Hepatitis Researcher or Anyone one else with a good idea

[St. George]

How would someone taper off Infergen at the end if they were taking 15 mcg daily the entire treatment?  Would they taper off a few months leading up to the end of their 48 week treatment or might they finish up the entire 48 weeks at full dosage(15 mcg) and then have a 1-2 month extension which would be used to taper down?  Any thoughts anyone?

[geterdone]

Good point below, but overall it was just the abstract and not the full text.

Many cirrhosis patients and HCV patients did drink prior to tx....these tend to substitute a lot of sugar and extra carbs for the now absent alcohol, and this could account for higher LDL and TG's as well.

My TG's topped out at 499 3 months post and too high to get an accurate LDL reading, two months later and a drastic reduction of fat and sugar intake TG's dropped to 379 and LDL are on the high end of the range at 85 and would expect both to continue to drop in the coming months and if this was the price to pay for the SVR and being a 1b, I'll take it and then work the rest off as part of the post tx experience. One year on the antifreeze and additives and one year off to repair the damage.

jasper  

[merryBe]

hmm...so you are thinking the higher TG's and LDL did you good based on this??

But actually, if you look at the overall rate of clearance it was 43%, so that's 20% dropage from the 50-53% averages in most type 1 studies.

I'm not sure a 20% drop means good news. Plus, they didn't GIVE the substances, they merely measured them.
Having LDL and TG's go up during tx is common, and may be partly do to liver/fat conversions but partly due to insulin changes common with INF tx. Not surprisingly as even HCV non treater have higher levels of these, and anything which pushes towards diebetes, like INF therapy, will only increase that.

So my next question would be, how far out did they watch....did the liver remain compromised with higher levels a year or 2 out...or did they return to normal. This might be a factor of what stage one treated in and how much repair went on, but it could just as easily be an effect of eating habits. Many cirhosis patients and HCV patients did drink prior to tx....these tend to substitute a lot of sugar and extra carbs for the now absent alcohol, and this could account for higher LDL and TG's as well.

I think what we need to prove the point GD is a study administering additional lipids not just watching them.
As far as the PPC goes, decrease in fibrosis is to be coveted, but so is disarming the virons. I hope that you see my logic on that at least.

lets try to find something conclusive one way or the other, because I'd like to return to PPC, and Apha lipioc, and MK-7 (vitamin K-2) but I need something substantive to convince me this will not simultaneously give the virus a leg up.
Thanks for discussing this with me.
mb

[geterdone]

Well merryBe, it seems that I had lucked out again in that while treating I had loaded up on the extra fat with the riba and may have contributed to my SVR.

jasper

Treatment of hepatitis C virus with peg-interferon and ribavirin combination therapy significantly affects lipid metabolism.

Tada S, Saito H, Ebinuma H, Ojiro K, Yamagishi Y, Kumagai N, Inagaki Y, Masuda T, Nishida J, Takahashi M, Nagata H, Hibi T.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

Aim: We investigated lipid metabolism in patients with chronic hepatitis C virus (HCV), serotype 1, undergoing combination therapy with PEG-IFN alpha-2b (PEG-IFN) and ribavirin (RBV). Methods: A total of 185 patients with chronic HCV (HCV serotype 1; HCV RNA levels >/= 100 KIU/mL) who received a combination of PEG-IFN and RBV were enrolled. Results: Sustained virological response (SVR) was obtained in 82 cases (44.3%). The median age, red blood cell and platelet counts differed significantly between the SVR and non-SVR groups before treatment. However there was no significant difference between total cholesterol (TC), LDL-cholesterol (LDL-C) and triglyceride (TG) levels before treatment. TC and LDL-C levels decreased during the treatment in both groups. In the SVR group, TC and LDL-C levels increased quickly after the end of the treatment and were higher than those before treatment. On the other hand, TC and LDL-C levels returned to pretreatment levels in the non-SVR group and were significantly lower than in the SVR group. TG levels were elevated in both groups after the beginning of treatment. After the end of treatment, this elevation persisted in the SVR group, while TG levels returned to pre-treatment levels in the non-SVR group. There was a significant difference in TG levels at 24 weeks after the end of the treatment between the 2 groups. In the non-SVR group some patients achieved normalization of ALT (alanine aminotransferase) but persistence of normal ALT levels did not contribute to the increase of TC and TG. Conclusion: TC, LDL-C and TG levels increase only in patients with HCV, serotype 1, undergoing combination therapy when a SVR is achieved.
PMID: 19054155 [PubMed - as supplied by publisher]


http://www.ncbi.nlm.nih.gov/pubmed/19054155?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

