Here's a related paper from the same group (Castillo, Rodriguez-Inigo, Pardo, et al):

<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16847959">Virus-specific T-cell responses associated with hepatitis C virus (HCV) persistence in the liver after apparent recovery from HCV infection</a>

(from the paper):

"<i>In conclusion, HCV-specific T-cells are detectable in apparently recovered individuals in whom HCV RNA can persist in the liver indicating that HCV replication may be prolonged in the face of an insufficient or inadequate virus-specific CD4(+) and CD8(+) T-cell response.</i>"


TnHepGuy

Here's a new paper where they measure T-cell response and determine active replication via occult:

<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17071928&query_hl=1&itool=pubmed_DocSum">Cellular immune responses associated with occult hepatitis C virus infection of the liver</a>

(from the paper):

"<i>These findings demonstrate that HCV-specific cellular immune responses are markers not only of previous exposure to and recovery from HCV but also of ongoing occult HCV infection.</i>"


TnHepGuy

thanks for posting the reference to the "dragon is back" thread; I had missed that discussion (vey easy to do given the current volume!). Accepting the presence of virus notwithstanding serum-UND results, accompanied by "an effective HCV specific immune response that also persists and keeps that tiny amount in permanent check", seems a very different interpretation than arguing that "none of these studies have been reproducible using methods commonly accepted".  

Note that in the Maylin'06 LB9 study they only had liver tissue for 116 patients and detected HCV RNA in 2 using the standard commercially-available Versant Qual TMA. Thus my earlier question about the alleged unreliability of the real-time amplification  of  reverse-transcriptase PCR used by Pham, Radkowski and Castillo. Whether the percentage of serum-UND patients with actively replicating HCV in liver cells is 2% (LB9), 95% (Castillo'06) or 75% (Mike's surgeon) seems to come down to amplification technique.

Perhaps this seems like quibbling over many RNAs fragments can hide on the head of a pin, but I think the answers may have important clinical impact (selfishly, even for me).  Since "It is after all the inflammatory response" which may kill a number of us prematurely, immunomodulatory drugs may be more expedient than the battery of new drugs that seek to block viral replication by inhibiting the function of its various proteins (polymerase, protease, etc.). That is, it may be more expedient to learn to live with the virus and keep it in check than to try to eliminate it.

hi and thanks for your contribution here. there has been much debate about the fibrosis serum marker tests. what is your opinion on the labcorp fibrosure test? how realible is this test in your opinion? i have read about being 80% accurate on the low and high end of F1 to F4 scale but wanted your opinion on it. thanks for you time.

To complete my thought on SS, above. Again, the point was not to criticize her diagnosis but to point out that even the best clinicians/researchers are as you say bound by the knowlege and technology of the day. This is true today as it was then and I believe is frequenty overlooked. Medicine can get very arrogant at times (not talking about SS) only to be proved wrong a few years down the road. Maybe this is in part why those in the pro-occult camp are so skeptical of what is termed "SVR" and why those in let's say the anti-occult camp are so skeptical of the conclusions of the pro-camp :) Skepticism is good, because history shows it is necessary, especially in a fast moving field like Hep C.

-- Jim

Thanks again for the info. Yes, SS was quite a figure, and I remember my hep doc at the time spoke of her in hallowed tones even though he was considered one of the best -- if not the best -- in this country. On good behavior I consider myself quite personable yet there seemed to be a wall of intimidation around the little lady that didn't allow you to speak unless spoken to. The slides, blood work, etc, she reviewed were for what was latter to be called hepatitis C, but in those days it was called "Chronic Persistent Hepatitis". The prevailing opinion then -- confirmed by SS -- was that if it Fibrosis didn't progress rapidly, the virus would burn out in 5-7 years. In my case, my initial biopsy was stage 0. Forgot if she was called in for my first or second biopsy but the thought was my fibrosis was not progressing therefore the outcome was good.
And, of course you are correct, one can not be held accountable for the technology of the day and I in no way meant to infer she made a mistake given the technology of the time -- as many doctors do, just read some of the posts here :) Bad analogy on my part.

Regarding some of the "Occult" and "Persistent" virus issues Willing discussed. I believe I have a good preview of your answer from your comments in the thread below "SVR for 4 years and now the Dragon is back". While I have not reserched this in the detail Willing has, I did discuss the issue with two well-known hepatologists I consulted with and I'll try and paraphrase what they said as best I can.

The first suggested that whatever viral particles were found were not fully "mature" -- my word -- and therefore of no real threat or consequence. The second questioned the actual methodology and said that none of these studies have been reproducable using methods commonly accepted. And of course, even in the other camp, almost all the studies have the disclaimer that no clinical significance has been demonstrated. I certainly don't pretend to have the answers on this and can only relate what I've been told so I'll leave it to the clinicians and researchers to battle it out and hopefully the future will tell more.

