Does HCV Ever Really Go Away?

[shastri20032003]

Does HCV Ever Really Go Away?
Highly sensitive assays indicated that patients with clinical resolution of HCV continued to harbor the virus and exhibit persistent active viral replication.


Long-term follow-up of patients who have cleared hepatitis C virus (HCV), either spontaneously or after successful therapy with interferon and ribavirin, suggests that the likelihood of recurrence is low. This conclusion is based on analysis of HCV RNA assays. However, HCV RNA assays have a variable range of detection, especially at low viral levels, and no assay results can completely eliminate the possibility of the virus's presence. Some evidence suggests that HCV is not only present in blood and liver, but also may be present in cells of the lymphatic and central nervous systems. If these locations harbor virus that is undetectable by standard assays, that could have important implications for disease recurrence. HCV antibodies can persist up to 20 years after resolution of clinical infection, suggesting that the virus and its antigens may persist, but at extremely low levels.

In this elegant study, researchers isolated specimens of serum peripheral blood mononuclear cells (PBMCs) and dendritic cells from 5 patients who had spontaneously cleared HCV infection and from 11 patients who had responded to antiviral treatment. Patients had been infected for 9 to 41 years, and treated patients had been followed for 12 to 60 months after completion of therapy. Using an extremely sensitive technique (involving reverse transcription and nested PCRs, followed by southern hybridization of the amplified products to virus-specific probes), the authors achieved a sensitivity limit 10 viral genomic equivalents/ mL: They identified positive-strand viral RNA in 4 of 5 patients with spontaneous clearance of the virus and in all 11 patients with therapeutic responses (in 15 of 17 serum samples, 88% positive overall). Examination of PBMCs cultured in the presence of a mitogen stimulator yielded similar results; 81% of specimens harbored detectable levels of positive viral RNA strands. Dendritic cells isolated from 7 patients indicated that 86% had positive HCV RNA strands. As evidence of active replication, the researchers also performed assays for negative RNA strands on PBMCs; 9 of 12 specimens (75%) had detectable levels of negative RNA, suggesting viral activity. Overall, all patients were found to be have detectable viral RNA either in serum, PBMCs, or both up to 60 months after completion of therapy.

Comment: All patients in this study had clinical resolution of HCV and met accepted criteria for sustained response: normalization of liver enzymes, undetectable viral RNA levels by standard assays, and improvement in histology. However, highly sensitive assays indicated that all patients continued to harbor the virus and that active viral replication persisted in about 75%. Whether such low viral levels can subsequently result in relapse of disease is unknown. Theoretically, the virus could be transmissible and could re-emerge in immunocompromised patients (e.g., post-transplant patients). Relapse rates in longitudinal studies have been as high as 8%, but whether this represents true relapse or "fresh superinfection" is uncertain. In a review of the current study, the authors mention similar findings that were recently reported by another group in which only 2 of 17 specimens were HCV RNA negative 40 to 109 months after successful interferon therapy (Hepatology 2005; 41:106).

— Kenneth D. Flora, MD

Published in Journal Watch Gastroenterology February 16, 2005

Heres the link

http://gastroentero logy.jwatch. org/cgi/content/ full/2005/ 216/1

[ladybug52]

Hi, glad to hear your good news regarding your latest pcr.
What an interesting study. I was told I could never be a blood or organ donor after tx, even if I cleared. Reading this study makes me understand why. I guess low levels of the virus are something we can live with, makes it another case against drinking though. I was starting to believe small amounts wouldn't hurt, I drank before I knew so much about the disease and didn't have significant damage, but this changes my perspective. I was just lucky once, I may not be as lucky again.
Someone posted once that hep c is caused by drinking. I was amazed that someone could post that, but there were links to more info posted as well. I think the drinking only brings out the disease that is harboring in the body, but here's some interesting info on that subject:

Clinicians have long observed a high incidence of HCV infection in heavy drinkers, including those without other risk factors such as intravenous drug abuse or history of blood transfusions. In addition, the virus is more likely to persist in heavy drinkers and to lead to such complications as cirrhosis and liver cancer. Suspected mechanisms for the latter effects include alcohol's capacity to compromise immune function and enhance oxidative stress. The role of alcohol use in HCV acquisition has been more of a mystery.

During the 1990s, several studies reported higher blood levels of HCV in drinkers than abstainers and in habitual than infrequent drinkers. Further, drinking reduction was shown to diminish the number of virus particles in the blood. These observations led Dr. Douglas and his colleagues to pursue the role of alcohol in HCV replication.
http://www.nih.gov/news/pr/jun2003/niaaa-26.htm

Well I guess this doesn't answer the question, but if the virus doesn't go away, the small amounts left in the body can increase with drinking. It's like fetal alcohol syndrome, no one knows a safe amount.
Take care,
Bug

[shastri20032003]

Strange...when I read  article I posted ...my first thought was that I should throw out of the window any thoughts and hopes I was harbouring in my mind of the possibility of having a drink or two in the distant future..just like you

This is further strengthened by the article you posted..its definitely out of the window unless I plan to committ harakiri!