[merryBe]

Yes I've been wondering about George too...not a peep in a good long while, maybe we should write him and say hello.

Yes well the lipid factor has always had me puzzled, more so in light of the statins helping (albeit most don't understand the risks there). Part of me thinks if you have fat on you, it won't matter how much you eliminate dietarily because they can always draw from fat stored in arteries of fat cells....(the little buggers do need to eat so th speak, so it could be statins make a difference in blood level, but blood levels alone may not translate to VL IF there's anything to my floater theory.  In other words if those lighter than air duded in full body armor AND raincoats and galoshes are the actual culprits that miss detection, AND the ones that come back to haunt...well...then some drug might be aimed at stripping them of their lipid shell..in fact that's in the works as a general effort of research now!  I just doubt it's specific to the floaters, but they have learned where in the lipid chain is most vunerable to attack...I think HR talked about that somewhere, been a while.

Meanwhile back at the factoy it brings up another good question:
has any study measured overall correlaries between levels of cholesterol, triglycerides etc and rates of SVR?
On my own, I decided to greatly reduce both meats and fats, hoping less lipids readily available in the blood stream might mean less well coated and ergo more vunerable virons.  I know it went against my PPC regime, but I finally thought of what needs to come first, reversing fibrosis, or killing the virus. I opted for a kill zone and lowered CH from an already low 150 to 111 by diet alone. Maybe it has helped who knows.

I know if you go too low you really can get sick, and go literally crazy (the cholesterol protects the brains and seretonin levels) so I've not gone to no fats cause that could be deleterious.  Hey there's one more squirrel question...did the folks who ended up most depressed clear at a higher rate? In other words is the stripping of cholesterol from the brain and subsequent sides a possible indicator of successful tx outcome.
Don't think they've gone there yet, but maybe.  They do say eat less fat....but that's mainly dur to difficulty in metabolism and wanting to avoid NASH,....

come to think of it....if eating less fat is recommended (by HR and others) why would lipids not also receive some cautionary notice??
I'm just too full of questions this week!

MB

[geterdone]

I wonder what ever happened to St George and did he make it to SVR?

jasper

[geterdone]

This topic of lipids and virus and centrifuging still has me baffled to this day and is a big unknown, and it is my belief that it holds the key as to why so many relapse after following soc protocol stringently and am sure research will bear this out in time going forward.

To the question of floaters, I was still uncomfortable about them (floaters) going into the end of treatment and had decided after reading all the related discussions to do things out side of the box, so to speak and because of insurance laps at the time it had afforded me the opportunity to get the additional meds needed going into the end of the journey.

My thinking was that every thing has a rhythm and comfort zone in which to thrive and when starting TX I was at the max dosages but had to drop back on the riba at 22 weeks from 1200 to 1000mg because of the sx’s but continued the INF at 180 so in the first 22 weeks it was a massacre for sure even though I had remained und. The next 22 weeks I had stayed at that level in the comfort zone but the adaptability of this virus to change and overcome its present environment had me reeling for answers in which none was found. Fear, just plain fear, leads me to defcon five to where the unknown of the lipid factor played a big part. To disrupt the comfort zone I had went back up to 1200mg of riba and increased the INF to 180 plus a quarter for two weeks in order to clean up what might be left and destabilize the environment of the comfort zone in which any super virions may have escaped and then tapered down off of the meds. HR’s pcr down to <2 reveled twice that the virus is under control of my immune system so far but will soon start statins to get the cholesterol under control and am going to be real ****** if the virus back because of the unearthing.

