Likda K's Thread cont/hepatitisresarcher/Willing/Ina/Others

Willing: Perhaps this seems like quibbling over many RNAs fragments can hide on the head of a pin
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Probably more HCV RNA on the head of a "needle" as opposed to "pin" per the Talmudic expression :)
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Anyway, Thought I'd open this up to continue the interesting dialogue with hepatitisresearcher and others. Hopefully, Linda K's original question got answered along the way :)

[jmjm530]

Willing: 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.
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Now you're starting to sound like Dr. Zhang and a number of other practioners of TCM :)

BTW the argument that "none of these studies have been reproducible using methods commonly accepted". is not mine, but what I was told by a leading clinician/researcher. One might argue that the more sensitive tests being used are valid, but that gets beyond my scope of knowledge.

But from what I have read, studies using the older and more established tests don't seem to find the virus anywhere near the extent that the newer tests do. I was going to reference again the study in the "Dragon is Back Thread" but for some reason that thread seems to have disappeared. I believe you first pointed that study out in one of the AASLD threads.

-- Jim

[cuteus]

the thread was archived and won't accept new comments:
http://www.medhelp.org/forums/Hepatitis/messages/43182.html

[jmjm530]

Thanks. Thought maybe someone posted an email address or something and it got zapped. Boy, that got archived fast didn't it? Some threads on the bottom are from many months back and this one was from the end of October. Don't get the system.

From one of my posts then:

Jim: "For example, someone here (Willing I believe)just posted that AASLD study abstract # LB9 suggests that the absence of post SVR virus in all compartments studied including PBMCs and Liver tissue with the exception of just a few cases. Other studies, using different amplification/centrifugal techniques suggest the virus is quite common in these same compartments."

[cuteus]

this subject thread, started in linda's post, is one of the most fascinating and intriguing we have had in a long time.  It attracted all the 'brains' that have been lurking and the regulars, and have promoted a rich, enlightening discussion.  Hopefully, it will continue, and everyone will join back in!  I hate when the threads end in suspension!

[jmjm530]

We've done this dance before but very nice when someone new and knowledgable in the field like HR shows up with fresh input. Hopefully, he'll stay around a bit and share some of his valuable time with us. Wonder what happened to DD? He may have found an intrafamilial ally in HR.

[DoubleDose]

I am hoping to hear your take on the final series of posts in LindaK's thread below, in which you discussed a wide range of HCV detection related issues, and questions about 'persistent' and 'occult' HCV earlier in the thread.  Additional questions were sent your way in that thread.

As Jim mentioned, I have been very interested in studying and understanding the long term implications of SVR, and whether there are still sub-detectable levels of HCV remaining in various cells or compartments, and if so, of what consequence.

Also, I have had many observations regarding symptomatic family members and close/intimate contacts, ranging over the past 20-25 years, that lead me to believe there may be some other, more 'occult' mode of infection with HCV, that does not show up upon HCV antibody tests.  I believe that Dr. John McHutchinson is preparing to launch a research study looking at tissues, fluids, and various cells in family members of long-infected HCV patients.  What might you know regarding this issue?  Right now, the number of people looking at, or trying to understand this potential transmission issue could probably fit on the head of a pin!  I have some serious concerns about 'atypical' intrafamilial transmission that may not result in a positive HCV antibody test result.  More of an 'organ specific' transmission that remains isolated, and maybe 'in-check' within the body, but yet causes chronic symptoms similar to extrahepatic HCV symptoms.

I look forward to more commentary from you, and hope you remain involved in the Forum for awhile.

Thanks for your interest.

DoubleDose

[Hepatitis Researcher]

Topics are numerous, thus focusing is needed. Two quick answers to questions asked: Fibrosure is not a bad test for liver fibrosis but it uses only statistical correlations with serum factors indicating stress on the liver and concludes by association that fibrosis is present. The fight is on between the noninvasive tests in the literature, but Fibroscan seems to be leading. It does measure fibrosis and not reasons for fibrosis.
NGI was FDA approved for HCV and HIV testing of plasmadonors in Sept 2001. 512 donors are mixed together and tested as one sample. Sensitivity is powerful enough to overcome that dilution factor. Ngis patient tests use basically the same technology.

The topic of stability of SVR was in important parts already covered from my side by the dragon thread that was archived as Jim said.Easy to find, however.

But it is important enough to continue assuming that the old comments are already considered:
I studied that critical paper by Castillo ; HCV replicates in the liver of patients who have a sustained response to antiviral treatment.
In particular I looked at the PCR methodology and the control methods design. No good news here: Solid as it can be. Older papers finding less are likely to have used inferior methodology. Thus everyone should look at this paper

[DoubleDose]

Thanks for your follow up.  How about your take on the questions about intra-familial, 'atypical' transmission, without development of a positive HCV antibody.  Is McHutchinson looking at something that may surprise the HCV community, do you think?