Cheers to that!

[SonicBandaid]

Yes.  This is a difficult issue though, and the data is still being collected.  

In some ways, it may not matter if viral particles do reamin in the liver so long as they are not actively replicating at high level or causing liver disease.  You could look at this in the same way as the Chicken pox virus or cold sores; Many people harbour these viruses indefinitely long term, but, for the most part, for most of these people the virus is completely dormant and NEVER causes any problems.  For some people, these viruses occasionally reactivate and a clinical problem (such as shingles or eruption of cold sores) then develops.  Some people with HBV do this as well (generally have a dormant virus that occasionally reactivates, causing hepatitis) and it is POSSIBLE some patients with these dormant viral genomes found in the liver after apparent clearance of viral from serum, may also reactivate with clinicsal hepatitis developing during prolonged follow up.

However, it is not at all certain that PCR amplifiable HCV RNA found within the liver after viral clearance actually equates to viable virus.  Only prolonged follow up of patients treated for HCV will answer the question.  I would say, however, that there have been a lot of patients who have now been followed up for >10 years after clearing virus and late relapse, as these papers might suggest would occur, really does not seem to be a major issue.

Cheers
Sonic

[mikesimon]

I am a transplant recipient - 6/2000. I became undetectable 4/2003 and stopped treatment 6/2004. I have monthly PCRs - Heptimax <5 IU/ml - and have been undetectable on every PCR since 4/2003. In May 2006 my immunosuppressive dose was drastically reduced and my enzymes started soaring. A biopsy on 6/3/2006 showed 30 IU/ml HCV. MY surgeon told me that the reduction in my anti-rejection dose stimulated my liver and it attacked the HCV in my liver and as a result bystander cells were being destroyed which caused the enzyme elevation. A PCR 2 weeks before and 1 week after my biopsy showed undetectable <5 IU/ml. So my take is that some virus may remain but replication is controlled by our immune system. My AR dose was increased and I did 6 months of half dose Pegasys and 200 mg ribavirin for 6 months. My enzymes came down quickly and have remained in the teens or low twenties and my monthly PCRs are undetectable - I have never been detectable since first becoming undetectable 4/2003. Mike

[spcecst2]

I hope so??

[DoubleDose]

Yes, this article directly addresses the $64 Million Question regarding HCV:
That is:  When we attain the SVR is the virus really eradicated, gone, done forever...or is it now controlled by a newly enabled immune system, keeping it in a 'remission' type state of existence.

The question of alcohol users having a much higher incidence of HCV is a subject I have posted about on the Forum many times.  It often goes overlooked, or is responded to by claiming that the alcoholics must also have been IVDU's at some point since they have some sort of 'character' problem.  This comment sure makes lots of assumptions, and totally ignores the clinical findings: that a much higher percentage of alcohol abusers harbor HCV.  Period!  

My hunch is that HCV may be out there in a sort of 'benign', or 'remission' type  infection in many people, without them having the antibody positive blood/liver active HCV infection.  In these people, alcohol may just allow the virus to overcome immune system controls, and then to become a true HCV infection.  I continue to suspect that HCV is being transmitted to intimate contacts in a 'different' form than the 'blood/liver' infection.  Maybe more like what we have after SVR....just some low level, compartmentalized virus, 'treading water', and staying undetected, unless a major immune system event occurs....like alcohol abuse, severe illness, or immunosuppressive drugs....etc.  

I do not believe that we know nearly the complete story about how HCV works in our bodies, nor how it might transmit in 'different' ways.  I do believe there is a low level, ''atypical' form of transmission possibly taking place, that allows others to harbor a silent form of the virus, in tissues, controlled by the immune system.

The bigger questions are:  What damage does this 'persisting virus' cause to SVR, Spontaneous clearers, or possible close contacts who may (or may not) now harbor a form of the virus?????  The article asks these questions, as well as questions about Central Nervous System infection, etc.  I suspect this is likely, given the range of HCV symptoms, and post-SVR symptoms.  Take a close look at intimate contacts, and determine if any chronic symptoms have developed in them that would seem similar to HCV extrahepatic sx.  

These contacts would also most likely test negative on any standard HCV testing...antibodies, PCR, etc.  The tests that might demonstrate the possibility of this type of infection would be 'cellular immune response' tests of various tissues and fluids!!!  (these have been done, and raise red flags!!!!)

Just some related thoughts and opinions!

I would love to hear other feedback, pro or con!!!

DoubleDose

[FlGuy]

What's the good word?  Noisy in your neighborhood Friday night, was that around shot time?

[spcecst2]

week 3 - 3 log drop, week 6 - <5

[ladybug52]

Are you the person I was referring to when I mentioned the alcohol and hep C relation? I know at the time I thought what a crazy idea, but I'm glad it was brought to my attention as I have now changed my thinking.
Bug

[ladybug52]

I agree totally with what you're saying. It just makes sense. If the infection has been around as long as some claims (400 yrs?) it has to be dormant in many, many people. It's the silent epidemic, with so many people unaware they are infected. Everett Koop is so great about trying to educate the public, but somehow not enough awareness has been raised.
Bug

[FlGuy]

Good deal!