Anyway, hope HR can shed some new light on the lipid factor.

jasper  

[merryBe]

on rereading this thread the following question popped in my head regarding the discussion (posts below)
, has anyone asked if possibly the Supervirions ARE the floaters?  I mean has anyone actually tried to isolate and study JUST the floaters? Maybe they are the badest guys???: People test as UND >1-2....yet the virus comes back....something about those boyant floaters may be a key....after all, HR mentioned that it's the lipids that protect these virons, and it would seem to me the floaters might have the most lipids, which is why they resist the centrifuge...fat floats.....
I don't know....I just wondered if our resident researchers knew if anyone had studied floaters yet to discover if they were the superviron survivors.

mb


>>>>>>>>HR -The important thing to understand is, that in most cases, the actual sensitivity is higer than "2iU", that is five copies of actual HCV virions. Typically a single HCV virion in the ml of serum submitted can be reliably detected, but sometimes

*** a "floater" does not come down, or molecular accidents happen***,


so a safe margin of 5 has been officially designated. So you understand what this , in practical terms mean: better than 1U in most cases, as good as less than .4 iU in many cases. That’s what a NEG /UND will mean here.

So, in my thoughts, the question would be why these FLOATERS or Molecular accidents when centrifuged do not go to the bottom of the tube and why are the floaters so buoyant at a given centrifugal RPM? and does it have some merit for further investigation as relating to your question as to SOC survivors.

[willing]

sorry  Jasper, you'll have to take that up with HR - I have no knowledge of the specific techniques involved in centrifuging serum as part of running  a pcr amplification. Not clear whether the problem would affect  sequence analysis of SOC survivors as I've never seen a study that monitored VL of a relapse-in-progress (several have monitored acute-in-progress). Ideally one would want to sequence virus directly from infected cells at EOT. By the time VL becomes detectible in blood sequence may have changed sufficiently to hide the characteristics that enabled them to survive.

As best I know, there's no data on how deep the gap between surviving infected cells and detectible VL, though the presence of abundant neutralizing antibodies etc.  at EOT suggests the virus must already have made quite a comeback by the time you get to measure it again.

[geterdone]

Not bad for a commoner who has read nothing pertaining to the EOT and tapering off these meds with out benefit of in depth research but thanks for the clarification of the topic at such a late date in previous and present discussions.

http://www3.interscience.wiley.com/cgi-bin/fulltext/106594360/PDFSTART

jasper

[SteveHepC]

Has this Norwegian study held up over the years?

Peginterferon Alfa-2b and Ribavirin for 14 or 24 Weeks in Patients with HCV Genotype 2 or 3 and Rapid Virological Response (RVR): the North-C Trial"

Olav Dalgard et al, Infectious Disease Dept, Ulleval University Hospital, Oslo, Norway

The aim of the study is to compare the virological response of 14 and 24 weeks of treatment to patients with genotype 2 or 3 infection and rapid virological response (RVR). This is a randomized, multicenter study: 49 hospitals in Sweden, Denmark, and Norway. It is a non-inferiority trial. Patients were required to have elevated ALT, no biopsy required, and were treatment-naïve. Patients received pegylated interferon alfa-2b s.c. 1.5 ug/kg/weekly, and ribavirin 800-1400 mg/daily weight-based dose. Rapid viral response was defined as HCV RNA <50 IU/mL at week 4. Sustained viral response (EVR) was HCV RNA <50 IU/mL 24 weeks after end of treatment. If patients were HCV RNA negative after 4 weeks they were randomized to an additional 10 or 20 weeks treatment. Patients who were HCV RNA positive received 24 weeks treatment. Dalgard had previously published results of a pilot study of 94 patients (Dalgard, Hepatology 2004) where the SVR rate was 91% and relapse rate was 9% with 14 weeks treatment.

[geterdone]

BTW thank for the links in your post, very interesting studies on lipids as well.

jasper

[geterdone]

sorry for bastardizing your last post but it is the only way to bring some aspect together.

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.)

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,

*** It seems very little is known about soc survivors. This seems an straightforward research area and it seems we know very little about what soc-resistant virus looks like.