I see similar symptoms (fatigue, arthralgias, dry eye, gastro. issues, short term memory, etc.) in family members and several past intimate partners, but no evidence of HCV on the antibody test in any of them.  Very concerning!

DoubleDose

[Hepatitis Researcher]

Re Intramilial transmission of HCV: Through collaboration with NIH I know of original research work done by Dr. Reherman on T helper  cell response in HCV patients and their families. There was this fascinating story pinpointing the essence of what likely is happening : A husband with high HCV VL was followed for immunological studies, together with his wife - not infected neg for antibody and HCV RNA. He was told, due to his flare, to abstain from sexual activity. When he was asked by the NIH Dr why he is having sex with his wife against the advice he was first outraged Like " Are you using hidden cameras in my bedroom".Not really funny however. We knew, by examing his wifes class II T cell response, that went up sharply, that he had restimulated her helper T-cell immunity.
If you ask yourself why a virus that produces a Trillion virions per day does not routinely infect all intimate contacts of a person, then the known fact THAT IS NOT TYPICALLY CAUSING A HEPATITIS in such contacts is truly surprising. The answer is likely that the local innate and Class II T cell responses are mostly  elicited and lead to local protection and destruction of HCV by localized IFN alpha and gamma production by such cells.

Thus McHutchinson is very likely to find such a scenario if he looks with proper immunological methods.
A hint re the mechanism by which HCV is less infective than HBV was also given at the Vancouver meeting on the Molecular Biology of Hepatitis B viruses that I attended a few weeks ago. Chisari ( the "pope" of HBV Biology) presented comparative studies of HCV and HBV infection of artificially infected chimpanzees. (Thats weekly liver biopsies and tons of tests from day one for these poor guys) It turns out that HBV is a "stealth" virus that does litle harm and ignites little innate responses when entering the body. In contrast HCV raised a quick innate response in the liver with IFN alpha production and more. Point: HCV is nasty and noisy when it enters the body so it gets most often caught by the door guards. HBV sneaks in.
However we know that HBV can also cause core antibody negative local infections by which only the class II response to HBV is found in the immune system - nothing else ( studies by Michalak et al.
PS.There is no commercial availabe lab to my knowledge at this point that will test for the class II response with HCVclass II peptides. That will change in the future.

[jmjm530]

HR: If you ask yourself why a virus that produces a Trillion virions per day does not routinely infect all intimate contacts of a person, then the known fact THAT IS NOT TYPICALLY CAUSING A HEPATITIS in such contacts is truly surprising. The answer is likely that the local innate and Class II T cell responses are mostly elicited and lead to local protection and destruction of HCV by localized IFN alpha and gamma production by such cells.
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1)If the local innate and Class II T cell response leads to local protection and destruction of HCV, then why doesn't this happen more frequently with more established forms of transmission such as IV drug use, transfusions before screenings, etc ? Is it the sheer volume of the virus that enters the system the key to transmission, or is it something unique about the route of the transmission, i.e. blood to blood?

2) Given your explanation of testing methods used for occult and persistent virus, why do you think these studies aren't universally embrased by leading hepatologists?

3) Re Fibroscan. Assuming my scan was done in a non-fasting state, my read on your previous comment is that my fibrosis level would be overestimated rather than underestimated. Is this correct?

4) A brief comment on Dr. Shiffman's thoughts on HCV RNA availiablity and its impact on pre-tx viral load as a predictor of SVR if you've had time to review his slide presentation.

Thanks again.

-- Jim

[DoubleDose]

Thank you very much for your knowledgable and scientific insights.  They make great sense, and also make me breathe a little easier about the transmission issue.

I still wonder though, if some of this local HCV gets caught up in a perpetual 'cellular immune reaction' syndrome within family members, that persists on its own, but never crosses the immune protection barricades to become a true HCV infection.  This is what I think I may be seeing in my own family.  Maybe the exposure to the virus, in salivary tissues, sexual organs, eyes, etc. causes a self perpetuating cycle of reaction, that creates symptoms within the affected organs/systems, but does not mount a full blood capable infection.  Maybe the virus is not quite 'killed off' but just kept in a state of 'cellular immune provoking' limbo.  

One very odd  chronic symptom that has developed in my family, and in several past intimate contacts from over twenty yers ago, is this:  A sort of non-allergic rhinitis characterized by constant throat clearing, post-nasal activity, sinus inflammation (but no infection), and a general dry eye, and irritated eyelid symptomatology.  I have seen this develop in more than seven close contacts over the years, and three have been tested thoroughly by otolaryngologists, only to be described as non-allergic, and non-infective type perrenial rhinitis...with no known etiology.  Nothing works in treating it either....not steroids, antibiotics, or anything else we have been prescribed.

The other noticable common symptom is periods of odd fatigue, and joint/muscle pain...both in adult contacts, and several children. Again, all of them are HCV negative on blood antibody tests.

