hepatitisresearcher

Finanancial, patent, and marketing issues aside - why couldn't S-P's alpha2b be combined with Roche's branched PEG molecule. It seems like a logical next step.

[Hepatitis Researcher]

Might be a good drug -a 40kd pegylated IFNalpha2b. Well the financial issues and the feasibility and the likelihood of this being an improvement over the existing 2a etc, etc  are all elements that his will not happen.

[returntosender]

So green tea is good or not good?  Having you over after a family fight is a little embarassing.  Thanks for taking the high road, but such a very high road that I cant get my scooter up there.  I do love it when you talk that science stuff - makes me pine for my high school chem class. I was a chem engineer major in the sixties who unfortunately discovered chemicals firsthand. Just kidding HR, as they say Ne bella! si fai un onore a passare di qua.

[desrt]

You sound like me: I wanted to be a pharmacist and settled for 'practical pharmacology';-o

[St. George]

I have been heavily researching the TH1 response of the human immune system and how it effects svr in hepatitis c. I have come to the conclusion that a heavy lean towards the TH1 arm is needed to topple as well as remain svr.  When it comes down to it Hepatitis c is a malfunction of the immune system which is stuck in the TH2 mode but adjuncts such as Maitake d-fraction, ahcc, beta glucans may assist the peg/ribavirin in creating and maintaining a th1 driven enviroment.  What are your thoughts?

[sfbaygirl]

"People in a caved in underground tunnel should calmly dig, never fight and waste no air. But of course, if the direction of digging is not clear..."
   Start grabbing for rocks? Or stop digging so you don't dig yourself in further?

Thankfully, we have researchers (like you) that can answer those questions, at least eventually. In the meanwhile there are many of us who grasp at information like it were water, because we need answers we don't seem to get from our doctors or current studies. Of course, we can get "indicates" this, or one study to support a particular theory, not 5. I understand this, as Hep C research is fairly new, underfunded, and not as "popular" a cause, as HIV or cancers with the general population. There is such stigma with this virus. Anyway, I won't rant anymore....

[St. George]

I must tell you that interferon/Riba combo isn't extremly scientific either.  My physician explained to me that when the first incarnations of the combo surfaced years ago the 3x's a week dosing schedule was put into effect because of the reserchers schedules.  Meaning, that they were in the clinic where it was being tested on Mon/wed/fri.  Now theres hard science for you.  Lets all bow down to the pharmaceutical giants and worship at their feet.

[jmjm530]

Here are the studies referenced in the article originally posted by St. George

References

G L Tipoe, T Leung, E C Liong, and others. Antioxidant and Antiinflammatory Effects of Green Tea Polyphenols in Carbon Tetrachloride Induced Liver Fibrosis in Mice. 57th AASLD. Boston, MA. October 27-31, 2006. Abstract 1062.

G L Tipoe, C Ho, E G Liong, and others. Green Tea Polyphenols Ameliorate Pathological Changes, Oxidative Stress and Pro-inflammatiory Markers in an Animal Model of Non-Alcoholic Fatty Liver Disease [NAFLD]. 57th AASLD. Boston, MA. October 27-31, 2006. Abstract 1063.

[sfbaygirl]

As I said earlier, there is little funding for Hep C, except through drug co's. It makes me angry too that more is not done, but what can we do? If we had some poster child for Hep C, I bet more researchers would work round the clock to help us. I am grateful for the ones that do. At least we have something that can work.

[sfbaygirl]

Who is Miles Keaton? I am bad with names....

[desrt]

Try mkandrew.com

[willing]

hr: you mentioned you would discuss cryo/hcv issues in a forthcoming post. It would be interesting to hear your comments on the validity of the data in <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16628675&query_hl=6&itool=pubmed_docsum">Giannini'06</a> which touches on a number of the topics discussed.

jim: re the apples vs oranges, it might be clearer if you look at it from the point of view of when one could use a sensitive test to discontinue tx. Consider the guys who had TMA-detectible serum at EOT and, not surprisingly, relapsed. Say all their tests had been done at high sensitivity, would this have helped them? If they showed VL at week 4 they certainly wouldn't have quit, nor if they had VL at 12 but had achieved a 2-log drop per the SOC definition of an EVR <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=12939591&query_hl=15&itool=pubmed_DocSum">Davis'03</a>.
They get to week 24, still have VL but at a low level, say 40. Per Davis above (and echoed in other studies) chances of getting to SVR if you have VL at 24 are tiny, but though there's lots of  patients, the study is base on an  NGI < 100 copies test (I think HR mentioned NGI's copy->iu factor below). Thus all that data tells you nothing about how many of the eventual SVRs still had residual low VL at 24 weeks. Since they meet the Davis criterion they push on to week 36 but there's no data to compare with, and then it's 48...