[Myown]

"I do not believe that we know nearly the complete story about how HCV works in our bodies, nor how it might transmit in 'different' ways. I do believe there is a low level, ''atypical' form of transmission possibly taking place, that allows others to harbor a silent form of the virus, in tissues, controlled by the immune system."
--------------------------------------------------------------------------------------------------------------
There is no way that anybody will ever convince me that this virus is transmitted only thru blood to blood contact. There has been mention of the virus sometimes being found in the liver yet not blood once svr. Well what about if it finds its way to a persons lungs? Respiratory virus's are highly contagious. Maybe if it became airborne and infected someone it would be under the radar until the persons immune system became compromised not just by disease or immunosuppressants but also including high amount of stress that can and does lower the immune system. I'm sure to some this would make a good science fiction movie to some, but thats okay because until they know how to 'really cure' us no one can convince me otherwise (that anything is possible.)

Take care.

[cruelworld]

shastri, you get my "post of the day" award. maybe "post of the decade" things were getting boring around here and you fixed that. thanks

mike , this is the first testimony of an example of a documented relapse that is
brought back to UND by the host (you of course) very very real evidence, and i dont cosider your case to be an anomaly. i would bet some, if not many SVR people go through this, but infrequent testing never reveals it. thanks greatly for that little tiny tid bit of earth shattering truth!

to double dose and the others who agree with him,
by going to the trouble of reposting valueable info you have shed an incrdible light of one of the more interesting and relevant issues that we all wonder about. ill admit that i am incredibly lazy, and while ive put a good dent in the archives i missed that one. and what a one to have missed! fantastic presentation, youve answered most of my few remaining important questions about HCV. it seems simple now that you explain it. if hcv is like
herpes and 60% of us harbour it (even though undetectable),the persons most likely
to enable the hcv proliferation are the alchoholics. the ones who suppress their immune system every day significantely with alcohol. WOW! this is somewhat scary news to me because i had hoped there would be an outside chance that i could drink again someday, while i know many doctors say light drinking is ok post SVR, this news may frighten me out of ever doing it again. aint nothing like goin to school around here!

  

[mikesimon]

I did not relapse. I have not been serum detectable since clearing in 2003 and that is the criteria for SVR. What the average SVR might show on biopsy is the issue my case raises. Also the question whether serum undetectability equals complete viral eradication. You should re-read my post because I suspect you might not have read it carefully.
Mike

[pigeonca]

I wish scientists would study ordinary people, who have a four or five drinks a month or thereabouts, as well as "heavy" ________ abusers (fill in the blank with drug of choice).  Many of us hope to resume ocasional drinking after SVR.  There are so many health benefits in red wine, for example - especially if your family has heart disease - that I would think the effects of moderate drinking should be investigated for that reason alone.  I don't need a "study" to know that heavy boozing is bad for you.  

[jmjm530]

Thank you for sharing your take on a subject that is sometimes controversial here with varying degrees of importance put on it. Your take is almost exactly the same take as two well-known hepatologists here in the States I've consulted with. I certainly agree (as do both doctors) that it certainly doesn't appear to be a "major issue", or perhaps even a minor one. In fact, even the studies that champion the "persistent virus" theory, almost always state that no clinical significance has yet to be proven. More troublesome to me, are the potential for "persistent" sfx's from the treatment itself, as opposed to the so-called "persistent virus".

All the best,

-- Jim

[ladybug52]

You were the first person I thought of when I thought of the hot debate over whether or not to drink after tx, Jimjim was next. I don't see a problem with responsible drinking. You are in the wine country and wine to you is more of savoring a special drink, than drinking to get drunk. JMJM has coronary issues and wine would have a beneficial effect. It's just a personal choice. Mothers drank during pregnacy before they found out about fetal alcohol syndrome. My dr always said if all the women who had drank a little during pregnacy had kids with fetal alcohol syndrome, he would have had two blithering idiots.
I really can see how large amounts can help the dormant virus emerge, but I'm not sure if it will cause damage and relapse in all. Shcnme posted that she knew people who drank before, during and after tx who were ok. I'm not going to get on the bandwagon for or against, like I've said, I respect everyones personal decision.
Take care,  Hugs,
Bug

[DoubleDose]

Jim, you are right, not much has been proven yet about the effects of remaining persistent virus after SVR, as far as its possible negative ramifications.....but it has been little studied, often denied by HCV doctors, and has not been proven to cause little or no harm either.  I do not think the medical world has a clue what the ramifications of long term persistent virus might be.  Also, does the fact that we (SVR's) have knocked out the blood/liver infection (to a major extent more or less, since there is still lingering virions) preclude the possibility that we might still have active viral issues in the central nervous system, brain, bone marrow, glandular system, etc.  Many doctors suspect that HCV is active in those tissues as well, and little has been proven about the effects of obtaining an 'SVR' in the blood and liver, on these organs and  compartments.  I still think we do not know nearly everything about this virus, and will not be surprised at news down the road that the virus is much more than a strictly 'blood/liver' virus.  I have always thought it strange to believe that a virus of this magnitude, stealth, and virulence, would ONLY infect blood and liver....especially given everything we now know about its effects...on the lymphatic system, salivary cells, connective tissue, etc. etc.