This has really been a nagging issue for me over the years...but ALL the HCV related doctors that I have discussed this with have just given me a 'blank' look.  Sort of like: are you nuts?

I make my living making observations and finding answers to human behavior issues, as a corporate consultant...so I do believe I have some pretty well developed analytic and observation skills.  
The doctors do not seem very interested in 'listening' from what I have seen, and even less interested in exploring the really complex issues surrounding this virus.  Thankfully there are a number of researchers out there, looking for the real answers.  

Thanks for your valuable input.

DD

[willing]

please ignore my comments above about Schiffman's estimates of VL variability being based on older data; I'm wrong. The most recent update of his review on treatment those who fail tx <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16527652&query_hl=21&itool=pubmed_docsum">Shiffman'06</a>
puts it at "The accuracy of the commercially available HCV RNA assays is reported to be ±0.5 log units " and cites <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11682522&query_hl=24&itool=pubmed_docsum">Shiffman'01</a> as support.

[jay1975]

OK, I understand, Thank you

[jmjm530]

Willing: As Jim said, we have danced this dance many times before on this forum, have gone over all the main research papers and editorials, but have never really gotten past the "there's something suspicious about their methods" argument.
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I think "there's something suspicious about their methods" argument has been only one piece of the previous exchange of differing theories. The other pieces have to do with what I believed was described as the "integrity" of the virus found as well as what clinical implications, if any, this all has. This seems to be very much key and another reason why many of the clinicians aren't overly impressed to date. I pretty much knew HR's position from previous threads, so I realized bringing it up here would add fuel to the occult fire. Just wish I could get several like him in the same room with some of those who think otherwise. Jerry Springer maybe :)
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Willing: Like Jim, I'm curious to hear any comments you have about the variability of VL readings. For example, how different are variances of multiple assays on the same vial of serum, multiple vials drawn from the same patient on the same day and multiple vials drawn from the same patient over long separations.
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Did you see Shiffman's recent slide presentation at the Clinical Options site. If not, I'm sure you would find it interesting. I think I pinpointed the exact slide in the original thread. The variances Shiffman describes are so great that it becomes understandable why a two-log drop is considered important to demonstrate tx is working. Not so much because of how much virus is being killed but to show that in fact ANY virus is being killed, at least according to the way I read his variance numbers. Of course, being non-detectible by sensitive PCR or TMA takes the variablity component out of the equation. While you're on the site, there's a nice little audio message by Dr. A in Boston on emerging treatments.

Willing: sorry, I didn't mean to go too californian on you. I just think if these results are true it redefines the tx goal somewhat.
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As someone who spent time in CA, I understand you can't help it:)
But seriously, if by "californian" you mean the virus is less of an evil spirit than the condition of the liver, we're pretty much in agreement. I put off treating as long as I possibly could. three years to be exact after they explained that my biopsy put me between stage 3 and 4. In fact, it wasn't until I started treating that I found out my actual stage at that time was probably closer to 2-3. If I had known that pre-tx, I would not have treated.

So what's with your search for the holy biopsy reader? I've had my slide read five times now but it will be frozen at five since I'm now SVR. Can you beat five :)

Be well.

-- Jim

[jmjm530]

My doctor uses the word "SVR" and "Cure" interchangeably, as do many doctors in the clinical sense.

The discussion here is mostly regarding the microbiological aspect of SVR which to date have no proven clinical implications.

The microbiological aspects of SVR is a very important topic and researchers like HR should be commended for their time and efforts. Still, as an SVR, IMO this should be of no practical concern in your day-to-day life. It certainly isn't in mine.

As the song says, Don't worry...Be happy. You're SVR!

Be well.

-- Jim

[jmjm530]

I guess the second sentence should read in part "clinical significance" not "clinical implications".
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And speaking of "dancing", anyone watch "Dancing with the Stars" last night?

I knew Joey was going to leave, but who do you think's going to win? Mario's obviously the better dancer, but the fact that Emett beat Joey (also a better dancer) leads me to believe there just might be an upset in the making.

Who do I think should win? I'll take Mario's professional dance partner Katrina. Talk about HOT HOT HOT :)

-- Jim

[Hepatitis Researcher]

The size of the viral inoculum is certainly important in the transmission route, but maybe more import might be the fact that surfaces -skin and mucosa are typically equipped densely with innate response cells like dendritic cells and macrophages that can quickly educate class II lymphocytes.All that before the virus can even enter the circulation. We have watchdogs where the invaders typically come.
Also consider HCV is more cytopathic than HBV thats probably why it is not " silent". The first cells infected quickly "feel the pain" and signaling starts right away, but you need containment in local tissues.

