mikesimon's thread, continued....

Sorry to all who may be unable to post a thread today because I took one up.  I found Mike's thread and it was full.  There are so many, many folks who helped me through tx and Mike is one of them.  I know more of you would like to say a word or two to Mike, so here's another place.

Mike, I haven't been on this site for quite some time and, obviously, found your thread.  Like so many who have commented, I was helped so much by your knowledge and calm compassion while I went through my own tx.  You, Kim, Barb, Majneni, Ken, Pearse, Jeff, and so many others got me through the black days and I was fortunate to be able to answer a few questions myself.  

I am so sorry you have to restart the poison but am hearteded amd humbled by your positive attitude.  I pray you beat it once and for all this time.

Galen

[jmjm530]

Oops! :)

[amirtracy]

I'm sorry. But i'm relieved you were'nt in rejection. but i'm sorry. somehow you'll do it again. want you to know i'm thinking of you and will always be here if you need a shoulder.   tracy

[jmjm530]

Not sure if Mike was HCV postive at time of transplant, but he was HCV negative via senstive TMA at some point after the transplant and until quite recently. In fact, it appears he may be TMA negative right now in spite of the fact that they apparently found HCV activity in the liver. This is what makes it a little confusing but I'm sure Mike will clear some of this up when he feels up to it. If it were me, I'd be pretty exhausted by now.

[mikesimon]

I was transplanted due to HCV in 2000. As you probably know, transplantation doesn't cure the HCV. It recurs universally post transplant. I started TX about 7 weeks after transplantation and you know the rest. 3 TXs and clear and SVR (?) after the last one. Mike

[jmjm530]

There has been a study on this I believe. Maybe Willing or someone else has it. I think it found hep c in liver tissue in a certain per cent of those with elevated ALT's but negative PCR's.  But I think this was in a population who had never treated.

[mikesimon]

I can well understand how my news might alarm some of you but remember, I am immune compromised and that changes the equation. Just because it was in my liver doesn't mean that it is there in all or most or even some of the SVRs. My thought is that it might very well be there but it will not rear its ugly head and just sit there and do nothing. I sure hope so anyway. Do not borrow trouble please. I think this presents an interesting example of how insidious this virus is but that doesn't mean that your SVR isn't going to be permanent - I think that it will for you guys. Mike

[willing]

gee, I thought we had been trough all this recently...there is no shortage of studies over the past 5 years confirming the presence of detectable HCV RNA in the tissues of patients (both SVRs and untreated) who show no detectable serum RNA. Whether this documented low-level infection has any therapeutic significance has not been established, but there is at least one data point that shows a correlation of post SVR PBMC infection with cryo.

I can dig up the list of studies again if the above seems controversial, but I thought we covered all  this a couple of weeks ago...

[willing]

Howdy! Hope all is well with you and the roomba. Drop in if you get a chance, you helped out  a lot of people during your time here.

[jmjm530]

I was only referring to one particular study of folks with elevated liver enzymes, where people were serum negative while HCV was found in the liver. The elevated enzymes aspect reminded me of Mike's case. I later found the study and posted it in "C8" in the thread above. As far as the rest, yes, that was covered a few weeks ago.

-- Jim

[mikesimon]

I think that the prudent approach for SVRs is to have blood work annually or every 18 months. The enzymes should alert us to any inflamation (inflammation) and or that may be occcurring. I just don't think routine biopsies would go over too well with anyone. Mike

[willing]

absolutely - I can't imagine a non-transplant SVR doing a bx just to be thorough. However in a transplant or research setting if there are existing reasons to bx, it seems to make sense to also check the cells for RNA. BTW, turns out the earlier Bizollon paper, <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12524414&query_hl=17&itool=pubmed_docsum">Bizollon'03</a> is free access, so I'm only going to try to mail the '05 one.

[DoubleDose]

I think what Jim is referring to is 'occult HCV, or instances of the virus being found at detectable and often substantial levels in liver tissue, but not in the serum.  Som of these cases are in those who have never treated (usually IVDU's from studies I have seen), and some cases are in those who treated, and cleared from the serum.  Usually the tipoff is elevated LFT's, BUT not in all cases.  I am sure, as in Mike's case, this can also happen in liver transplant / tx cases.