I added "DD" to the post which abreviates one of our member's moniker, "Double Dose". Double Dose is very intersted in intrafamiliar issues, specifically hepatitis-like symptomology within families where someone is HCV serum positive and the other symptomatic members are both serum and antibody negative.

Lastly, since you seem to be an outside of the box kinda guy, are you familiar with what I believe has been termed "pulse" therapy. It's where they administer peg and riba until the patient becomes non-detectible and then stop treatment immeditely be it one week, three weeks or twelve weeks. Then they monitor vl weekly and only start the peg and riba when vl is detectible. In theory this cycle is then repeated until SVR is attained although as of the last time I spoke to someone on this issue, no SVRs so far although apparently they have gotten people non-detectible for up to 3-4 months. My understanding is that these researchers feel that another agent in addition to peg and riba may be needed to prevent these relapses. The neat thing about this approach is that in theory it can potentially significantly limit the exposure to the treatment drugs and at the same time give the patient "rest" periods (when they're off the drugs) during treatment which from personal experience could be quite a relief both physcially and mentally. There was a study on this some time ago but most of the above was derived from a discussion with a clinician/researcher.

Thank you again for all your information and unique insights and like the others, hope you stick around.

Be well.

-- Jim

thanks for your reply, though perhaps I didn't put my question clearly. I was hoping you might give us some insight into a question that has been puzzling patients on this forum for some time. There is a growing discrepancy between on the one hand researchers who have reported detectable HCV RNA (+ and - strand) in liver, PBMC, macrophage and other cells extracted from patients who were UND in serum tests (either SVRs or treatment naive) and other researchers who dismiss such results as spurious/insignificant. There seem to be about a dozen recent papers in the former camp, including the Radkowski one linked above and others by Pham, Castillo, etc. The camp that is skeptical that serum-UND infection represents true infection seems to reflect prevailing opinion and includes prominent names in the field (eg Pawlotsky who you mentioned above).

Among the reasons given for dismissing serum-UND infection as true infection perhaps the most puzzling one, and the one I hoped you would give us your opinion on, is the reliability of the measurement protocols. The only differences seem to be that those reporting serum-UND infection examined cells rather than serum and that quantification was based on real-time PCR. However neither of these differences of themselves would seem to make their findings questionable. Perhaps the findings can be dismissed as contamination, but given the number of independent confirmations that seems an unlikely explanation. (Of course the "clinical significance" of serum-UND infection is a separate issue from its existence).

Thank you for your response and suggestion.

Would you kindly clarify several issues.
Like you said,the NGI Quantasure # 140639 is made up of three portions...Super Quant, Ultra Qual, and Poisson.

I read that NGI was the only Lab in the US to get FDA approval for a test that was used in testing the National blood supply.
This FDA approved test was not approved for commercial use, but NGI uses the same approved methodology in it's Ultra qual, which is part of the Quantasure.
Did I understand this correctly?
Makes me feel better to know that I am having a test done that was sanctioned by the FDA.
-------------------------


Jim
I am beaten up from the biopsy today. I catch you another time at another post.
This thread is filling up, and it's best to leave room for researcher. When a visitor of this caliber comes by, we got to pick his brains before he silently disappears LOL.
He may be gone already.

Ina

Re Sheila Sherlock - yes - historical figure in Hepatology. Was that a chronic HCV biopsy she was looking at?( Sorry, dont know your personal hepatitis data) In Medicine, even the uttermost genius can only build upon the technology available around them. Sometimes it takes new technology to tackle critical problems, like e.g. to measure HCV in the blood of people. The hepatologist has to wait for a molecular biologist to develop such means - then a new world of testing, understanding and treating can unfold. I am deeply interested in the borderline issues of HCV and HBv  like intrafamiliar spread, stabiity of SVR, optimization of treatment approaches, speed of progression  etc. You are right that everything has to be questioned. But then who has the answers - often nobody -and action ( like some form of Tx) is still a pressing need.
When I spoke at the AASLD to the Echosens people - they are not yet aware for the need to be fasting for reproducible results. It is not part of the official protocol. What I found is the following ; In patients who had regression of fibrosis or cirrhosis it seems to matter more how engorged the liver is because some remnant fibrous strands might get pretensioned by the engorgement that follows a meal ( All the increased intestinal blood flow  has to go through the liver!) Then, when the elastic pulse wave hits along such a fibrous strand you get dramatic stiffness. The Fibroscan measures the speed with which this elastic wave propagates which can be very high if local remnant strands are hit. If the liver is relaxed, like in the fasting state, there is no pretensioning and the average collagen content of the parechyma determines wave velocity.