The reason why these type of immunological studies are not popular research activities of hepatologists is simply that they are more clinically trained and educated. For these studies you need trained immunologists  ( like Dr. Rehermann) and a spezialized laboratory with emphasis on advanced immunological methods. Elispots, tetramers, peptide arrays are all still relatively young techniques. But look at all these studies by Vincente Carreno - he goes a long way of explaining the vexing complexities of anti HCV T cell responses. Tcells are at the heart of antiviral defenses, not Antibodies. They work in HBV also only when already present when infection takes place.

I will look at Dr Shiffmans slides another time.

[willing]

many thanks for  your assessment of the  the Castillo methods. As Jim said, we have danced this dance many times before on this forum, have gone over all the main research papers and editorials, but have never really gotten past the "there's something suspicious about their methods" argument. The authors of Castillo'06 seem to go to great pains to establish the reliability of their results, so presumably they expect to be challenged on them.

Regarding the "senescence" argument, did you see any evidence in the phylogenetic analysis included in Castillo that indicated the residual virus was somehow less fit? Given the sloppiness of HCV's polymerase and the rate of HCV replication it wouldn't seem to take very long for it to mutate out of any lack of fitness. However the long-term follow up data seems unanimous in reporting the durability of serum-UND status. Also I thought the "mutation-catastrophe" explanation for riba's synergy with ifn was still very much in question whereas you seem to imply it's the accepted mechanism. Is this the case ?

Like Jim, I'm curious to hear any comments you have about the variability of VL readings. For example, how different are variances of multiple assays on the same vial of serum, multiple vials drawn from the same patient on the same day and multiple vials drawn from the same patient over long separations.

I recall that Shiffman's comments (which also appear in a review he wrote a while back) are based on some fairly old data on VL variability and wonder if there are any more recent measurements of variability. Serum-VL may not correlate with fibrosis-inducing inflammation, but the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16847959">Quiroga'06</a>
paper seems to suggest it correlates with intensity of the HCV-specific T CD4/8 T-cell response, which presumably helps explain why low serum VL is a good predictor of SVR outcome.

jim: sorry, I didn't mean to go too californian on you. I just think if these results are true it redefines the tx goal somewhat.

[jay1975]

you guys are way over my head but i am trying to grasp this.  i have tested negative many times for HCV since my exposure and all tests have been negative.  I am at a point in my life where if i dont let this go I am going to lose my wife my job and my life.  I have already lost many friends because I will not let go of my fears of having HCV.  
From what I am reading here, all my testing could mean nothing and i could be infected and the tests are not picking it up!!

Does all this mean that there is NO END to HCV and you may never know if your infected????????

[Hepatitis Researcher]

You write :     I still wonder though, if some of this local HCV gets caught up in a perpetual 'cellular immune reaction' syndrome within family members, that persists on its own, but never crosses the immune protection barricades to become a true HCV infection. This is what I think I may be seeing in my own family. Maybe the exposure to the virus, in salivary tissues, sexual organs, eyes, etc. causes a self perpetuating cycle of reaction, that creates symptoms within the affected organs/systems, but does not mount a full blood capable infection. Maybe the virus is not quite 'killed off' but just kept in a state of 'cellular immune provoking' limbo.

You gave an excellent description here  as this is likely the scenario in some of these cases. We do know however that in  cases examined thus far,  the "invisible HCV burden" dimnishes over time - even month- only and so does the memory response that we can measure. But your description of a cryptic immune stimulation -cytokine mediated syndrome might be just that. Well, that type of mechanism is believed by many to be the basis for what is called chronic fatique syndrome, probably a mixed pot of mild chronic overresponse ( or qualitative insufficient response) of the immune system against remnant low level infection.

[Kalio1]

If you have tested negative for HCV, you are negative, you don't have it. Maybe you would benefit more if you address the worry and anxiety over having a virus you obviously do not actually have as the problem and speak to your doctor about how to address your unfounded fears and anxieties.

[jay1975]

I know...I do hear you.  I shouldnt even be reading this stuff.  Its just scary reading the above.  I DO NOT want to make anyone mad cause I know all you guys have told me I'm negative and to just leave it alone. Just freaked about the above!!!

[Hepatitis Researcher]

Re Ribavirins mechanism of action:The error catastrophy concept is still only under discussion - difficult to prove actually
Here is one of the attempts:

To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy. METHODS: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B. RESULTS: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy."
Well you could also interpret this result simply in the sense that under IFN many lines of the virus died out and only a few strains with a genetic makeup fit to survive under these harsh conditions survived.Here is an esoteric analogy:  When the German soldiers were marched from Stalingrad to Siberia they arrived gentically less distant than the starting group (only strong healthy  types survived). The fact that on the way the Russians gave them poisoned food did not change that drift towards genetic convergence in the short run, but later many got cancer in the Siberian barracks or were simply too weak or sick to flee the camp (SVR).

The alternative theory how Riba works is that it shifts the immune  systems response towards Th1. The Th1 state has superior efficacy against viral infections. What speaks somewhat against this is the fact that Riba does not seem to help against HBV.