What Willing has referred to, is the research studies showing 'persistent HCV RNA' in those who have treated, cleared, and are considered SVR, both from a serum AND liver standpoint.  In these cases (and many researchers would argue that it includes most if not all SVR's) the HCV viral RNA is found in 'low level amounts' in the PBMC, lymphatic system, sometimes muscle, bone marrow, and or brain tissue, etc.  The emphasis from these researchers is that the residual virus is there long term,(after SVR) is obviously replicating, and seems to stay at this very low, residual level, without 'reinfecting' the individual.

Doctors are still in great disagreement over: whether this actually exists,;  if it does, whether it has any consequences;
and whether this 'residual virus, if it is a reality, could ever cause a recurrence of the full blown infection.  Many doctors, and a good handful of researchers still feel this claim has no real validity, and that the residual virus is either old, inert pieces of inactive virus, or is actually just a false reading on the tests (doubtful, in my opinion).

I hope this helps differentiate between 'Occult HCV', and 'Persistent HCV'.  Occult HCV, finally, seems to be an actual, active infection, in the liver only, causing damage over time, and something to take very seriously.

Persistent HCV has yet to be assigned any negative consequences, is much more controversial as to its very existence, and seems to be considered 'benign' at worst, PRESENTLY.

Good Luck Mike, we are all with you.  You WILL finish the job this time around!!!!

DoubleDose

[jmjm530]

Thanks. Yes, <a href="http://www.natap.org/2005/HCV/090505_20.htm">the study</a> I was referring to was regarding "occult" virus, as defined by the authors.

BTW skin problems still not resolving. Now it appears I have rosacea mixed in with my seb dermatitis and psoriasis, and the sun is just making things worse.

Hope this finds you well.

-- Jim

[Southernboy]

Hi Mike,

Don't visit often anymore but was made aware that you were having some problems.  I just wanted to let you know that you are in my thoughts and am sending all the positive energy I can your way.  You have always been a piller of strength and a great source of information to all here and I am sure I can speak for all when I say; "If you need anything, and it is within my power to get it, it is yours."  Just let me know.

Best to you, and I am SURE it will work out well,
Steve

[DoubleDose]

You are right, they are both 'active' infections, I was just pointing out that the 'occult' liver infection appears to be damaging in a similar way to full blown HCV infection, where  the 'persistent' HCV liver infection is usually present only under extreme amplification, and seems to not cause progressing liver disease.  So, I meant 'inactive' only in that figurative sense.  Of course, any negative strand virus that hangs around for six or eight years after SVR is certainly 'active'.  The research questions must focus on what damage, if any, is being done, and how can we eradicate this 'vestige' of the full blown infection.  I cannot imagine that the 'persistent', or 'residual' infection is doing us any good! Especially our immune systems, and related reactions.

Some days I feel like the infection is still going strong, even though I will soon be 3 years SVR.  I feel the fatigue, depression, brain fog, joint aches, and other pre-tx sx as if the virus were alive and kicking....maybe in the brain...CNS...connective tissue...lymphatic system.........
OR.. is it just the lingering effects of the interferon???

I hope the latter...I fear the former.
Maybe this is a disease that never fully disappears.  Maybe it just takes different forms, or only leaves certain compartments.

Scary thoughts!

DoubleDose

[TnHepGuy_]

From the <a href="http://www.mlo-online.com/articles/0206/0206clinical_issues.pdf">Pham summary paper (PDF)</a>, he states that:

"<i>In addition to consistent identification of HCV RNA in ex vivo stimulated peripheral lymphoid cells, HCV RNA has also been detected in liver tissue of asymptomatic individuals with a sustained response to antiviral treatment.3,5 Although these patients generally exhibit histologically apparent improvement after IFN-alpha/Ribavirin therapy, including partial regression of fibrosis, <b>liver biopsies from many of them show evidence of persistent minimal inflammation or even of active chronic hepatitis</b>.3,5</i>"


And, the <a href="http://hepcassoc.org/messbrd/index.php?s=b3ebdd8c3ecfccef4dc81b22dff2f60b&showtopic=11631">Giannini</a> paper (thanks "willing") seems to point to a direct relationship between persistent/occult and mixed cryoglobulinemia in 9 post-SVR's:

"<i>...the hypothesis that the challenge of liver lymphoid infiltrates with viral epitopes represents the key factor in MC pathogenesis was suggested. In this respect, data we recently obtained may be of interest. We analyzed 9 consecutive HCV-positive patients with MC who showed sustained virological response after treatment. An extensive follow-up showed persistent HCV RNA negativity both in serum and liver samples via very sensitive detection methods (Table 1). In contrast, mitogen-stimulated[11] and uncultured PBMCs were HCV RNA-positive in 5 cases (Table 1). Detection of negative-strand HCV RNA via Tth-based reverse-transcriptase polymerase chain reaction confirmed active cell infection in most cases.</i>"


Evidence is beginning to trickle in on the potential long-term nasties of post-SVR occult.


