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

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

Thanks for all your great info!

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

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.

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

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.

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

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

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

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...

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.

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

<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

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.

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

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....

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"

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.

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.

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)

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

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

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.

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