[jmjm530]

Rev: (The durabiity of SVR) is an open debate both here and among medical science.
=======================

I know we've covered this ground before but maybe not for Jay's benefit. According to recent studies, SVR is durable 5-10 years out.

They don't have statistics further out than that so that's where the 5-10 years comes in.

Your position as I understand it is how do we know it will stay durable beyond 10 years. My position is that there is no evidence that it won't remain durable beyond ten years.

Hopefully I'm not putting words into your mouth, just trying to clarify the issues here both for Jay and myself.

That said, I think Jay is more concerned about the "persistent" issues put forth by HR and Willing, i.e. where virus may be detected in some compartments after SVR even when standards tests show one is non-detectible.

-- Jim

[Hepatitis Researcher]

I forgot to answer your question regarding the fibroscan: Non fasting will shift the results towards higher median stiffness.
While I discussed that with Echonsens at the AASLD 06 I am sure it will not cause any protocol change now that they have progressed so nicely. I certainly do not want them to be mad at me, since I need them to service my machine and give me software updates.

[jmjm530]

Given that I assume most labs don't separate their steps by city blocks, I can understand better why there may be so many false positives. Actually, my worry was more about false negatives and that's why I ordered redundant tests post treatment. What a mess if it turned out that my Heptimax was positive and my HCV RNA qualitative was negative or vice versa. Fortunately, it didn't happen or maybe it did and the lab computer picked it up :)

As to Shiffman, assuming the half log variance in either direction, if someone tested pre-tx at 1 million IU/ml, then in actuality (if my math is correct) they could be anywhere from 450,000 IU/ml to 5,000,000 IU/ml. If so, this seems to destroy the theory of pre-tx viral load as being a predictor of SVR in the sense that the cutoff of "low" VL is usually around 600,000 IU/ml. So is this person low or not? Maybe it all balances out statistically with large populations but an individual has to wonder where they really stand.

-- Jim

[jmjm530]

Thanks for getting back and what you say makes sense. It is also a bit reassuring since I took my second scan non-fasting and either took my first scan fasting or non-fasting can't remember. In either event I dropped close to a stage or possibly more given one of the fast/not fast scenarios.

That said, my understanding is that part of these trials is to come up with correlations in the American "model" between the computer generated Fibroscan number, and fibrosis stage as measured by needle biospsy.

Assuming that these subjects are a mishmash of fasting and non-fasting participants I assume this would throw the final fibrosis scores off for any one individual, and yet, these scores are being compared to relatively recent liver biopsies with apparently very good correlations. I assume this is because the differences between fasting and non-fasting readings are relatively small? For example, how much of a difference have you seen between let's say someone who reads stage 3 in a fasting state and then re-tests same day in a non-fasting state?

Thanks again for all your information and insights.

-- Jim

[willing]

not quite: 1 million IU is 6 log units so +- 0.5 log units puts the range at 5.5 to 6.5 in logIU or 316,000 to 3,162,000 in IU, but I agree that it seems a very wide range ((that's actually one of the examples in Shiffman's review)). As a counterexample to Shiffman, look at abstract 350 from the recent AASLD. T Berg reported that low-VL as an SVR predictor was distinctly superior when a cutoff of 400,000 was used rather than the older 800,000. However, per Shiffman if your "true" VL is 800,000 readings down to 251,000 are within the margin of error.. (I tend to believe Berg here)

[Hepatitis Researcher]

The Shiffman 06 paper was not accessible in full text through UCLA, the o1 paper did not contain the .5 log accuracy info that you are referring to and the link to the clinical care options did not work and the search for Shiffman on the internet proves that it is a very common name in the US.
Thus I cannot yet comment on the .5 log Shiffman accuracy in discussion. I have to check NGIs database to see where NGIs superquant PCR accuracy stands. It should be much better than .5 logs. bDNA for values over a Million are BTW very reliable. I do know that Amplicor was doing badly in the past and could explain at length why that is - a very technical issue.

[jmjm530]

I guess the lower your acutal number, the lower the range, so maybe statistically it all works out with large numbers of patients, but appears to leave some doubt on a single patients viral load result. Fortuantly, as viral load decreases toward zero, this becomes less of a problem or we'd really have a mess in dx those non-detectible. For example, a half log variance at 10 IU/ml would be -- I'm approximating so don't kill me here :) -- anywhere between 5 IU/ml and 50 IU/ml. Certainly a much smaller absolute spread.

[jmjm530]

If you want to pursue the Shiffman presentation:

(1) Go to: http://www.clinicaloptions.com/Hepatitis.aspx

(2) Register for the site or you can't get in.

(3) Enter "Shiffman" in "Search Site" or "Enter Search Term" at top of page.

(4)Scroll down to "HCV Core Curriculum 8/10/06"

(5) Click on "Begin Program". Then skip to slide 24 if you want.