As far as occult being considered an "active" infection and persistent possibly "inactive", any negative-strand RNA - and it is found in both cases - suggests that viral replication is taking place, thereby making each a form/type of "active" infection.


TnHepGuy

[willing]

dd: I believe you may be making a distinction between occult/persistent that differs from the conventional use of those terms in the literature. HCV, like all viruses, replicates inside cells. In HCV's case, liver cells are preferred, but, as you pointed out, there is a  long list of cell types in which it can replicate. It is easier to collect body fluids (blood serum, tears, saliva, etc.)and test for HCV RNA than to collect and examine tissue cells However, this is always an approximation; absence of HCV RNA in fluids by no means indicates absence of HCV in cells, as every relapser who spends 36 weeks or more with an UND VL is well aware. So "persistent" infection refers to the presence of HCV-infected cells which for some reason are not detectable by a conventional serum test (eg virus is not replicating efficiently and/or immune response is rapidly destroying free-floating virions). However, I don't believe the term is restricted to a particular type of tissue (the infected cells can be in the liver, PBMCs, etc.)

On the other hand, "occult" is used in HBV infection to refer to detectable HBC DNA without accompanying antibodies :
<em>"patients with chronic HCV infection frequently have a special form of HBV infection, termed occult HBV infection (2, 8, 10, 12). This is characterized by the presence of low levels of HBV DNA in serum and/or in liver in the absence of detectable HBsAg in serum."</em> from <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16306629&query_hl=2&itool=pubmed_docsum">Rodriguesz-Inico'05</a>.
This term has been carried over to HCV to mean either absence of both antibodies and serum RNA:
<em>"Occult hepatitis C virus (HCV) infection is characterised by the presence of HCV-RNA in the liver in the absence of anti-HCV, and serum viral RNA"</em> from <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15831916&query_hl=2&itool=pubmed_DocSum">Castillo'05</a>, or just serum RNA (eg <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16144125&query_hl=2&itool=pubmed_DocSum">Gordon'05</a>. In the latter case, "occult" and "persistent" are indistinguishable; a distinction only seems to arise when specifically referring to the absence of ABs. In neither case is tissue type involved, as far as I can tell.

[DoubleDose]

I agree with some of what you said, but again will clarify where I think occult and persistent are used to describe two distinctly different phenomena.  Occult and persistent HCV can be found in the liver, but the occult version can be a full blown liver infection, minus either the serum infection and/or the antibodies.  This can be a serious, life threatening infection.  Occult refers to the fact that it is not easily detected since it is missing from the blood on testing, or the antibody test is negative on testing.  But, again, the occult version, can and usually does cause serious liver degradation over time.

Persistent HCV is a term used for SVR's, who now seem to have a barely detectable form of the virus, in various tissues, cells, blood components, often including the liver.  The liver component in the persistent infection, does not seem to produce abnormal LFT's, so far has not been implicated in causing further liver damage (in fact, most SVR's with supposed persistent HCV tend to see fibrosis regression and liver healing over time), and seems to be a somewhat more 'benign' version of the infection....if it is a 'true' infection in the same way that HCV is.  Maybe persistent HCV ends up being more akin to a virus in remission.  Lying at low levels, being held in-check, and not doing the rampant damage that the full blown infection does to ones body.

I hope my explanation is more clear this time.  I do believe that this is what the researchers are referring to as well.

DoubleDose

[TnHepGuy_]

In this paper<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16685484&query_hl=2&itool=pubmed_DocSum">Virus persistence in hepatitis C: lifelong infection despite therapy</a>, they seem to say that 'occult' is a patient w/out antibodies and 'persistent' is one who has completed tx.