As long as the high sensitivity tests come out und they give you reason to smile, but as far as actually guiding a tx decision, (it's not going to work..) they don't really help because there's not yet much to compare with (the "new" 4 and 12 week Berg/Sanchez data being the exception).

[sfbaygirl]

You talkin' to me? So much bantering, it's hard to tell. LOL

I have no idea how my liver is. Hopefully, getting clear of the virus and fibrosis. My ultrasound said that I had....fatty liver versus cirrhosis. I haven't had a biopsy for over 5 years. It was a stage 1 then. No telling now, except a poor ultrasound. That's why I am hoping to get a fibroscan.

[jmjm530]

Here are some brief exerpts that should not violate any copyright infringements:

...According to the researchers, green tea polyphenols exhibit both antioxidant and anti-inflammatory properties. These polyphenols consist of several components, including (-)-epigallocatechins gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epicatechin. EGCG, the strongest antioxidant, modulates a number of events in the progression of liver injury, such as oxidative stress and inflammation.

Study 1

The first study investigated the effect of EGCG on artificially induced (by CCI4) inflammatory response and oxidative stress in liver fibrosis in mice. Male ICR mice were injected with CCl4 with or without EGCG for a period of 8 weeks. EGCG (85% pure, 50 mg/kg) was injected 3 times weekly....


Results

    An extensive amount of induced liver injury in CCl4-treated mice was detected, as shown by a high level of serum ALT, greater areas of collagen, increased oxidative stress as indicated by high levels of nitrotyrosine formation, and increased DNA-binding activity of NF-kB.

    Expression levels of NF-kB regulated genes TNF-alpha, COX-2, and iNOS were markedly up-regulated after CCl4 administration.

    Pretreatment with EGCG effectively reduced CCl4-induced liver injury as shown by the lower level of serum ALT (P < 0.01) and collagen accumulation (P < 0.001).

    Treatment with EGCG was also associated with significant reduction in the expression of COX-2, iNOS, TNF-alpha, nitrotyrosine, and NF-kB (P < 0.01).

    "Our results suggest that EGCG attenuates CCl4-induced fibrosis, probably through the inhibition of proinflammatory mediators and the reduction in the level of oxidative stress," the researchers concluded. "The decreased expression of proinflammatory mediators is mediated by decreased activity of NF-kB, which leads to a decrease in levels of proinflammatory mediators."

Study 2

In the second study, the same research team examined the effect of an 85% pure EGCG extract on the development of pathological and biochemical changes in a recently described dietary model of non-alcoholic fatty liver disease (NAFLD)....


Results

    The NAFLD rats showed significant fatty changes, necrosis, and inflammation.

    The presence of fatty liver and necroinflammation was accompanied by a significant increase in NF-kB activity and upregulation of TNF-alpha, COX-2, iNOS, and nitrotyrosine compared with the controls (P < 0.01).

    Fibrosis was also greater in the NAFLD group.

    Treatment with EGCG significantly attenuated the pathological changes, including fibrosis, and down-regulated expression of TNF-alpha, COX-2, iNOS, and nitrotyrosine (P < 0.01).

    Treatment with EGCG also significantly decreased NF-kB activity (P < 0.01).
    "EGCG reduced the severity of liver injury in an experimental model of NAFLD," the researchers stated. "The improved pathology occurred in association with lower concentrations of lipid peroxides and pro-inflammatory mediators."

Based on the results of both studies, the researchers suggested that green tea polyphenols may be a useful therapeutic agent for treatment of hepatic fibrosis and a useful supplement in the treatment of NAFLD...

[St. George]

This half assed 3x's weekly dosing schedule went uncontested for years.  That is not proper science, lady or sir.

[desrt]

My understanding of 3x/wk dosing was that it was based on what the human body could stand of IntronA - not on half-life, scheduling, or anything else.
But that's purely anecdotal.

