 PIs, iIt seems very little is known about soc survivors. This seems an straightforward research area. Even without collecting tissue bx at EOT (which would be preferable) it should be sufficient to monitor patients weekly post-EOT clone the first serum-detectable virus, analyze it for mutations, quasi-species phylogeny etc. and compare it to the last observabe sequences at start of tx. Yet this does not appear to have been done; it seems we know very little about what soc-resistant virus looks like.
- re the inadequate concentration of hcv proteins, there is an '05 study by Bartenschlager ("Quantitative analysis of the hepatitis C virus replication complex." PMID 16227280) that gives some insight into concentration and RNA/protein ratios:
"Every active replication complex must contain at least one negative-strand RNA molecule; therefore, the amount of negative-strand RNA gives the closest estimate of the maximal number of HCV replication complexes per cell. Based on this assumption, we found on average fewer than forty active replication complexes per cell, but each was accompanied by 20,000 to 40,000 copies of NS proteins.". This was in huh-7 cells, not in-vivo. However, given their conclusion, "Based on this knowledge and on our data, we estimate that only about 1,000 positive-strand RNA molecules are synthesized per day per cell by ca. 100 replicase complexes but more than 1,000,000 copies of NS proteins" it would seem failure to detetct infected cells is more likely due to poor presentation than concentration.
- the ntz as misfolding agent theory is interesting. I never found anything that elaborated on the claim for ifn2-a phosphorylation inhibition in their aasld abstract. This would presumably make ntz's effect independent of the ifn->pkr path, a big plus. There also seems to be some evidence that hcv might be able to get itself translated even without the benefit of *any* initiation factors ("Initiation factor-independent translation mediated by the hepatitis C virus internal ribosome entry site" - PMID 16556939) . Though that feat required non-physiologic mg2+ in the lab, I wouldn't put it past the wily virus.
The last post belongs in another thread. Please disregard.
OK. Here's something a little bit more upbeat. It's Magnum's first post when he's starting. However, if you scroll down the thread, you'll see some other posts, including one by one of our member's "Double Dose".
Apparently Double Dose did exactly what you are doing (without the pre-dosing riba) and he was UND at week 2, however he did not SVR that time (he did SVR with later treatments). He speculated that he didn't SVR that time because he had to drop his riba dose.Anyway here, and note he apparently broke up the Infergen injections as opposed to taking all 30 at once.
http://www.medhelp.org/forums/hepatitis/messages/39818.html
Yes, and he's also a fan of extending treatment up to 2 years for those with significant liver damage, regardless of RVR -- and 3 years in some cases. Could there be a correlation between this and the tapering-in approach? Unless tapering-in is trialed, and trialed successfully, I think it's starting the game with a short deck.
-- Jim
Isn't Dr Cecil a fan of the tapering in approach???
Rangle: My enzymes were extremely high,.. (they went as high in the summer as 2300/1800 ALT AST),... that was the reason for tapering in.
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I'm unaware of people treating with enzymes that high, so I can't really comment on whether "tapering in" makes sense in that scenario. However, I can offer thoughts and questions.
1) How long have your enzymes been this high and did your doctor investigate what the reasons might have been? Is it possible you were in the acute stage? What about liver toxins such as taking the wrong supplements, meds, etc?
2)Why didn't your doctors wait until your enzymes came down some before treating. My enzymes were around 1000 at one point due to some herbal supplements and my doc told me to wait till they dropped some.
3) Is your doctor a liver specialist (hepatologist) or a GI? In any event, you might want to get a second consult from a hepatologist, regarding your entire treatment approcah. It may turn out that your medical team did exactly the right thing with this tapering-in approach due to your very elevated enzymes -- on the other hand, it may turn out that they don't know what they're doing. I would want to know which one it is. If it turns out the latter, then I'd swtich.
All the best,
-- Jim