I DO like to keep a good thread going when I have the chance!!....things HAVE indeed gotten very boring on the site in recent months  Where are all the tough, controversial questions, comments, etc??.  I don't mind taking the flak!  I just say what I believe, and discuss what I observe. Wrong or right.

DD

[SonicBandaid]

Hi DoubleDose,
I don't think HCV Docs deny the issues you raise, DoubleDose, its just they may not actually be very important, and its difficult to study these problems (anyone for brain biopsy so we could do the study? etc etc) in patients.  The techniques are also extremely difficult; I did a study about 15 years ago that I THOUGHT suggested convincingly HCV replicated in lymphocytes.  I took me a long time of thought and review of the data/ techniques and implications etc to realize I shouldn't publish the paper in full (it was published as an abstract) becuase I couldn't be ABSOLUTELY certain I wasn't looking at PCR contamination (we were using strand-specific priming, which, it turns out, isn't absolutely strand specific at all).

The issue for us is primarily, so what?  If the virus isn't actually causing any measurable problem (and the data long term in terms of liver function testing / repeat post-clearance biopsies etc etc) certainly suggests this IN MOST PEOPLE post SVR, why should we panic people into beliveing they have a problem?  Most people (most living things actually) harbour viruses of one form or another (with "endogenous retroviruses being most topical) and the evidence suggests most of these NEVER cause clinical problems. I harbour a suspicion, in fact, that some of them may actually be beneficial and exert a comensal antiviral effect on "nasty' viruses in the same sort of way that commensal gut bacteria (like the lactobacilli people take with yoghurt etc etc) do for bad intestinal "bugs".

Its early days, but I agree with JmJm's Doc contacts that the late / latent HCV issue may be a furphy, at least for most folk.
Cheers,
Sonic

[meki]

OK - well - here's something to throw in the mix.

I don't drink very often. (ALL OF MY LIFE - alcohol kind of makes my asthma react... not all the time, just every once in awhile, plus it's always given me a heck of a headache.)

I'm not a drug user.

I'm not promiscuous, nor associated with promiscuity in others. (in other words - very few and far between - long term relationships and married - and guaranteed safe sex with anyone besides hubby prior to marriage for both of us.)

Believe I was infected with Rhogam shot necessary to keep daughter alive.

So - knowing that - alcohol plays little to NO part in my disease popping up.

Family is HCV free. Including daughter born, we believe, after I became infected.

My curiosity doesn't really stem from wanting to know how I got it.

My questions are:

*I want to know if it's ever going to come back

*Why my family ---- whom I've bled around - been involved intimately with my husband (shared razors, toothbrushes, towels, bodily fluids, etc.) and gave birth to my daughter... they have not gotten it, but I did... IS it REALLY ----  THAT ---- contagious?

*Am I still contagious after 3 months post tx non-detectable?

[shastri20032003]

Like Double Dose stated, 'the 64 million dollar question regarding HCV' but which still goes unanswered beyond reasonable doubt

A lot of varied opinions here and a somewhat accepted concensus that low levels of these viron still persist in our body though in a dormant state after SVR, which makes it easier for the doctors to dictate how we should live our lifestyle after SVR but makes it more difficult for us heppers to expedite!

Also it seems there's a lot to be  known yet about the contagious element of HCV after SVR which means we have to still tread cautiously so that our near and dear ones donot contract this virus from us even though we are "cured"

Post tx alcohol hopefuls...throw your last bottle of wine out of the window or better sell it to someone after reading this thread....thats my personal opinion

[SonicBandaid]

Hi shastri20032003,
Look, I wouldn't be so negative.

The evidence is even from people who have high level virus, the probability of HCV transmission, outside of the context of donating blood, or organ donation, is exceptionally small.  there is no doubt sexual transmission, and vertical (from mother to unborn baby) do occur, but they are not common.  Estimates of transmission from and infected man to a non-infected woman suggest a transmission rate of <1% per year within a "normal" married sexual relationship (whatever that means).  

The risk of transmission to family members with whom non-intimate relationships (siblings / grandchildren in a "normal" family) occur is virtually zero.  I have never seen convincing proof that people can be infected in this way and, personally for example, would have no issues kissing an HCV positive person.  

The risk, then, to "near and dear" people within families of people who have experienced SVR, but in whom sophisticated molecular tests suggest persistence of HCV RNA fragments (or dormant virus) within the liver (but NOT serum) will be even less, probably orders of magnitude less.  