While there, Afdhal has a nice little audio address and Dieterich and Jensen have a very good video summary of newer re-treatment protocols. That can be searched under "Doc Eye for the Hep Guy"

[willing]

For what it's worth, the other two citations referenced in support of that 0.5 log iu claim (in addition to Shiffman'01) are

[17] Ferreira-Gonzalez A, Shiffman ML. Use of diagnostic testing for managing hepatitis C virus infection. Semin Liver Dis 2004;24(Suppl 2):9–18.
and
[25] Morishima C, Gretch DR. Clinical use of hepatitisCvirus tests for diagnosis and monitoring during therapy. Clin Liver Dis 1999;3:717–40.

however, given that your time to respond to our endless questions is no doubt quite limited, I'd be more curious to hear your anecdotal impression of the importance of pcr-pcr,sample-sample and year-year variability (given that, as the HCV kineticists see it, this is supposed to be a steady-state system). Also any thoughts you had re the senescence questions above....

[DoubleDose]

Your comments on CFS fit right into my theory.  I do believe that it would make sense to examine the people exhibiting CFS, CFIDS, Fibromyalgia to determine if some percentage of them are harboring low levels of HCV in various tissues, fluids, or organs.  MAYBE there are numbers of people who have been exposed casually to HCV, and who have developed a 'cellular immune reaction' to it, either in salivary tissues, sexual organs, gastric mucosa, etc.  Maybe these people comprise a segment of the CFS/FM population.  Possibly testing these people for cellular immune reactions specific to HCV would identify a causitive agent for the illness in many of them.

  This is a hunch that I have had as a result of my own observations, and I think it would make sense to look closely at this as a possibility.  So far no one has made a big connection between HCV and CFS only because they are looking ONLY for HCV+ individuals.  These people would NOT test positive for HCV on standard antibody tests, but probably would test positive on local cell/organ tissue antibody tests with amplification, or just HCV-specific cellular immune responses in these tissues.

What if there is a silent mode (undetected on testing) of HCV infection that does not attack liver or blood, but causes a CFS type system-wide reaction?
It (the HCV infection) might remain perpetually suppressed, but cause major problems as far as health, and symptomatology. There are a variety of immune system related illnesses that have mushroomed in the general population in recent decades....diabetes, asthma, allergies, inflammatory diseases, etc.  Could there be a connection to the prevalance of HCV in our society, and a silent, localized transmission that might alter immune function, thus producing a host of these types of diseases?

Out of the box thoughts , I know....but....this is how new insights come about.  I am going out on a limb...but with some logic and inductive reasoning to support my suppositions, I believe.

Thanks for your thorough descriptions, and reasoned answers.  Your commentary is enlightening for all of us.

DoubleDose

[jmjm530]

Speking of "steady state" system, which Shiffman also I believe discusses -- how can you have a steady state with such apparent variance. And how do you account for my test results for example. I was 16,000 IU/ml three months prior to tx and 1.5 million IU/ml the day before treatment, using the same lab. This is greater than the 1/2 log variablity so def not "steady state" as I understand the term to be used.

[TnHepGuy_]

<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17051492&query_hl=9&itool=pubmed_DocSum">Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment</a>

(from the paper):

"<i>Liver necroinflammation was still present in the posttreatment liver biopsy specimens of 15 patients...</i>"


<a href="http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2893.2006.00783.x">Comparative study between occult hepatitis C virus infection and chronic hepatitis C</a>

(from the paper):

"<i>This occult HCV infection is a milder disease than chronic HCV, and this could be related to the significantly lower number of infected hepatocytes observed in occult HCV.</i>"

<a href="http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/504692">Detection of Hepatitis C Virus (HCV) RNA in the Liver of Healthy, Anti-HCV AntibodyPositive, Serum HCV RNANegative Patients with Normal Alanine Aminotransferase Levels</a>

(from the paper):

"<i>HCV may persist and replicate in the liver and PBMCs of healthy, anti-HCV antibodypositive, serum HCV RNAnegative patients who have persistently normal ALT levels. These patients should be followed up, because they have an ongoing viral infection.</i>"


Also, in case this one got overlooked from the post below, here's another recent Castillo(et al) paper: <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>"


And for anyone who's interested in occult Hep C, Pham's <a href="http://www.mlo-online.com/articles/0206/0206clinical_issues.pdf">Occult hepatits C virus persistence: identification and characteristics</a> (PDF) paper is the best overview out there right now on the subject.


TnHepGuy

[jmjm530]

Before I turn off the lights -- and I'm sure I'm talking for many -- would just like to say how much we appreciate your time and participation in the forum of late. Apology on my end for so many questions, and please only answer if your time permits and certainly no hurry on any of this.

For those that may not have read all of HR's threads, he came here initially looking for anecdotal experiences of those who have treated with Alinia and perhaps some of us can help him in that respect.