[sfbaygirl]

Of course science isn't always accurate. This is why we have "experiments" and "trials". I am awful at science, but I know you have to start somewhere. Where would we be without those scientists who did the interferon on their schedules, perhaps we wouldn't even have it now. It might have been prohibitive to do otherwise. It eventually led to pegalated interferon....

[bobbyullc]

3x a week was on interferon. when peg-interferon was developed it was like  the time release capsules for a cold. it lasted in the system longer so therefore less injections were required for the same results. it had nothing to do with clinic schedules. that is like saying the drs. were willing to let people die or at least suffer so they would not be inconvienced. i have a much higher opinion of my fellow man and dedicated researches than that. if i am wrong why not go now...life s@cks.
bobby

[jmjm530]

Briefly, I think some more advanced clinicians would accelerate/extend treatment if someone was TMA positive at week 12 but under let's say 100 or 50 IU/ml. And the same clinician might discontinue/alter/acellerate tx in certain cases given the same scenario at week 24.  

However, if all that was available was the less sensitive assay, then there may be no accelerations, extensions or discontinuances because the PCR Negative/TMA positive patient would be seemingly negative the entire time when in fact they had virus somewhere between 5 and 50 or 100 IU/ml.  At least this is the sense I get from what heard and how I was treated. Again, when I asked someone who has written extensively on RVR, he emphasized that the fact I was non-detectible *using very sensitive assays* for the duration of treatment suggested I not extend beyond 48 weeks.  Had I tested using a less sensitive assay, he might not have been as adamant in that opinion.

As far as actual study data, I'm a bit at a loss because the viral sensitivity of tests used under the heading of "non-detectible" is in most cases not detailed in the abstracts, and much of the older study data, especially from Europe only goes down to 50 IU/ml.  Just looked up Drusano, for example, and I couldn't find their definition of non-detectible in terms of VL on the abstract. You mention Berg/Sanchez, and wasn't there another similar study that Dr. J discussed with NY Girl. What sensitivities did they use to define "non-detectible" ? Last point, about the "smile" -- yes, the more sensitive tests might make me smile but do you really think that's the only reason more and more clinician's are using the very sensitive tests now? I'll try and look some more stuff up on this but for now this is the best I can do.

-- Jim

[jmjm530]

First paragraph a bit unclear. It should have read:

Briefly, I think some more advanced clinicians would accelerate/extend treatment if someone was TMA positive at week 12 but let's say between 5 IU/ml and either 50 or 100 IU/ml. And the same clinician might discontinue/alter/acellerate tx in certain cases given the same scenario at week 24.

[jmjm530]

Come to think of it maybe HR can help here since he was involved in developing some of these more sensitive tests. I guess the basic question is how much value do sensitive tests have in terms of treatment decision making. As a pre-emptive, I do remember HR stating some time earlier that the most sensitive test may not be needed until the patient starts approaching being non-detectible, but I'll argue that in a case like mine -- where I had weekly VL tests from week 1 until I became non-detectible -- that a very sensitive assay would have been useful from the very beginning since you never really know how fast any one particular person will drop. As mentioned my week 2 viral load test was non-detectible at <600 IU/ml. More data could have been gleaned if we had used a more sensitive test, and perhaps I could have been yanked off my double-dose and high-dose riba a little earlier and back to SOC.

-- Jim

[desrt]

My next question would then be, is high induction dosage to force a serum undetectible result  a 'True' undetectible or just another type of 'artificial undie'.

[jmjm530]

Gave this a little more thought last night and this may be one of those cases where I may disagree with myself if that is
permitted :)

In re-reading some of my older posts, I realize I have been using 50 IU/ml as a working definition of a "sensitive" viral load test because of its use in many of the studies, for equal comparison purposes as you say.

So perhaps then, a revised thought is that a test with a sensitivity of 50 IU/ml is adequate for tx decisions based results at let's say week 4, 12 and 24. The caveat here though is that the newer trend seems to be "non-detectible" and not a "two-log" drop as I think you inferred from some of the older studies. But it does appear to be that under 50 IU/ml and "undetectable" are synonomous in many of these studies.

That said, once non-detectible to 50 IU/ml, the advantage of the even more sensitive TMA, as I see it, is that it will further test to make sure that the virus continues heading in the right direction with is South.

Then, once non-detectible by sensitive TMA -- quantitative or qualitative -- it seems logical that one should continue with the more sensitive assay to make sure the virus stays South as opposed to bumping back up somewhere between let's say 5 and 50 or 100 IU/ml -- as it appears to sometimes do in the group of PCR negatives who are TMA positive.