These are interesting issues, but I wouldn't quarantine a family member on the strength of what has been published about "persistent" HCV.
Cheers,
Sonic

[desrt]

Several more studies subsequent to this one have all shown similiar results: persistence of positive and negative strand HCV RNA in the liver and 'compartmentalized systems' of people who are considered SVR to IFN tx or who 'cleared' it on their own. All studies give roughly the same percentages - 80%-90% range.
Interesting fact and  may be of relevance somewhere down the line, but I'm not about to get a biopsy of my spinal fluid to find out if I'm 'totally' undetected or not.

[shastri20032003]

Thanks Sonic ....your point well taken
Probably i was just being overcautious which sometimes happens when we go thru an ordeal and donot want a repeat peformance for ourselves or a similar perfomance for those close to us
Take care
Shastri

[wyntre9]

Just wanted to let you know once again how truly grateful I am for your insight and your suggestions.

Thanks for taking the time to educate and share.

Wyntre

[nygirl7]

C2  bug Strange...when I read article I posted ...my first thought was that I should throw out of the window any thoughts and hopes I was harbouring in my mind of the possibility of having a drink or two in the distant future..just like you



Ahhhhhhhhhhhhhhhhhhhhhhh me too.  Just one margarita sitting by the ocean.....just one...........................

But you are right - and lately I've been feeling VERY weak so I needed the wakeup call - thank you guys...............

(waaaaaa)

[shastri20032003]

Sorry.....I am not sure whether I spoilt your day or made your day.! LOL
Look at the bright side,there are more things to life than a margarita like.......?.......?...duh...wil get back to you soon!

[mikesimon]

Intellectual curiosity and discussion doesn't have to inspire panic. There are issues that surface, infrequently perhaps, but they surface nevertheless and I find them to be thought provoking. You didn't address my post and I am curious why that is. I have been told by my transplant surgeon that when all detectable traces (serum and biopsy) of HCV in transplant recipients have been eradicated rejection often occurs. Assuming he is correct about that and I have nor reason not to believe him, why do you suppose that occurs? I believe that for the overwhelming majority of people SVR is durable and confers tremendous benefit. But, there might be circumstances where persistent or occult or whatever you chose to call left over virus could affect an SVR. I am thinking about a shock to the immune system such as a bolus solu-medrol intravenous treatment. Might that reactivate what may be characterized as dormant or benign HCV remaining in the body? I think it is a possibility but there are few, if any, studies that support that theory. I asked my surgeon what percentage of SVRs in the general (non-transplant) population he thought would show HCV on biopsy and his response was roughly 75%.
You say "there have been a lot of patients who have now been followed up for >10 years after clearing virus and late relapse, as these papers might suggest would occur, really does not seem to be a major issue." I would like a citation where I could find supporting information for that statement because I haven't found many large studies that really looked at this closely and fewer that did for >10 year SVRs. I am not saying that I believe it to be "a major issue" but I do find it an interesting subject and I am surprised that you seem to think otherwise. You didn't offer an opinion about my case and though I am certainly not the typical HCV patient I would think an HCV scholar would at least weigh in on it. I have spoken with several noted hepatologists and every one of them found it interesting and worthy of an opinion, although none were certain about what happened or why it happened. They seemed a bit confused by my situation to be straight with you. Two believed it was rejection due to anti rejection reduction. One believed my surgeon was correct about my stimulated immune system attacking the "benign virus" and causing bystander cell death - collateral cellular damage. That might cast some light on my surgeon's experience that complete eradication in transplant recipients can lead to organ rejection.
I just hoped you'd have an idea or opinion. Mike

[DoubleDose]

Now this is what I call and EXCELLENT thread!!!!

Mike, you are so right, intelligent discussion should never cause panic.  The issues raised will be clarified down the road, whether we discuss / debate them or not.  I am certainly not 'screaming down the street', on the contrary, I am enjoying SVR, and pushing myself to recuperate, and regain lost capability, everyday, and enjoying life....and even a glass or two of fine wine every week or so.  Yet, I still have plenty of concerns about the realities of the virus.  Whether they prove true or not, I will continue to have fun, and not worry about what might be.  

Let's keep the comments coming, everyone!!!!  This is how the board used to be everyday!

DoubleDose

[mikesimon]

Yes I agree completely. And the board used to explore issues like this one as thoroughly as the information we could locate allowed but times change and that seems not to be in vogue these days. I too am enjoying SVR and I am overjoyed to have achieved that status. I feel good and I am very optimistic about my future. I do believe that in time some, if not most, of our questions will be answered. I have been reluctant to bring my case up because when I first ran into difficulties it was explored pretty comprehensively - as comprehensively as we could. But now we have so many new members and so many threads that I don't think many people are aware of it or some of the possibilities/questions that it raises. I am biased big time but I do think my case is thought provoking but apparently that sentiment isn't shared by many. Mike

[missy60051]

I just want to thank everyone for their thoughts and comments,as per my appointment I had with my new Dr. (heptatologist) last week these exact questions and concerns have been on my mind.
Something for all of us to think about
Missy

[jimjetjock]

I've heard that 50% of those treated with Peg/Ribavarin either do not clear the virus (no response), or have it return after treatment (transient response). Both of these are (erroneously?) categorized as "non-responders".  I am the latter.

