HCV is an RNA retrovirus; it uses human polymerase to make cDNA (complimentary DNA) which is then inserted into our DNA by an enzyme called integrase. When transcription occurs (DNA to RNA), the viral genome is replicated again in its RNA form and the cycle continues. RNA is not a stable molecule. It is quickly degraded by enzymes called RNases. Therefore, if HCV RNA is found in serum, PBMCs, or elsewhere, it can be assumed that the virus is currently replicating. Researchers have found this RNA positive strand in many patients who have achieved SVR, which is why they speculate that occult infection occurs commonly. I've read that some people have consistently high liver enzymes, progressive liver fibrosis, and HCV-related autoimmune problems such as arthritis after SVR. So the question is what kind of damage is occult infection doing? By the way to all of you on tx, just a note of encouragement: my 5 month post-tx PCR shows no virus. Close enough to call an SVR?
by the same line, if there is no fibrotic tissue, mild damage by biopsy, there should not be any HCV hiding in the liver, right? Late relapsers seem to fall in the high liver damage category, which gives the theory of rna remnants in the liver some thought. In speaking briefly with Dr. Cecil he believes hcv might remain in fibrotic/cirrhotic tissue at some level. I plan to get a PCR on my sample next time I get a Bx.
holding_on: congratulations on your post-tx results!
However your HCV lifecycle description is not quite right. HCV, unlike HIV,is not a retrovirus, does not use integrase or embed itself into our genome and does not use our (human) polymerase to make copies but packs its own polymerase in its proteins NS5B. Here's a good <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15566499&query_hl=4">primer on the molecular virology of hepatitis c</a>. Their Figure 1, pretty much summarizes the full life cycle. The main human component hcv hijacks in its life cycle is the ribosome.
cuteus: examining the bx sample for hcv rna seems like an interesting bit of data - though I think you'll have to find a univ lab to do the work (all the commercial assays are serum-based as far as I know). But why would you be getting a bx if you're SVR?
twinmick: as holding_on points out, biomolecules have a pretty short lifetime. Everything is constantly getting chopped up and recycled. Also, as evident from Figure 1 above, presence of -strand hcv rna is evidence of active replication.
BTW - a huge step, (yup it's a BREAKTHROUGH) in our understanding of this virus will follow from the (just published) ability to <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15947137&query_hl=2">grow it in cell culture</a>. Apart from saving the lives of many chimpanzees, this will greatly accelerate the pace of hcv research.
I doubt I'll be able to get my HMO to order it, but I would like to biopsy post-tx to see if there's been any fibrosis regression. Started out between stages 2 and 3 so I'm not certain the Fibrosure test would be helpful in my case, as I'm in that muddled middle area. What would YOU do? (One more piece of data: thais would make biopsy #7, which my liver could probably do without.)
Another take of post-SVR persistance: <a href="http://www.hcvets.com/data/hcv_liver/curedefined.htm">What Defines Cure for HCV Infection?</a>
My take on post-SVR bx's: Since Stage 3, 4 and cirrhosis are strong precursers of HCC, a post-tx bx could potentially be in order for any SVR patient who began with that level of damage. If histology remained unchanged - or even progressed - during tx, they might be considered a candidate for an anti-fibrotic tx in an attempt to speed reversal of the damgage and to "put some distance" between now and HCC. Though one wouldn't expect any further progression post-SVR, SVR itself is not a guarantee of histological reversal.
Though I've never heard of this line of post-SVR tx, if I were left with a high amount of damage and staring the unknown odds of HCC square-in-the-face, I would persue this avenue until I found a doc who would go along - or definitive research that told me not to bother.
sorry guys, this makes no sense to me. Apart from their considerable cost, biopsies are not risk free. I don't know what the current statistics for guided bxs are but the risk of infection, puncture, etc. is small but real. This suggests having one only if the outcome will guide a course of action. I have never seen a study suggesting that, in the absence of auxiliary liver disease, hcv-induced inflammation continued after the virus became undetectable. The whole stellate cell inflammation pathway is triggered by the body's response to the virus and once the virus is "gone" that's the end of that pathway. One might be curious to know whether the body is eliminating existing scarring, but what action can you take on that information? Obviously, if you expect ongoing damage from other sources this doesn't apply, but if your only source of damage was the presence of hcv, I think you're done! Monitoring of liver enzymes and hcc screens obviously should continue.
All very compelling arguments. Maybe it's because I'm still under the influence that I would even entertain the notion of doing maintenance therapy if there were still appreciable fibrosis remaining. It's just as well, however, that I won't be doing any decision-making about this until I'm post-tx and have recovered a few of my wits.
Yep, a little curiosity can be a dangerous thing. It's certainly what got me here in the first place. :)
Thanks for your answers. One of the reasons for taking this up is: am I still infectious?