**********************************************************************

Willing to me this would bring back a prior comment on another thread that kind of got washed out but may be an input here. It pertained to the Labcorp’s HCV NGI ultraqual 2-3IU/ml and that this test performed prior to or at the EOT be it 48 or 72 weeks would show what viroins survived the duration of treatment and may give some clues as to why they had survived.

***********************************************************************

Previous thread comments,

I would tend to think that these left over Super Virions would be the focal point of any ongoing studies and maybe they are but it would seem to me that after 48 weeks of tx what purpose would it be to increase dosage at the eot if after the specified number of weeks these few virions are left. Would they not be the Most Resistant, therefore the std combo would be useless at this point.

I understand that there are two different scenarios working here, one is RVR and the other is a slow responder but either way at the end of tx, be it after 48 or 72 weeks and these different blood test are completed and both show traces of the Super Virions left even down to 2 what would be the course of action at that point?

That was the other question I had for HR but may have not been put point blank.
He has invented these sensitive blood test and has been able to get the vl down to its lowest point at the present time and I am sure he has used the ten vial study or else he would not have mentioned it. So, the next question would be, for me at least, if after 48/72 weeks of sdt soc what would make these few SV so resistant (or lasting longer than the others) over that time and is he involved in any on going study in connection with his inventions and other researchers as to why these virions are so resistant or what separates them from the others that have been eradicated or mutilated beyond the replication stage.


HR -The important thing to understand is, that in most cases, the actual sensitivity is higer than "2iU", that is five copies of actual HCV virions. Typically a single HCV virion in the ml of serum submitted can be reliably detected, but sometimes

*** a "floater" does not come down, or molecular accidents happen***,


so a safe margin of 5 has been officially designated. So you understand what this , in practical terms mean: better than 1U in most cases, as good as less than .4 iU in many cases. That’s what a NEG /UND will mean here.

So, in my thoughts, the question would be why these FLOATERS or Molecular accidents when centrifuged do not go to the bottom of the tube and why are the floaters so buoyant at a given centrifugal RPM? and does it have some merit for further investigation as relating to your question as to SOC survivors.

jasper

[willing]

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.

[jmjm530]

The last post belongs in another thread. Please disregard.

[jmjm530]

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

[jmjm530]

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

[GoofyDad]

Isn't Dr Cecil a fan of the tapering in approach???

[jmjm530]

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.
-------------------------
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

[jmjm530]

I answered more fully in your other thread with same question. But briefly, sounds like your doctors shot you in the foot with this "tapering-in" approach that goes against the "hit it hard, hit it fast" approach used by most leading hepatologists with the aim of reaching RVR. So, yes, your're in a dilemma because it's unclear if you would have been RVR with full-dose meds, and it's also unclear if a slower viral response with underdosing (as in your case) should be handled in the same way -- or differently -- as a slower viral response with normal dosing. Getting weekly VL tests on normal doses should help you somewhat in the decision to see the difference the increase will make.

-- Jim

[geterdone]

HCV and IFN Induction (Dr. Michael Gale, Jr., University of Washington)

In cultured hepatocytes, HCV RNA is sufficient to trigger IFN production through processes that signal the activation of IRF-3. This signaling is initiated by RIG-I, which binds to double-stranded regions of the HCV RNA and signals downstream IRF-3 activation. To evade this process and to attenuate the production of IFN during infection, HCV directs a blockade of RIG-I signaling through the actions of the NS3/4A protease.[18] Studies in the past year have identified an essential adaptor protein of RIG-I signaling, IPS-1. Remarkably, the HCV NS3/4A protease targets and cleaves IPS-1 early during infection, thus ablating RIG-I signaling of IFN production by the infected cell[11] (Fig. 2A). These findings indicate that HCV evades the innate immune system and turns down adaptive immune responses through intracellular alteration in IFN induction and thus allows for persistent infection and perhaps blunting of therapeutic effects of exogenously applied.
If this holds true in the beginning of the virus cycle and the suppression of the natural occurring interferon would it also not hold true at the EOT?