Probably the best way to poll this group would be to start a new thread with "Alinia" in the heading, but I really don't want to step on someone else's interest here unless given a green light.

All the best.

-- Jim

[willing]

indeed, the methods aspect is only one part of the overall picture, but personally I found it one of the most vexing, since everything else depends on it.  For example, in Castillo the description of PCR primers/reagents/temperatures etc. seems on par with details given in the methods section of a typical paper but I think you really have to be an expert with direct experience to recognize flaws (I had no idea pcr-product contamination was such a problem you had to use different rooms!)

Re Shiffman, I had seen those numbers on VL variability in a review by him a while back (I think he does a yearly update with A Sethi) and (mis) remembered they were based on vintage data. Not so, as corrected above. Nevertheless I'm still not clear on how that 0.5log variance  breaks down  (how much is pcr-to-pcr, how mch vial-to-vial and how much patient year-to-year).

thanks for asking about the bx; I  lost interest in getting  further readings of my last slides after TN posted his  biopsy report. A good part of the information content seems to be depend on the skill/luck of the Dr. extracting the sample (how much of the liver architecture can you see in the samnple) and on how many slides are mounted (still don't understand why they mount so little of the tissue). By the time you get down to a couple of  slides all that's over with and I think the two readings I got pretty much exhausted the available information since they were in close agreement.

[willing]

the analogy between a death march and long-duration combo treatment seems very appropriate! (though in thise case I guess it's the dwindling group of virions who have to keep putting "one foot after the other").
Presumably there is something to be learned by analyzing the genomes of the "survivors", which is why the phylogenetic analysis in Castillo would seem to be promising. Long-lasting serum-UND must result from some combination of decreased viral production and increased host clearance. Is it too simple-minded to expect to see evidence of the former by changes in the genomes of the survivors?

Anyway, yet another topic I'd be interesting to hear your thoughts on, and which relates to Ina's question is HCV cell specificity. Recently <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16618405">Pal'06</a> made the  remarkable claim that, in one case of HCV infection they analyzed, more serum virus was genetically similar to lymph-resident virus than to liver-resident virus. This claim was quickly challenged, including a  letter  (<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16901578&query_hl=6&itool=pubmed_docsum"> Dahari'06</a>) by Neumann and Perelson who I think of as the founding fathers of HCV kinetics. Do you think the findings are credible ? Is it possible for HCV replication outside the liver to be that significant?

Jim : I think it must be tripping over the math again. The  <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9756471&query_hl=9&itool=pubmed_docsum"> Neumann/Perelson equation </a> is a simple first-order ODE; you just needed to bring your calc book with you when you took the VL test...

[Eisbein]

you said:
Well you could also interpret this result simply in the sense that under IFN many lines of the virus died out and only a few strains with a genetic makeup fit to survive under these harsh conditions survived.

I used to call these strains that survived King Kong viruses, or super bugs.
When I asked my doctor if it wouldn't be a good idea to bombard any hidden King Kongs at the end of tx with higher doses of Peg for a couple of month, his answer was "YES". But only the Interferon, not upping the Riba he added.

I was too sick at the end of tx to double up on the Peg, but I surely wanted to.

Any comment on my docs suggestions.

Ina

[jmjm530]

To clarify, I was talking about the seeming inconsistency of serum HCV RNA being stable over time versus the inherent variability of the HCV RNA assays per M. Shiffman's presentation. Those two values I gave were my pre-tx values unaffected by any decline caused by the tx drugs suggesting HCV RNA instability over time. Like yourself, I also found the Stalingrad analogy apt especially in regard to the "poisoned food". Comparing ribavirin to poisioned food is a metaphor anyone who has treated can well relate to! That said, I certainly hope HR is wrong in the respect that newer
non-riba based therapies (see C7)may not result in SVR. We will have a first look within the year as data from the non-riba VX 950 SVR arm(s)rolls in, and other looks down the road if/when different protease inhibitors are combined in some sort of cocktail approach, and/or when other non riba based approaches are tested down the road. If I remember correctly, your biopsy reads sounded fairly consistent so I guess I will declare myself the winner with 5
reads:) BTW I hope you weren't suggesting they mount your entire liver on a slide.

Be well.

-- Jim

[Eisbein]

I apologize, above sentence should have read:
When I asked my doctor if it would be a good idea.....
                

                       and NOT      

When I asked my doctor if it wouldn't be a good idea...

Ina

[Eisbein]

I wish I could put my thoughts into fancy wording like you, or my fellow members here, but since I can't, I try to say this very plainly.
Some of us here, including myself, have taken a sledge hammer approach to killing our HCV.
Doubledose did double Peg for 72 weeks, Sandi tx with standard drugs for 2 1/2 years, and I treated non stop for 111 weeks with standard Peg and 800mg Riba (type 2a).