To me, on a practical level, it's merely semantics. If each category has patients w/ replicating HCV (via testing showing negative strand) - then they both would appear to be at equal risk for any/all potential consequences that may follow.


Also, notice that in the above paper - as well as the Pham paper - they mention that "<i>...<b>it can lead to a deterioration of the liver histology.</i></b>"

And they mention the matter of transmissibility: "<i>it is also unclear if patients with occult hepatitis C as well as with evidence of HCV RNA in the liver and/or extrahepatic compartments after seemingly successful antiviral treatment are to be regarded as infectious.</i>"


So much still to be learned about this rotten virus - in all of it's various forms.



TnHepGuy

[willing]

I'll be happy to revise my thinking if anyone can point me to the appropriate citations but until then will continue to labor under the illusion that, per tn's previous post, "occult" and "persistent" are synonymous in post-tx patients except where "occult" is specifically  being used to flag absence of ABs. The terminology for describing whether an occult/persistent infection is a health concern would seem to be benign vs pathological etc. On that point, a bit more  insight to the quote tn highlighted from the Pham review, is given in Bizollon'05 (remember their post transplant patients had yearly post-SVR bxs) :

<em>"In this study we observed a decreased of activity score in 62% of SVR patients. In patients with SVR, analysis of biopsies showed that the improvement was observed in most patients after the second year of follow-up. Two explanations can be put forward for this result. First, the constant presence of inflammatory infiltrates may be due to the persistence of some degree of graft immune response to HCV, which probably takes many years to disappear. Second, the technique may not be sufficiently sensitive to detect low levels of HCV RNA replication and the explanation that there is a continuing low level of HCV RNA replication cannot be entirely excluded. An ideal assessment of this phenomenon would be to assay the liver graft tissue for HCV RNA and follow the host and immune cytokine mediated response over time in those patients who respond to treatment."</em>

Also, re Scott's point, here's the outlook from Jeffrey Glenn, a hepatologist at Stanford :
<em>"Three generations of anti-HCV therapy can be defined. First generation therapies are those that are currently approved, consist of interferon and ribavirin, were available before the identification of the HCV genome, and are thus not really specific for HCV. Second generation agents are those that are specifically designed against HCV targets (such as the protease and polymerase) and are in various stages of advanced development. Third generation agents consist of the therapies of the future, and increased knowledge of HCV molecular virology is expected to expand their number. Ultimate effective pharmacologic control of HCV is likely to result from combination therapy with a cocktail of multiple drugs, each targeting an independent virus-specific function."</em> from <a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16527650&query_hl=3&itool=pubmed_docsum">Glenn'05</a>.

If the HCV-specific, 2nd and 3rd generation meds prove to be sufficiently effective, we will need much less of the "natural", general-purpose anti-viral, ifn. I've been trying to understand how much we know about the 100+genes activated in response to ifn and not making much progress, but the answer seems to be not much. This is an ancient and complex pathway that has served our species well. However the ifn response looks (and feels!) like an emergency response and its long-term, heavily amplified, use, as per standard tx, is not something we have been evolutionarily prepared to weather.

[DoubleDose]

I won't quibble with you guys about the finer differences between persistent and occult HCV, it probably doesn't make much difference to any of us,... but I will say that lately I am surprised a bit by the number of forum members who are more or less coming from my side of the fence regarding 'viral pessistence', and the possibility of long term viral consequences AFTER SVR.  I was kind of hoping that the more 'erudite' members of the group would eventually talk me out of my preposterous opinions!  Hey, now I have to keep on worrying about this stuff!

Just wait...once we have all this new data digested, and under our belts, I am going to come up with a NEW set of issues that are even more concerning!  I am sort of joking, but...not really.
Once we find out more about issues of 'viral persistence', compartmentalized infection', 'transmissibility after SVR', and 'viral recurrence after SVR', I will push forward with some additional hypotheses which right now are not sufficiently supported by research for discussion.  Its true that science is way behind regarding HCV, and medicine in general for that matter.  Only the 'tip of the iceberg' is currently understood regarding most disease and infectious processes.

At any rate, I just hope that the treatments keep pace with the new discoveries, as far as HCV goes.  We are heading toward second and eventually third generation treatments, but...will they be sufficient to treat the HCV infection that we will come to understand in the future????  In other words, will 'persistent' and 'occult' be somewhat the tip of the iceberg for a more enigmatic and maybe sinister sort of HCV infection that may be producing much more in the way of symptoms, dysfunction, and behavior, than ever previously understood.