OK. now that I've disagreed with myself, I'm going to paint another scenario where I disagree with my new reasoning and agree with my older, if I may be permitted :)

I want to forget all the studies for a minute except the one that says a certain percent of EOT PCR negatives are TMA positive and 100 per cent of that group will relapse.

Extrapolating backwards, it seems logical some (perhaps many or all) in this particular group -- let's call them
"False Negatives" -- were false negatives not just at EOT but back as early as week 24, maybe week 12, maybe from the beginning. In other words, they were never "True Negatives" which we can define as being negative with a highly sensitive assay of 5 IU/ml.

So, if this group has always been false negative it seems like the handwriting was on the wall for their relapse very early on in treatment IF they took a highly sensitive assay, early on.

Using this assumption, it then seems reasonable for clinicians who want to optimize treatment outcomes by individualizing treatment programs to use these highly-sensitive assays very early on so that they can get this particular group -- and keep this particular group -- at True Negative status to prevent them from ending up in the unfortunate group of EOT PCR negs who turn out to be TMA positives, which I sort of characterized once before as EOT ostriches with their head in the VL sand :)

In summary, "sensitive test" (50 IU/ml) until non-detectible and then a "highly sensitive test" (<5-10 IU/ml) after that both during and after treatment. Hope this makes more sense.

-- Jim

[jmjm530]

Briefly, what's your take (if any) on Quest's Heptimax versus Quest's HV RNA Qualitative TMA using Bayer Versant technology? I'm talking about for someone who already demonstrated that they are non-detectible with either.  Both measure to 5 IU/ml. I started with the quantitative  Heptimax but now post tx use the Qualitative TMA because one doc suggested there may be fewer false positives. And lastly, how do you compare either test to the Ultraqual. Thanks.

[Hepatitis Researcher]

Its hard to judge other tests since there are always claims out and we have seen exagerated claims when there was an actual blinded comparison. Thus I do only know NGIs sensitivity for sure and i know that a comparison with heptimax was made and it came out to be about even.
With HBV there is another story re testing, that i have not told yet. It is a bit easier to get ultrasensitive with HBV since it pellets better in the ultracentrifugation step. Anyway, for research purposes only I have developed and occasionally use a test that detects down to .1 (1/10) of a copy. And it is quantitative too. With that test thus far I found nobody with PCR negativity" that was truly negative. Even people that had acute HBV years ago, "Cleared" the virus, Anti HbS pos... But that really is nothing too surprising. Too bad we cannot do that for HCV so easily.

[jmjm530]

Your area of work is fascinating. "Occult" and "Persistent" virus aside, if a test could be developed that correlated well with onventional SVR, it would mean that no one would have to treat one day longer (or one day shorter) than necessary. My doctor suggested that such a test is out there in theory and involves the T-cell response. Not his exact words, but he said something like if we could identify a "true" T-cell response from an interferon-induced T-cell response, then would know if someone would remain non-detectible after stopping the treatment drugs. This probably makes more sense to you than to me but I've love to hear your comments if necessary.

-- Jim

[jmjm530]

That must have been a very proud moment. Congratulations and thanks for your contributions, not to mention your answer.

[Hepatitis Researcher]

Just briefly to the issue of using "sensitive "tests as predictors" At the Chicago AASLD (I think it was 98) a late breaker abstract came out that compared the predictive power of ( I can say so) my ultrasensitive PCR ( about 2 iu/ml) with the HCV amplicor test. I will never forget that moment (I had a heavy cold and had to pay$500/night for that crazy last minute swissotel room) because that abstract # 2442 yes, that high! - from France showed that neg by amplicor at week4 was 42% predictive of SVR while NGIs was 92% predictive. So I called the fiancial partner in excitement ; How would patients like to know at week 4 of they will be SVR and which test would you use if your health depended on this... Somehow the full impact did not stick and the cold got a little worse.

So TMA and NGIs ultraqual are about the same and yes you need such sensitive testing from the beginning thats why there is now this " quantasure"... that will first do the quant ( 100 copy cutoff) then reflex to the ultraqual 5 or so copies! cutoff. if neg you only do the ultrasensitive from thereon.

[jmjm530]

Last sentence indicates that the rx for me is some sleep -- took the flu shot today and more tired than usual -- but I think you know what I mean.