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.
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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...

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

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.

OK, I understand, Thank you

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

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

I guess the second sentence should read in part "clinical significance" not "clinical implications".
--------------------------------

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

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.

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.

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????????

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.

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.

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!!!

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.

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