1)
My question is this...since I tx so long, any of the cells in which HCV can be found, liver or otherwise, must have turned over at least once, and have taken any remaining virus with it.
What I am saying, do those of us that have tx so aggressively have a better chance of having gotten rid of residual virus.

2)
Since most of us SVR's don't have post tx biopsies which could detect occult virus, our only option is to watch for mild elevations of ALT's or GGT's which is not very reliable.
However, since I had also Type II Cryo, which cleared with HCV, can I assume, that should Cryo ever become detectible again, while remaining PCR neg, that I still have some low levels of virus somewhere?
Do you think that crippled leftover viruses can stimulate the B-cells enough to start this auto-immune response again.
Willing here linked a paper that lets me to believe my thoughts are on the right track.

I am concered about about reidual (occult) virus and the damage it might do to our livers over a 20 year period. Most of us here are at the age were other disease (cancer) occur more frequenly.
It would be comforting to know that we can endure possible chemotherapy without having to worry about our compromised livers.

I think I speak for all of us....you are greatly appreciated here.
Ina

Jim, thanks for opening this thread.

[mikesimon]

Thanks to everyone who participated for providing us with a stimulating discussion. It is a complex subject and I appreciate all of your efforts. Mike

[willing]

that was just my weak attempt at a joke. The "steady-state" condition is modeled by 3  differential equations (1-3 in the link above) that relate infected cells, host clearance rate, viral production rate, etc. A very simple model, but apparently a successful one since it seems widely accepted and is also used for modeling HIV and other viral infections. I'm hoping HR will give us some insight into how realistic its underlying assumptions are. For example, how common are VL swings like the one you experienced.

Re the bx, I'm  puzzled that they don't slice and mount the entire sample drawn rather than just making a couple of slides.

[jmjm530]

W: that was just my weak attempt at a joke.
-------------------------------------------------
I thought so, but never can be completely sure with you left coasters :)

I think studies have been done showing how much "meat" is necessary. I imagine they slice them thin to get a better read from the microscope. Maybe you can stop by HR's shop for a scan :)

As to VL swings, if I remember correctly from previous posts here, a number of others have had similar swings although not sure how many re-tested within 3 months. The reason those two tests were so close together was because I wanted a baseline the day before treatment.

To do it all over again -- only in my nightmares :) -- I'd might test viral load monthly and then treat when I hit a low-point. For example, knowing what I do now -- knew nothing then -- I should have started the day I got the results of that 16,000 IU/ml test. Things worked out fine as is, but 16,000 theoretically would have had better odds than 1.5 million.

Haven't read the reasoning behind better results with low viral load but I always thought it might have to do with perhaps the  ebb and flow of the immune system. So, if you're lucky enough to start tx when the immmune system is strong (low vl) then the chances are better. As mentioned, 3 years prior to tx, my vl was over 30 million. That also happened to be my original start date which was then put off for various reasons, including a spike in enzynmes from perhaps some chinese herbs or the hep b vaccine. Looking back, I may have been fortunate not to have treated earlier given my VL dropped to 1.5 million just prior to tx.

-- Jim

[sfbaygirl]

When you say that HCV hits the body quickly (meaning acute?) how quickly can a person feel the symtoms (symptoms) of this acute stage? Can it be immediate or within several days?

Thanks for all your great info!

[DoubleDose]

Regarding your question about HCV replication outside the liver, and how significant the replication might be, here are my thoughts:
Much of the focus on HCV and the liver is chiefly due to the fact that HCV replicating in the liver over many years can kill you.  The liver seems to slowly shut down over shorter or longer spans of time.  HCV MAY also be replicating in other affected organs and tissues, without the same dire consequences as the liver.  Maybe there is a resident HCV load in the lymphatic system (which may cause the frequent cases of Lymphoma, etc.), in the gastric mucosa (which may cause varying degrees of gastric distress), in the brain (which may cause the brain fog, fatigue, and other CNS related issues), in the connective tissues (which may cause the arthritic problems), and so on.  Maybe the load is less evident in these organs, but pathological in effect nonetheless.  

So maybe the liver has been the focus because it is easily 'seen' on LFT's, liver disease, ESLD, etc....but at the same time, maybe HCV is not a Liver-only disease.  Maybe a liver-plus disease, or a multi-organ viral disease.  We are just beginning to see research implicating HCV as lymphotropic, rheumatologic, and now who knows what else....maybe CNS, lung, cardiovascular, etc.  I do not believe that any of this has been absolutely ruled out, and if anything, researchers seem to be on a path to exploring and understanding where else the virus resides.  I personally believe that the virus can propogate in most soft tissues, and loves the liver, salivary tissues, lymph glands, gastric tissues, and sexual organs.  I think we need studies that will use next generation PCR technologies to determine just what the realities are.

Don't you sometimes feel that the ramifications of this virus are often grossly 'underplayed' in the HCV medical community?

Anyway, just some thoughts for the day.

DoubleDose