(Laymen here so be easy) So, form what I gather is that the immune systems is weakened by the onslaught of the virus and subsequent chronic condition of the same over time, which has pushed the natural producing INF to below normal levels by the HVC blocking mechanisms IRF-3 which is initiated by the RIG-1 and keeps it at that state of alteration during the infection cycle, but with the induction of the synthetic interferon, it raises it and keeps it at a artificially higher level during treatment but when abruptly stopped at the EOT there is a void or lag time because coming off of the interferon is in such a short duration and is faster than the immune system; which has been depressed for a long period of time by the HVC blockade has not had the time to regenerate its cellular pathways to start producing its own natural interferon, which may take a week, month or longer, who knows but the bottom line is that during that time any weakened stragglers or super virions left behind may have the golden opportunity to start replication and faster because of the absents or lack of natural acting interferon. So the tapering off of the interferon would allow all the systems to readjust theoretically at the same controlled time and at some point there would be an equilibrium point reached between the synthetic interferon and the autoimmune response interferon in which any weakened remaining remnants of the virus would be put into check or eradicated.

jasper

[Hepatitis Researcher]

willing
" It seems likely  that the stock of available CTLs are not doing their job either because (1) the infected cells are not presenting MHC-I attached viral epitopes or (2) CTLs with the appropriate receptors have not been activated"
So, if you dont reduce the IFN at least somewhat gradually, you might temporarily shut down MHC-1 expression to the extent that the CTLs have little to find on the cells surface, leading to an unfavorable high colony size by the time the MHC expression intensity situation has come back to "normal" by the slowly kicking in of the intrinsic IFN production.


Let us not forget that the real situation with respect to epitopes is never black and white, but there are numerous shades of "epitope quality" and, very importantly,  epitope QUANTITY available for presentation/recognition. There are many dynamic equations going on simultaneously, with a net overall effect.
In this context considering the relevance of the intensity of nonstructural HCV protein expression and the extent to which those are being processd in proteasomes might be the crucial aspect ( Low MHC - too low presentation of an already nonabundant epitope class).
We can genrally assume that the nonstructural proteins - with quite a quantitative margin/difference  even within that class have potentially less adapted epitopes/= potentially more reactive ones, because the number is small and they have not been selected against and because of higher structural/functional sequence constraints they are harder to mutate away from  for the virus..


In HBV we have exaclty this situation, and it is well researched and proven : The Polymerase contains an abundance of good CTL epitopes, and the blood of acute and astonishingly some chronics contains quite reactive CTLs to those epitopes - yet no cytolytic action - no effective defense.
The reason for the insufficiency of these epitopes, that are well binding and effective  ex vivo - is actually quite simple : there are very few polymerase molecules  synthesized per cell and they are not typically processed into the class I pathway, so the hepatocyte surface only rarely shows even a single one of these epitopes.
So we have to keep this in mind.

Why by the way do we (or the mice in the model) still have CTLs agains these? Again, simple answer: The large amount of virion debris picked up by the peripheral dendritic cells will digest these remnants and  - using class II to class I transpresentation pathways - will certainly mount a CTL response that you can find in the circulation - DOING UNFORTUNATELY NOTHING USEFUL.
Transfer experiments of these CTLs in the Chisari mouse model have confirmed that these highly active CTls working on well sticking epitopes do very little upon transfer to a recipient, while the CTLs directed  towards an abundant epitope  - like the eAg/core one - upon passive transfer - lead to fulinant hepatitis in the passive recipient!!

Thus the abundance  AND presentation/intracellular processing of a nonabundant viral protein with potentially reactive epitopes is an extremely important variable in the understanding of the final "vigor/actual effectiveness" of a CTL/epitope pair.

I have detailed this thought,( that even Tcell vaccine developers sometimes are missing ( looking only at the "vigor" of the response as measured in the CTL assays) and not if these CTLs can actually find something where needed)
because it leads up to my current pet theory on how Nitazoxanide might actually work:

It causes misfolding of a substantial portion of viral proteins - including nonstructural ones.
This misfolding , as you know, will invariably lead to a redirection of a very substantial portion of the HCV protein processing into the proteasome - the garbage can of the cell.
Now these nonstructural epitopes appear on the hepatocyte surface in much higher numbers - and we have a new high quality CTL recognition/killing/noncytolytic local cytokine antiviral effect!