Is the typical 'blood/liver' active HCV infection REALLY the only form of HCV infection out there in the world???  One scenario already says NO.  Those who have spontaneously cleared, or SVR'ed...and who now have a 'persistent', but very low level infection.  What else might exist?

Just some additional thoughts for the day.

DoubleDose

[TnHepGuy_]

<u>Scott</u> - Good to see you.

How are things doing with you health-wise? I believe that you are not a candidate for any form of current tx at the moment due to the AIH and the Hep C. Makes me wonder if Alinia/Nitazoxanide might turn out to be an option for you - no interferon and a purported EVR rate of 50% at 24 weeks of tx (though I'm not sure if they have any SVR numbers yet). Have you taken a look at the (limited) information that's out there on it? You may want to run it past your doc to see what he has to say.

Hope all is well with you and your family.


<u>willing</u> - your description of "extended interferon overload" on our bodies/immune systems sounds right on the mark. And the consequences of it are a rather large and glaring blank slate in medicine/research. I've come up mostly empty in searching for post-interferon effects.



TnHepGuy

[willing]

Your description of your post-tx hip/joint and HgB problems along with DD's posts are part of the motivation for my recent reading. <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11585785&query_hl=6&itool=pubmed_docsum">Sameul'01</a> is a good, free-text, review that has been extensively cited - but I can tell it's going to be a long while before any of this makes much sense. A key question is how quickly reversible is the upregulation of the ifn-stimulated genes; the long lasting AIH and thyroid problems indicate some of the changes are long-lasting, but these seem to occur very infrequently. Anyway, I hope you are doing well. The slow but steady normalization of your HgB certainly seems  very encouraging.

[DoubleDose]

Here's another thought regarding sx, both those generated by therapy, and those that many have experienced, pre-tx, from just having HCV.

It seems that often the two sets of sx are similar, even interchangeable in many cases, and may BOTH be from upregulation of various interferon stimulated genes.  I would assume that the virus provokes ongoing and sometimes intense internal self-stimulated interferon bursts, in various parts of the body and various organs.  Maybe this is the crux of the joint issues, salivary and eye problems, brain fog, gastric problems, etc. etc. that often come along with HCV.

The addition of a long term tx, and the interferon that is introduced into in the system only makes all these often 'pre-existing' symptoms much worse, and much more noticable.  Your question is a very good one: when does the upregulation fade away, after tx, and especially after successful tx.

The other variable for the successful tx'ers, is that enigma again: persistent HCV after SVR.  Could this residual virus actually continue to provoke the inf. upregulation, even after the effects of the tx. related interferon has mitigated?
Maybe the after-effects of tx are prolonged because the body still retains a 'trigger' (the persistent virus) that constantly turns-on various genes.

Just a few thoughts.

DoubleDose

[willing]

Yes, I've been mulling over similar thoughts as I try to make sense of the immunology alphabet soup. IFN is expressed in response to viral detection by immune cells. HCV has developed a couple of ways of shutting down IFN expression (<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16690858&query_hl=11&itool=pubmed_docsum">Type 1 interferons and the virus-host relationship: a lesson in detente </a>), in fact the NS3/4A protein targeted by VX-950 is the same one  responsible for HCV's interferon interference.  Nonetheless, some is bound to get expressed and I'd expect measurements of inf to be significantly higher in the HCV infected, though I  haven't yet found a source that proves this. Then when we go and actually inject the stuff, our levels obviously go way up. The intf's job is  just to change the pattern of expression in  cells with intf receptors and I've seen estimates of from "100+" to "several hundred" affected genes. These changes in gene expression are presumably the ones that kick off the side effects. Unfortunately, it looks like out of that pile, only a handful (<10) pathways are understood/known, so the likelihood of getting an answer to the question of "when/how do things settle back down?" seems a bit dim.