How often to scan: Easy answer to that one: When there is reason to fear that your fibrosis has intensified ( flare up etc) or hope that the treatment has reduced fibrosis you want to know where you stand. Severe fibrosis can develop in several month of intense hepatitis ( or take 20 years to develop in some) Thus it all depends on the circumstances that might have induced a change. Once a year is a good guess some might need more frequent intervals.

The issue of measurement variability in VLs is also important but difficult to discuss in this format. Quality control is the critical issue here and at NGI I introduced four independent PCrs for each sample at different cycle numbers to increase the reliability of quantitation.
Treatment decisions should not be made based on placements of Vl in the midrange. It is after all the inflammatory response to the presence of virus proteins  in the liver that causes the damage and stellate cell activation to increase collagen production and fibrosis which impedes diffusion in the Disse space making it harder for the liver to process the portal blood and the distortion in architecture of the lobulus. Vl is not linearly related to inflammation, although there are some connections - because the immune activation in the periphery is caused by virions travelling to these peripheral lymphnode sites.

RE CONTAMINATION; In the old days we used special pipettes, negative Air rooms and more gadgets to avoid post PCr product to prePCR testing material contamination. When I read that the Mayo clinic had just opened a facility with nice room separations neg, air etc for HCV I was smiling, because I had based NGI on the fundamental concept that there is only one way to really prevent postPCR contamination: Half a mile of city air in between labs, Zero contact between personnel, one way visitors only.
Labcorps Taqman test is not done at NGI and i do not know their precautions in any detail.
You are 9month post tx and neg so far on sensitive tests. That looks good. The proper test for you from NGI/Labcorps menu is LC# 140609 NGI HCV Ultraqual.

On a similar note, I heard from very well repected clinician/researcher that he stopped using Heptimax because of what he believed to be some false positives, I assume in the TMA portion of the test. Because of this, I switched from Heptimax to Quest's
HCV RNA Qualitative TMA using the Bayer Versant technology. Actually, I did both (Heptimax and Versant) the first time and then for my six-month post tx test only used the qualitative. Could you comment on false positives and/or accuracy of the quantitative TMA portion of Heptimax versus the HCV RNA qualitative. Both go down to 5 IU/ml. Thanks.

Ina,

Don't know if you saw my post below but broke down and had some soy sauce with my sushi last night :) Been off bread and hopefully all foods containing gluten for about a six days. Not sure if it's helping my stomach other than I'm losing some weight. LOL. Also, been thinking of seeing a doctor of TCM about some herbs for my post tx problems such as skin and digestion.

-- Jim

Sorry I missed your posting of your enzymes until after I posted the above. Sorry about that, that is odd. What does the doctor say? Didn't you have a clear PCR post tx yet or am I mixing you up with someone else?

Thanks for the links.

So as I figure it then, I have 4,825,000 Copies of the virus.  So if the doc says we will treat for 48 weeks (as opposed to 24 weeks) should I still insist on having a bx?

At National Genetics the VL is always reported both in copies/ml as well as IU/ml. The conversion factor is 2.5.
If your VL is 2000000 IU,  it is 5 Million copies. That is quite high. NGi actually normally only measures up to 5 Million. Liver damage occurs over a wide range of VLs. Normal ALT is good, but not sufficient to rule out substantial fibrotic disease. There is a whole group of HCV patients with PNAL (Persistently Normal Alts) that is constantly discussed in HCV Hepatology and they have statistically a lower chance of disease progression, but for an individual patient this info is not very useful.

HCV normally progresses slowly. Knowing where you stand is important, also how fast are you progressing ( there are slow and fast fibrosers). In a few years combo treatments will be available with a clearly increased chance to become a SVR across all Genotypes.

Kalio, how low was your VL at your first and second treatment after four weeks.

At the NIh Hepatitis meeting in spring Jean Pawlotsky said that only IU should be used in the future. A storm of disagreement broke from the audience. If you can count something like people or viruses then give the real number - not an artificial pseudounit.

Just to reinforce what Friole is saying, my VL was 730,000 and I have cirrhosis. a biopsy was not recommended and only when I failed the first tx did I find out how damaged my liver was. I'd also encourage you to discuss Riba dosage with the others. I did 800 the first time and it should have been 1200.

VL is not a measure of liver damage, it tells you how much viremia is circulating in your serum and gives you a number when you start tx to go by so you can see when you reach undetectable status. Other than it's value in seeing if tx is working, it doesn't tell you much.

Lindy, either way - 24 or 48, I would insist on the biopsy.  I think he will want to treat for 24 weeks, with the option to extend to 48.  The other thing to push for is a PCR at 4 weeks.  THat, to me, is imperative.  The standard is 12 weeks but ask him for one at 4 weeks and if he says no, check with your insurance company.  They should pay for it if the doctor orders it, and that 4 week PCR is a pretty good predictor.  Some with 2&3 have even shortened their treatment to 12 or 16 weeks if clear at 4 weeks.  