[geterdone]

1/8 at 53 got it and thank you very much for clarifying what was thought to be a very logical final step of treatment.

I do have another question and it pertains to a recent post and has to do with HCV NGI ultraqual" (2-3 IU/ml) thread where it was mentioned about the centrifuge and “floaters” not being pushed to the bottom. These “floaters” has stuck in my mind and begs the question why do they not go to the bottom with the rest when centrifuged but that would a topic for another thread, again Thanks HR!

Jasper


On a lighter note from the beginning of my posting journey,

Looks like parole from Hepmax Prison Blues is imminent and the guy Three Doors Down in cell #3 that sang In Constant Sorrow all his live long days is looking back up three cells with questioning eyes are you going to The Big Rock Candy Mountain! Yup! but I’m moving the tracks a little further down the line, but I’ll see you all in the coming fall, in the….!

Geterdone/jasper

[willing]

as the authors of that study note "One shortcoming of the present study was that genotyping was not performed". The importance of that shortcoming may not have been as evident 12 years ago since the  difference in susceptibility of different genotypes to tx were still speculative: "The role of
subtype analysis as a predictor of response is rapidly evolving and will no doubt be one of many host and virological factors with chronic hepatitis C treated with alpha interferon"

From their Figure 1, of the starting 106 patients, only 47 had normal ALT at 6 months and thus were eligible for tapering. Of these 47, 21 were assigned to the stop group and 25 to the taper group. If we assume the national distribution of geno 1 at 70% that would give 14 geno 1s stopping at an inadequate 24 weeks in the first group and 17 geno 1s continuing to something more closely resembling the current SOC (inadequate dose towards end of tx, but 4 weeks longer).

Their definition  is "Sustained response was defined as persistent normalization of serum ALT from the time IFN was discontinued until the end of the 24-month protocol", which clearly doesn't match the  current VL-based one, but from the last line of their  table 3 it seems that only 16 of the 47, or 34% got to SVR, not a very exciting number. It's hard to gauge how much of this was due to inadequate tx duration for the 1s, how much to the lack of riba, how much to the 3-weekly 3MU ifn dosing.

The concept of gradually reducing the ifn dosage seems very reasonable, but I believe the inadequate tx duration for 1s among this patient group makes it hard/impossible to gauge the strength of that effect from that study. I didn't do a full citation search, but an abbreviated one only turned 3 cites, two of them self-references from Shiffman's other reviews.

My personal hunch, based on the notion of EOT as a rerun of acute,  is that if in fact riba *is* an hcv mutagen, which unfortunately it appears not to be, it would make more sense to continue the riba than the ifn. We know virus-infected cells remain  at EOT (or there would be no relapse). We know the HCV-specific CTLs are in a whipped up state because they long-ago eliminated all serum virus (and also because their mis-directed cousins are triggering various autoimmune disorders such as psoriasis and thyroid function). However notwithstanding this frenzy they have not been able to kill off the remaining infected cells. Possibly they need more time, but even extension has a moderate impact on overall relapse reduction. It seems likely  that the stock of available CTLs are not doing their job either because (1) the infected cells are not presenting MHC-I attached viral epitopes or (2) CTLs with the appropriate receptors have not been activated.

Either way, continuing the artificial stimulation induced by more IFN seems less valuable than having the infected cells finally give themselves away by exposing  epitopes that will be recognized. The virus may be able to shut down ifn generation in infected cells but the normal ifn synthesis pathways should kick in healthy cells as the infection starts to spread. Continuing external ifn for a bit longer may help avoid the situation where the speed of viral replication overwhelms the ifn response but the larger omission seems to be something that will make infected cells visible to the CTLs.

[Rangle]

I hope this is not a stupid question? ...they tapered off the riba also?

all the best
Rangle