[DoubleDose]

A follow-on to your comments is that I had elevated ANA's tests for years before tx, and before diagnosis of HCV.  The doctors were not sure what to make of it, since it did not seem to EXACTLY fit the Lupus guidelines, etc.  I have seen others with HCV that also have had the elevated ANA's for years, and have read that this is common.  My bet is that the ANA's are a good indicator that interferon is being produced and aimed somewhere in the body, on a continuing basis.  Autoimmunity may be ultimately not much more than having internally generated interferon upregulate certain or other genes.  Maybe the genes that get upregulated then determine which sort of autoimmune disease appears.  With HCV they seem to be a mild mix of RA, Sjogren's, and Lupus.

I am amazed that there often seems to be more pure scientific analysis and debate taking place here on the forum, than in most of the medical circles.  There is not much 'out of the box' thinking going on in much of the medical community...which I find disturbing.  Part of the problem is that many seem to relegate this virus and resultant disease into a somewhat 'benign' category, feeling that it does not warrant extreme attention or dollars.  I think they are sadly mistaken.

DoubleDose

[willing]

auttoimmune problems are widespread (and apparently in sharp increase in developing countries) independently of HCV so its doubtful you can conclusively pin the ANA to either the hcv or the ifn. However both of those certainly have at least the potential of complicating any existing immune disorder. I was surprised by the frequency of complications : <em>" The frequency of autoimmune disorders in patients undergoing IFNa therapy ranges from 4% to 19% (19,20), the most common being immune-mediated thyroid dysfunction."</em> from <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10902743&query_hl=4&itool=pubmed_docsum">Ioannou,'00</a> an authoritative review that has been cited 66 times since 00.

Their list of manifestation includes :

Immune-mediated thyroid disease (19,20)
Thyrotoxicosis
Hypothyroidism
Systemic lupus erythematosus (19,20,22,24–27,29)
Polymyositis (22,32)
“Mixed connective tissue disease” (undifferentiated autoimmune
rheumatic disease) (22)
Rheumatoid arthritis (19,27,34)
Seronegative monarthritis (37,38)
Psoriatic arthropathy (36)
Reiter’s syndrome (35)
Sarcoidosis (27)
Autoimmune hemolysis (22,27)
Immune thrombocytopenia (19,27,103)
Vitiligo (21,22)
Psoriatic flare (21)
Autoimmune hepatitis (19)
Diabetes mellitus (19,21)

A more recent update is <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16729722&query_hl=8&itool=pubmed_DocSum">Selmi'06</a> but I can't get access to the article. I doubt that anything regarding immunity is simple; I've never come across an area of biology more likely to induce headaches. Everything seems to depend on balance and the same molecules can have opposite effects depending on context. A review by <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11905836&query_hl=11&itool=pubmed_docsum">O'Shea'02</a> highlights this good-cop/bad-cop duality and includes the following cautionary note regarding the introduction of cytokines like ifn into an established disease :

<em>"With the many layers of inhibitory mechanisms used by the vertebrate immune system, it comes as no surprise that cytokines, even those thought to promote immune responses, have essential inhibitory functions. Apparently, they push on both ends of the balance in this effort to maintain effective host defence mechanisms while preventing autoimmunity. As we rush to the clinic with new therapies in hand, we need to keep in mind that blocking cytokines are used to prevent autoimmune disease in most experimental systems, and are not used to treat established disease. Often paradoxical effects occur when cytokines are administered during the course of disease; the exact timing and duration of exposure to these cytokines can evidently have variable and unexpected effects. Apparently, cytokines can switch sides in the balancing act in surprising ways (Fig. 4)."</em>

I'm not getting any closer to wanting to do more tx...

[DoubleDose]

Why son if you are gonna be askin' big questions like that, you are gunna have to talk to mah big daddies at Schering Plough.  We'll get ya some rebuttal data.

Dr. Schnoosenfrassel

[DoubleDose]

Great info. from both of you.  It is a compelling topic, and very important to us, who have subjected ourselves to many months of interferon.  I guess from a pragmatic standpoint, we are not going to get much help or additional knowledge anytime soon regarding the consequences of inf., so we basically are stuck with the task of restoring whatever level of good health and function that we are capable of.