None of you have touched that. I do not now if any researchers have tested it, but one way could be to take a blood sample from a SVR and inject it into a chimp. No ethical correct, but they have done this with HIV. Those 20 chimps are now a problem, they are carriers, but do not develop AIDS. They do not want to put them to sleep of ethical reasons, but they must keep them separated from other chimps to avoid infections. BTW they should be interesting research objects. How can the keep the infections asleep not causing any AIDS??
Again, since HCV is a RNA virus and not a DNA (like HBV), how can it be occult? Are there other RNA viruses showing the same behaviour?
califia: glad you posted that projects in knowledge link - it's a great resource
tn: the therapeutic significance of the residual virus isn't at all clear yet, but BiSceglie's comment that "this information is interesting, but it needs to be confirmed independently by a different laboratory using the same samples" reminds me a bit of the call for more research to prove global warming. Even <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11870385&query_hl=28">McHutchison,2002</a>, which BiSceglie points to as evidence of eradication, had 7/400 +bx/-serum results. More importantly, the McHutchison paper made no attempt to calibrate the sensitivity of their RT-PCR, whereas Radkowski, Laskus etc have a long publication record (eg <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=10623766&dopt=Abstract">2000</a>, <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11752151&query_hl=29">2002a</a>,<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12208987&query_hl=29">2002b</a>,<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14739225&query_hl=29">2004</a>) of carefully calibrated rna detection research at different labs (Mayo, U. Pittsburgh, Warsaw). When you add to this the independent confirmation by <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15140984&query_hl=33">Pham</a>, it seems like the burden of proof shifts more to the eradication camp. BTW, as a footnote, I noticed that even in Radkowski's small sample one of the 17, (patient 8) had a genotype switch : 51 weeks after tx he had gone to 1a from 3a.
I will take my cue from you...if you are not worried about your young bride, I will cross off "non-serum infection" from my current list of "Things To Stress About". I'm tempted to ask your very knowledgeable self about the "better things" to worry about, but I'm not going to because then I REALLY won't sleep. Thanks for your help!
I think this is the same question carpedi raised in a thread below. The short answer is nobody knows yet. Publication of <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14702147&query_hl=2">Castillo 2004</a> last year was accompanied by a fair amount of distress:"
would their blood have been acceptable for donation? Can HCV be transmitted by these occult HCV-infected patients? With antibody testing for HCV and the newer nucleic acid testing, the risk for post-transfusion HCV infection has been reported as extremely low. Are PBMCs with occult HCV not a source for infection, or does the recipient also develop occult infection? Could we be detecting viral RNA at such small levels that it is not clinically important? " (from one of the editorial comments). There was another flurry when Radkowski published in Jan of this year but as far as I know there have been no changes in public health guidelines. Common sense indicates the risk of post-SVR infection is very small. However, it's not impossible as suggested by <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15831916&query_hl=1">Castillo 2005</a>.
Sorry I missed this`thread....on vacation with little access to PC.
Summarizing the studies it seems we (SVR's) have either 1. Eradicated the virus, and have some 'dead remnants' floating around, or 2. have transformed the liver/serum infection into another form of infection, about which very little is known.
I wonder what will be found when the investigators start looking closely at other tissues in SVR's, such as salivary tissues, gastric lining, sexual organs, eyes, brain, lymphatic system, etc? Will we find that the 'occult' list for the residual virus continues to grow??? or will we find an essentially 'clean' set of organs?
How about when they start looking very closely at spouses, and close casual contacts for evidence of 'occult' type infection in the same tissues??? This issue is one that might blow the lid off a bigger national problem, if evidence of tangential, occult infection is demonstrated. We have seen hints of this in recent studies which refer to 'HCV reactivity' in various tissues of close contacts, or a type of 'HCV cellular immunity' in these contacts. Who knows what symptoms are being provoked by 'occult' type HCV infections? Autoimmunity is at the top of the suspect list, in my opinion.
The quest for a real cure may become a moving target, and we may all be in for some additional steps in our recoveries.
Great Thread, and thanks to all the thought provoking contributors. It might be nice to get all the HCV docs actively engaged in this discussion!
Thanks for taking the time to research and post all of the above information. And for taking the time to include your thoughts. All greatly informative in an area of much grey.
I would hope that at some point soon, seperate studies of Hep C non-SVR patients who have spontaneously cleared the virus will also be done in an effort to compare and contrast any 'persistance' in them relative to SVR's. Perhaps there is something to be gleaned there if any differences occur.
And in case you haven't seen this one, here's is Jules Levin's article from back in January about: <a href="http://www.natap.org/2005/HCV/010505_02.htm">Studies Showing that HCV is Not Persistent & SVR is Durable</a>
It looks to me that in terms of relapse, SVR and spontaneous clearances are durable over time. Perhaps as with occult Hep B, the main threat to reinfection from occult Hep C only arises when the immune system is hugely compromised (e.g. - transplant situations, etc.). I think some of the larger questions that remain are ones such as: what threat/risk do these 'remnants' pose today and over time? Does the body's response to them create an ongoing concern? Are we at a greater risk of HCC with them? If a medication (or set of meds) come along sometime in the future that can 'fully' eradicate the 'crumbs', will SVR's (and by extension spontaneous') need to re-tx? Can we really look to occult Hep B experiences and extrapolate to occult Hep C patients - or are the differences to distinct? Do the number of remnants decrease 'on their own' as time passes? And, as they discover more about the remnants and in what parts of the body the exist and persist, can that give us a look into previously unknown extra-hepatic regions where the virus roams and the associated negative clinical manifestations therein?