One mr thing to push for is sensitive testing.  Find out which lab is used - LabCorp and Quest are the two most popular. The most sensative Quest test is the Heptimax and the most sensitive LabCorp is the QuantaSure.

Good luck
frijole

4 week testing with most sensitive tests is indeed critical.If you are negative then , your chances to become a SVR are very high.If you are not neg by week 12 chances are very low. The most sensitive test is Labcorps NGI Ultraqual ( LC# 140609) limit 2 Iu per ml. For dynamic range Labcorps NGI quantasure is slightly less sensitive, but gives you quant results 2- 2000000 IU/ml ( LC# 140639)

You seem to really know of what you speak! Are you a researcher with NGI?  I think only IU's should be given for viral loads too but am really curious what copies are in the first place.  Is a copy one viron?  If so, why are conversions different with different lab test?

Now I really want to know the difference between those labcorp test.  My doctor lets me pick the one I want and I would like to know what to ask for next time (which will be my 6 month post PCR).   You said ......"The most sensitive test is Labcorps NGI Ultraqual ( LC# 140609) limit 2 Iu per ml. For dynamic range Labcorps NGI quantasure is slightly less sensitive, but gives you quant results 2- 2000000 IU/ml ( LC# 140639)"

So this means the NGI Ultraqual - a qualitative test - is more sensitive than the Quantasure which tests to 2??????  Please explain.
Thanks, frijole

First round, I was  UND by week 12, at that time a year ago I didn't know the importance of requesting testing at week 4. This round, I was clear by week 4. I did double doses of IFN for a month and 1600 riba a day for that month. Then I went to 1200 and regular IFN doses.

Got my fingers crossed for good news this spring!

How about you? Are you treating?

Isn't hind site grand?  Right about now I am wishing I did those full 72!  You re definitely reight about the low viral loads and liver damage.  It is down right scarey.

What scares me is doctors saying this stuff to patients. That and it is pretty standard to not do biopsies on geno 2 and 3. that is a dumb stance, they should encourage all to have a biopsy (and hurry up with the noninvasive "biopsies")I think the patient risk of NOT having a biopsy is higher than if they do. Here they are, shocked they have this illness then the doctor fills them up with misinformation. If they don't do the research their health can suffer the consequences. To me judging by low viral load or low enzymes is very risky. Once a doctor has given a pateint incorrect or false info, then it is much harder to get them to listen to "the facts" because they trust in their doctors. Oh it frustrates me so! Had one of the many doctors I was seeing over my back surgeries and other various problems I had diagnosed me right I might have saved my liver some. Every one of them misdiagnosed my symptoms because my enzymes weren't HIGH. I had so many CBC's during that time, I had a PCP, a neurosurgeon, a pain control doctor and an ortho! I mean, come on guys! I had to get dang sick and happened to move to a new place and got a new doctor who was fresh out of med school and he finally caught it. I never had a VL over 730,000 nor did my enzymes go more than slightly over "normal"  So when people depend on those numbers, I think they do so at their own peril.

I was clear at 56 weeks when I stopped (and have been clear since week 20).  My doc doesn't seem to have anything to say about the increased enzymes.  I guess, in the long scheme of things they aren't too high but for me they are.   I will know soon...

Good to hear that. I know other things can make them go up some too. I think they fluctuate some just normally. That must be stressful. Hang in there, it's probably nothing to worry about.

The good news is you're a geno 3 and not a geno 1. The not so good news is that the treatment decision protocol outlined by your doctor doesn't seem to make sense.

Viral load at any particular point in time is not associated with the amount of liver damage. A 2 million IU/ml is more of a mid-range load, neither high nor load. Also, keep in mind that some of today's viral load tests can be off as much as an entire log, which is perhaps one reason only a two-log move is considered significant.*

In regard to biopsy, some doctors will biopsy only geno 1's and some will suggest biopsy for all genotypes. Part of the reasoning is that some doctors feel all geno 2's and 3's should treat therefore why bother to biopsy? Counter arguments run that you might not want to treat with little or no fibrosis and that even if you decide to treat knowing your fibrosis stage can be useful information on how agressive you want to proceed with treatment. To me, this is a personal decision. I would definitely biopsy if I was inclined to wait. An alternative would be to get a Fibroscan in either Boston, NY or Miami, if available.

Unless you read your doctor incorrectly, my suggestion is to get a second opinion from a hepatologist (liver specialist) on treating that does not rest on your viral load.


*Source http://www.clinicaloptions.com/Hepatitis.aspx
(Dr. Shiffman Slide Presentation)