During the treatment, and for some months (years?) later,  it appeared as if the virus was gone or very low, and that  little damage was being done to my liver.

I had tolerated the treatment very well (not even a cold for almost nine months), so when I recently had elevate numbers, I thought there would be some "maintenance" alternative to keep the virus under control when it came back. Wrongo!

Lacking any long-term studies,  the FDA  has evidentally not approved continued dosages intended to simply limit the damage of the virus rather than eliminating it.  Because it's not approved the VA hospital won't do it.

This is ridiculous. I could easily tolerate a shot a week forever, if it truly kept the virus low and the damage to my liver to a minimum

I'll bet this is the case with at least 25% of HEP-C patients!

What am I missing here?

Jim

[orphanedhawk]

I thought the fact they say we are UND proves that no one is willing to say we are free of HCV.
   A friend says her heptologist/researcher told her alcohol sends HCV into a reproduction orgy. Coffee they hate and there is some evidence of heavy coffee drinkers being protected from damage by the virus.

[SonicBandaid]

Dear mikesimon,
Sorry!  The reason I didn't respond to it was that I didn't see it initially; I scrolled to the bottom of the thread to post the second time and missed your important " I am a transplant recipient - 6/2000. ,,,etc " post, before, as Jmjm put it, I had to count sheep.

I think your take on your situation is probably pretty accurate, but I suspect the bottom line is you wont ever have a problem with HCV recurrence (and you are one of the lucky ones; I wrote one of the first HCV post transplant recurrence papers when I was a peon, and the results then (without ribavirin, I might add) were not great.

There is though a large number of papers (maybe >30, sample below) addressing the long term outcome following clearance issue, and while none have reported 10 year data (though such data exists) they are all consistent and show that if you are clear (from serum) at 1 year you remain clear with normal liver function as long as testing has been done (with very rare exceptions, amny of whom are explained by re-infection rather than re-activation).  It is difficult to do these studies as many patients, reasonably, having been cleared of a nasty infection using drugs they hate often don’t want to see their hepatologist 10 years later.  Personally, I have about 30 patients who have cleared at 10 years+ (from the old interferon alone days in some cases) and they have remained HCV negative.

And while “panic’ may not be the operative term (although the people who post here are not representative, probably, of the average punter with HCV, some of whom do genuinely PANIC (“I am not allowed to hold my grandson…” etc etc), telling someone they may not ever clear the virus but we don’t know what that means…. Is hardly likely to win someone’s confidence prior to suggesting potentially miserable therapy, is it?
Cheers,
Sonic


References

1. Kim JH, Han KH, Lee KS, Park YN, Ahn SH, Chon CY, Moon YM: Efficacy and long-term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea. Yonsei Med J 2006, 47:793-798.
2. Wiegand J, Jackel E, Cornberg M, Hinrichsen H, Dietrich M, Kroeger J, Fritsch WP, Kubitschke A, Aslan N, Tillmann HL, et al: Long-term follow-up after successful interferon therapy of acute hepatitis C. Hepatology 2004, 40:98-107.
3. Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland O: Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999, 30:783-787.
4. Hopf U, Berg T, Konig V, Kuther S, Heuft HG, Lobeck H: Treatment of chronic hepatitis C with interferon alpha: long-term follow-up and prognostic relevance of HCV genotypes. J Hepatol 1996, 24:67-73.

[SonicBandaid]

You also raised a couple of other interesting (sorry I I implied I didn't think this was in interesting issue; it obviously is, I just think attention to the problems posed by that large number of folk who don't clear with treatment, have intolerable side effects or who have decompensated liver disease is more pressing at the moment) issues:

"I asked my surgeon what percentage of SVRs in the general (non-transplant) population he thought would show HCV on biopsy and his response was roughly 75%."  I am not sure I would agree with this but I guess it depends on what is meant by HCV.  What probably needs to be done it to take the biopsy material of someone in this situation and innoculate it into an animal model to see if infection develops.  PCR by itself would not answer the question aas to whether these fragments of RNA have a clinical significance, but transmission experiments would.  Unfortunately, the only animal model of HCV infection is the chimpanzee and I am not sure I would be happy wassting a chimpanzee to answer a question that may not (and probably does not) have clinical significance.

with reagard to: " I am thinking about a shock to the immune system such as a bolus solu-medrol intravenous treatment. "  I think if viable virus was present this, if anything, would result in reactivation. The fact is it has been used many times in this setting now and reactivation has not been seen (in the context of SVR long term I mean, not just post OLT).
cheers,
Sonic

[TnHepGuy_]

"The fact is it has been used many times in this setting now and reactivation has not been seen (in the context of SVR long term I mean, not just post OLT)."


see: "Reemergence of hepatitis C virus after 8.5 years in a patient with hypogammaglobulinemia: evidence for an occult viral reservoir."