I do believe that both HCV and Interferon naturally stimulate a sort of 'autoimmunity' in many people.  The HCV because, as many researchers surmise (that autoimmune disease is the result of latent viruses), it acts as a viral trigger to establish autoimmunity.  It is a chronic virus that probably stimulates various immune responses, while never allowing for enough response to fully eliminate the virus. (save for those early-on with acute HCV who spontaneously clear).  Probably many ,if not most, people have UNDERLYING tendencies toward autoimmunity; its just that most people never have the disease triggered.  Similarly cancer probably has a potential in almost all of us, but the triggers (and genetics) determine who and when.
I think that HCV and Interferon sets off the autoimmune process in many of us, and probably over time, increasingly more so.

TnHep:  Your telephone conversations are a GREAT idea, and I also would like to connect with top researchers to discuss real questions, and observations that arise in our conversations.  I think that intelligent dialogue with these guys might really stimulate some 'out of the box' thinking and study.  We see the issues at 'ground level' and can contribute quite a lot to the understanding of the virus, and the treatment, and the consequences.  We need to keep the questions alive on the forum, and continue to solicit lots of feedback and input from members.  We are a good 'slice' or microcosm of the greater global HCV and tx community.  Our analytic observations can be valuable to the scientific community in many ways.

Thanks for a stimulating thread.  Best to both of you!!!

DoubleDose

[cuteus]

I see we are at it again, to my reading pleasure, in the 'few answers" persistance issue. One item strikes my attention in an above abstract: "Despite favorable longterm data with regard to viremia, liver histology and serum liver enzymes in treated patients who comply with the criteria of sustained virological response, a complete elimination of the hepatitis C virus (HCV) is rarely observed"  'Rarely observed' is quite a definitive, blanket statement, in my view, given the fact that most svrs are not getting biopsies post tx. Still, he leaves room for the possibility that some do experience a complete elimination. I will stick to that until post tx biopsies become common and confirm the percentages presented in his article.
I also wondered if the theorized immune system changes post tx, can be actually positive in nature, in adittion to the 'problems' regularly mentioned here. What if some of us actually have a better system with no new problems? Like I posted before, I have not had the flu or a chest cold in yrs,(during tx and post) and it used to be bad seasonally, where I needed an inhaler. Has the tx improved my system? I only read about continuing problems attributed to the immune system or tx. Anyone else out there wondering with me?
The post tx symptoms I have are basically the pre tx ones, and I am seeing the rheumy today for those, as a follow up to bloodwork done two wks ago. I have offered her my medical status, should she know of any studies or researchers reaching out to colleagues for further study of hep c extra hepatic symptoms, so we'll see.
To add to the list of extraheptic symptoms and conditions, I just had a ct scan on Monday and among other things, possible 'cysts' might be present in the kidneys and the line "no signinificant retroperitoneal lymphadenoma observed" caught my attention. So I looked it up and found an article on its possible  relation to hep c infection. Does the line mean that no lymphadenoma was observed or that what was seen is not that important? It irks me that is so general (the ct scan report) and no follow was suggested.  How advanced does hep c have to be in order to get renal involvement? Did I have 'significant'  before tx? at only stage one? Now, post tx has become 'not significant'? why even mentioned it if something was not seen? It was my first ct scan ever, so I have no idea what the report should say and how it should be worded.
can I ask for a re reading and more detail report? at least I am getting a free cd of the scan and x rays!

[cuteus]

should read lymphadenopathy. 1st edition was from memory.

[willing]

Many thanks for the interesting posts. I agree that it seems very unlikely any researcher will be able to provide definite answers to our questions about long term effects of ifn usage. The state of the art seems to include a pretty good mapping of the pathways that connect viral detection to expression of ifn alpha/beta and of the jak/stat pathways that connect the ifn receptors to the expression of the 100+ ifn-induced genes. However at that point, the trail seems to get cold. The antiviral effect of a  handful of pathways (including PKR, OAS and Mx) seems well-established <a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15858013&query_hl=3&itool=pubmed_docsum>Taylor’05</a>, along with the virus’ ability to defeat some of these mechanisms <a href=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10390359&query_hl=7&itool=pubmed_docsum>Taylor’99</a>, but it seems we’re a <em>long</em> way from understanding the overall ifn response, let alone why some of its effects may persist. One interesting question to ask the NIH researcher may be whether there is any insight into what causes the persistence of  the more explicit disorders , eg AIH or thyroiditis.