There seems to be so much to be explored and learned in this line of research. Let's hope it gets funded and persued vigorously.
Gee, just when I was heaving a sigh of relief that it seems highly unlikely SVR's need to worry about transmitting the virus, I read your post. I admit that I am scientifically challenged, know next to nothing about medicine, biology, viruses and the like, and tend to "angst" inordinately over anything human, so it's not unusual for me to misinterpret or misunderstand what I read. Double, so that I can sleep tonignt, please tell me that you're not saying that my husband of 44 years, who has so far tested negative (every year since 2000), for HCV, could be harboring some kind of occult infection that I somehow "shared" with him. My feeble mind tell me the virus needs transportation to the other tissues - so how could it get there without being in the bloodstream and therefore it would have to be detectable, right? Can you straighten me out on this?
dd,tn : a very good list of questions...The durability of SVR is why I personally believe "cured" is the right word. It's interesting that the virus-fighting skills acquired by SVRs extend not only to the original infection but to new ones <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15546094&query_hl=4">Backmund 04 </a> - clearly the body has learned to do something it couldn't do before. Much of the current confusion re hcv reflects the state of our very uneven understanding of biology. The tools available for detecting minute amounts of RNA are far more advanced than our understanding of larger systemic issues such as mechanisms of infection and disease. For example, as pointed out in one of the editorials above, small residual levels of virus could be an intrinsic part of maintaining immunity. Ironically, I think we'll make much faster progress eliminating the dreaded virus than we will in eliminating liver disease - which is our real enemy. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15947137&query_hl=2">Lindenbach</a< means we can expect very rapid progress in our understanding of HCV . Now that we can grow it, it can't hide, and I suspect within the year we'll have several additional closely tailored ways of shutting down its reproductive machinery. Not so for fibrosis reversal or hcc progression, unfortunately..
carpedi: please don't lose sleep over this. My wife (of only 27 years) is sleeping fine, regardless of how much hcv is quietly replicating inside me. So far non-serum infection has been doumented in a chimp <a href="http://vir.sgmjournals.org/cgi/content/abstract/79/6/1383?ijkey=b2010524c9ad66cae9f296fa41c0f4264129c259&keytype2=tf_ipsecsha">Shimizu '98<a/> but remain speculative in humans. There really are better things to worry about.
We certainly have opened a can of worms in this thread. Most mainstream HCV treatment professionals would like to gloss over the issues raised, and either totally minimize the potential impact of this 'HCV persistence' after SVR, or just stick their head in the sand by claiming faulty research, as in Willing's comment on global warming. At some point the evidence forces us to take note, and ask tough questions.
It would be one thing if all the SVR's went on to feeling just fantastic after a recovery period from tx. But the reality seems to be quite varied, with many, many SVR's claiming to experience a wide variety of ongoing problems, and frequently similar symptoms to when they had HCV in their blood and livers.
Who knows, maybe the majority of our symptoms with HCV were not produced by the serum or liver infection at all? Could the potential for PBMC, lymphocyte, nerve tissue, brain, connective tissue infection, at very low levels, have been more the culprit??? Could there possibly be ongoing residual sub-clinical levels of infection in some or all of these tissues AFTER SVR, which might account for ongoing symptoms??? Symptoms like fatigue, brain fog, autoimmune attacks, neuropathies, arthralgias, skin problems, depression, mood disorders, etc. etc.???
I believe these are the questions that we most need answers for. After almost two years from the end of my tx, and remaining SVR, I often feel much like I did during my symptomatic HCV+ days. I bet Lance Armstrong does not experience the same issues, after beating cancer. Many people seem to 'feel' cured after beating other major diseases. With HCV, I get the feeling that many of the formerly termed 'cures' now called 'sustained undetectables' are not exactly swinging from the vines! Many are still wrestling with lots of physical and psychological issues, trying to restore a semblance of good, vital health.
I hope these serious questions get lots of attention. They deserve it.
On the issue of potential 'infectivity', I will hold off on my concerns and observations until more information is available. I suspect some strange things are happening with close contacts, but for now, it is just my own anecdotal impressions. If it turns out that 'other tissues' are indeed capable of harboring the virus (like salivary tissues, lymphocytes, and sexual membranes) then I think we will see further probing of 'other states or modes of infection', different than serum/liver infection, which happens in blood to blood exchanges. I have a hunch.....but let's first see how the above questions unfold.
Fantastic discussion and info!!! Thanks Willing, David, and others!!!
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