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=16107964&ordinalpos=45&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

(from the article)

"...Here, we describe a patient with hypogammaglobulinemia whose acute hepatitis C virus (HCV) infection appeared to resolve after receipt of interferon therapy, relapse immediately, and then clear spontaneously--only to relapse after receipt of corticosteroid therapy, and clear again, 8.5 years later. ..."


TnHepGuy

[SonicBandaid]

Have read that article many times.

the key is "hypogammaglobulinemia"

This can be viewed as similar to the post transplant setting as a type of quite abnormal immune system disorder and it not at all similar to people with normal immunological responses after SVR receiving steroids.
cheers,
Sonic

[rosebud57]

In May 2006 my immunosuppressive dose was drastically reduced and my enzymes started soaring.
-------------------
just curious, were these AR meds intentially decreased?

obviously i am not the most knowledgeable about hep c technical stuff. but it sounds like HIV  (something else i know little of) where even if "UND" there is a likelyhood of it hiding somewhere in body.

re SVR: my thought is if it is slow growing anyway, and body can keep in check for many years so maybe we could anticipate relatively good health and something else will be our demise...  but i am left to wonder if we could infect someone if it still hides in our bodies somewhere, even though not in blood. (somewhat like myown thoughts) --  certainly makes sense why organ donation is a no.

[mikesimon]

Yes, the decrease was ordered by my surgeon. My center is aggressive on lowering and where possible eliminating immunosuppressive drugs. My surgeon said this is a trickier process with HCV transplant recipients.
Sonic, do you have any opinion on why transplant recipients are more prone to rejection when all traces of HCV are eradicated? I have no study supporting the fact that they do - just my surgeon's discussion.
Mike

[mikesimon]

From: http://www.mlo-online.com/articles/0206/0206clinical_issues.pdf
Occult hepatits C virus persistence: identification and characteristics
By Tram N.Q. Pham, PhD, and Tomasz I. Michalak, MD, PhD

In this regard, the presence of low amounts of the replicating
virus could provide continuous antigenic stimuli beneficial
to immunocompetent individuals in maintaining an effective
antiviral immune response and keeping the occult infection
under control. On the other hand, virus persisting at very
low levels may provide a means for reactivation of infection
when the host’s immune system becomes compromised due to
a disease or therapy. Indeed, reactivation of HCV infection
has been documented in patients receiving immunosuppressive
treatment.21,22
Footnote 21. Melisko M E, Fox R, Venook A. Reactivation of hepatitis C virus after chemotherapy for colon cancer. Clin Oncol. 2004;16:204-205.
Footnote 22. Vento S, Cainelli F, Longhi MS. Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy: an unresolved issue. The Lancet Oncol. 2002;3:333-34)

From: http://www3.interscience.wiley.com/cgi-bin/abstract/109860426/ABSTRACT
Persistence of hepatitis C virus after successful treatment of chronic hepatitis C: Is hepatitis C infection for life?

In conclusion, these results imply that HCV RNA can persist at very low levels in the serum and peripheral lymphoid cells and that an intermediate replicative form of the HCV genome can persist in PBMC for many years after apparently complete spontaneous or antiviral therapy-induced resolution of chronic hepatitis C. (J Virol 2004;78:5867-5874.)

From: http://jvi.asm.org/cgi/content/full/78/11/5867?view=long&pmid=15140984
Hepatitis C Virus Persistence after Spontaneous or Treatment-Induced Resolution of Hepatitis C
Tram N. Q. Pham,1 Sonya A. MacParland,1 Patricia M. Mulrooney,1 Helen Cooksley,2 Nikolai V. Naoumov,2 and Tomasz I. Michalak1,3*

The present study shows that HCV RNA can persist, albeit at very low levels, in the serum and circulating lymphoid cells for years after apparently complete clinical and virological resolution of chronic hepatitis C. If the present findings reflect the existence of the biologically competent, infectious virus, this silent persistence may have important epidemiological and pathogenic implications. Among other factors, these trace amounts of the virus may lead to reactivation of hepatitis C after termination of antiviral therapy or due to severe immunosuppression and may support perpetuation on the subclinical level of liver disease which becomes symptomatic years after exposure to the virus. They may also constitute a source from which HCV may spread through blood and organ donations to susceptible individuals.

Mike

[DoubleDose]

That very last paragraph is a 'killer!'......everyone should read it closely.  When people claim that there are no negative ramifications from the possibility of SVR's having 'persistent, low level virus' in their systems....I think the last paragraph quoted raises many red flags, for both spontaneous clearers, and SVR's as far as having POSSIBLE down road consequences of this persistent virus.  Not to mention their mention of the possibility of transmission through blood/blood contact, cell , tissue,or blood donations, etc.

People often love to gloss over these sorts of studies and comments.  I have heard doctors even say, 'their methodology must have been faulty' because we believe there is no reproducing virus left after SVR'...... Great...we believe it....so it must be so...even if other scientists meticulously demonstrate that the belief is incorrect....well then heck, we still believe it.

[willing]

first thanks for your informed discussion on a topic that has long been of interest around here.
The closing section of a recent review of hcv soc practices

Scott, JD, Gretch ,"Molecular diagnostics of hepatitis C virus infection: a systematic review." JAMA, '07 297(7):724-32

cites several of the papers regarding serum-UND infection we have been discussing here over the last couple of years (radkowski,pham,castillo, etc.). It was interesting to see this topic raised in a mainstream review, given that most physicians appear dismissive of these results.  Since you have done testing in this area I am curious about your opinions on why no rebuttal has been forthcoming:

- if it is contamination, surely the results should not replicate in all circumestances yet there seem to be no published results that applied similar PCR protocols and obtained insignificant/no RNA product?

- if the PCR-amplified RNA  is not indicative of viable/infectious virions why has there been not attempt to assess this in either chimp or in one of the synthetic cell lines recently developed for studying hcv infection?
(I like chimps too, but given the costs of hcv it seems a bit presumptuous to assume a-priori that such testing would be wasteful, particularly because of the  possible effect of blood supply)

- why have there been no sequencing studies to assess the viability of the residual RNA?

A number of patients here report post-SVR complications of varying degree. Surely it would be interesting to know whether these are at leat in part due to continued immune response to residual virus. Also, while the durability of SVR is unchallenged the reduction in liver disease and hcc risk among SVRs is not as dramatic as one might hope. Is this likely to primarily reflect irreversible damage or might it be related to ongoing low-level infection?

[SonicBandaid]

willing, you raise very valid and good points.
Many of the studies you mention should be done (and I agree, they should) are underway.  The problems with sequencing include: 1) it is technically difficult (from small liver biopsy samples that are generally taken for diagnostic, not research purposes) tedious and very time consuming (I did this years ago and it took me almost a year, from large quantities of serum, albeit working almost alone) and expensive. 2) even if full length HCV is demonstrated it MAY not been its viable in an infectious sense; most HCV (or HIV or HBV for that matter) circulating in patients blood consists of non-viable and non-infectious genomes.  Estimates of HIV, in fact, suggest the non-viable genomes outnumber viable virus by >10,000:1.

We are not dismissive of it, entirely, we (and I am being presumptious suggesting a collective opinion), I think, just don't believe the evidence supports their being a major ongoing problem for patients lucky enough to develop SVR.  As implied above, this is an active area of research, though, and its early days.  My personal take, for what its worth, is that if I had sustained an SVR, I'd crack a [small] bottle of champagne and look forward with complete optimism.

With regard to the blood supply, that is important, of course, but where I am the Red Cross Blood Bank wouldn't touch the blood of anyone who had HCV [but cleared even with an SVR] with a barge-pole, and rightly so (we don't even use the blood of people who LIVED in the UK during the 80's-90's because of concerns about mad cow disease). My guess would be the Red Cross in the US would take a similar line, at least with HCV patients.
Cheers,
Sonic

[Bazaaa]

GUYS.... I was waiting sooo badly to my first guinnes after the therapy... and now you want to RUIN it for me?? ...I'l newer forgive this...  ;)

[willing]

in the US, I'm under the impression that individual antibody tests are run on blood samples (many come here after getting their first thanks but no thanks notice) but PCRs are only run on pooled samples.

Are the full-length, non-viable, hcv genomes, fragments awaiting assembly or fully packaged virions that are not infectious? I didn't realize the latter could develop and ciruclate, though the detection of both + and - strand RNA would seem to be strong evidence of functional, replicating, virus.

bazaa: as the good dr. said, I wouldn't let anything stand between you and that glass of guiness when the time comes...

[SonicBandaid]

Hi willing,
That is also a good point, but believe me it is almost impossible to demonstrate that an isolate of HCV RNA or a virion is full length and double stranded and packaged.  Even if it was it still may not be infectious.

Even if someone was ONCE HCV Ab positive (let alone HCV RNA positive) the blood banks here won't use their blood.  They have used PCR on individual donations since 1995 or 6 here. Cheers,
Sonic

[mikesimon]

Have we learned anything? If we have, please tell what it is. It's always a pleasure seeing your name here and reading your posts. Mike

[willing]

sonic: thanks for your insights. If you have the chance, please post some details on the techniques/problems  in that year-long quest to pcr-amplify fragments derived from tissue biopsy. Not that many of here will have the opportunity to do the lab work, but I think it may be helpful in understanding the difficulties of quantifying viral load.

mike : I'm not sure we ever really know anything, but every time we walk around the same loop the landscape looks a little more familiar. Good to hear from you, as always. Be well.

[jmjm530]

I posted the link above, but thought it just might be easier to bring back the old post, as the new software allows it.

[geterdone]

I would love to see those days come back. The learning curve was great! Heading out camping, nice to see you post.
jasper