As patients,  I think understanding the limits of what is/is-not known is helpful in guiding treatment decisions. For example, embarking on 72 weeks of heavy dosage infergen seems as much of a shot in the dark as alinia  (Don’t you just love that line they put into heavy dosage studies “.. and the dosage seemed well tolerated…”). Focused, local-effect drugs like vx-950 with a known mechanism just seem so much safer than a major systemic player like ifn, though we’re going to need quite a toolbox of them to contain mutations.

I also really like the idea of inviting researchers to comment on questions that come up here. Perhaps we could cobble up some of our questions and  mail them to Pham/Radkowski/Pawlotsky etc. inviting them to a sort of  “guest-post-of-the-month”.

tn: good luck with your Hg question and please post that NK study if you get a chance – I hadn’t seen that.

dd: if in fact many of the sx of untreated HCV come down to infection-triggered cytokines it seems a bit ironic that we treat by taking even more of them!

cuteus: unfortunately that study is in German (maybe Forsee can translate it for us) but it seemed a bit far out in its insistence on “rarely observed”; I believe the available data is not that conclusive. I’m very glad to hear whatever post-tx  immune changes you’re experiencing  seem like improvements and I wouldn’t worry too much about that scan. Lymph node swelling may be something that they routinely check for and are simply confirming the absence of. There was similar language about bile duct size in in my recent ultrasound.

[TnHepGuy_]

I just did a PubMed search to try and come up w/ the paper finding lower levels of NK's post-tx - and haven't been able to relocate it. Interestingly, the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16322112&query_hl=2&itool=pubmed_DocSum">newest one</a> I did find in my search shows three sub-sets of NK's at normal levels post-tx. If I can locate the one I'm thinking of, I'll post it.

I'm all for contacting Pham, etc. Be interesting to see what direction(s) they are heading, what response to their work they have received, what kind of funding and backing is out there for this work and, what they might speculate/recommend SVR's do in the future given what is known at this point in time.

As far as the majority of post-SVR's having remaining HCV RNA, I wonder if our own mikesimon's case falls into this type scenario: where serum is clear, yet negative-strand remains in the liver. And the end result being that playing with the doses of his anti-rejection meds possibly upset the "happy balance" that existed between his immune system and the occult, thereby allowing it to "express" itself via increasing liver damage (i.e. - the rise in his LFT's), but not able to escape enough to become fully systemic. His doc not being surprised at such a result makes me wonder if this would be something more common to transplant SVR's or to all SVR's in general.



Well, as typing this I decided to try NIH again. I just got off the phone w/ <http://intramural.niddk.nih.gov/research/faculty.asp?People_ID=1617">Dr. Jay Hoofnagle</a>. As opposed to the researcher at ISICR, he didn't give me a half-hour - more like 5 minutes. In a nutshell: he believes that post-interferon problems for the most part don't exist - that once the drug leaves the body the immune system returns to it's "normal state". Also, that any autoimmunity should express itself during or shortly after tx, unless there is a family history of it. He felt that my low Hg wasn't really low at this point in time (even though it's over 1.5 points below baseline) and that any low blood counts this long after finishing tx are due to something unrelated. And finally, he thinks occult is a crock. When I asked why, he said that the tests being used to "find" it are not the standardized tests and that so far no one has been able to replicate their findings using the standardized tests. He thinks it doesn't exist.



I guess if we contact Pham, et al - we'll need to ask what their response is to this rather large refutation.



TnHepGuy

[DoubleDose]

Why am I not surprised at his responses?  Sounds like all the mainstream HCV docs' compressed into one voice.  No interferon after-effects....no persistent HCV in the body....no lingering sides....except , of course, to the loonies out there who 'imagine' all these things.  Kind of sounds like what they used to say years ago when someone with HCV complained of symptoms!  My gosh son, HCV has no symptoms!!!!  I am afraid you must have some other problem, or something.....could I line you up with this shrink that I know????  

I just love the level of exploration and curiousity some of these guys are exhibiting.  See no evil, hear no evil.......

"Y'all is cuuured, boah!  Naw get on outta here and haav ya'seff
some fuunnn!!!  Ain't nottin' but yoah 'head' a playin' wit ya!"

Great response!

DoubleDose

[willing]

thanks for the link. As I read it they're saying the receptors that activate NK cells are downregulated by HCV infection but restored by SVR : <em>"The finding that NCR expression levels in patients who had cleared the virus by antiviral therapy were comparable with those observed in healthy individuals together with the fact that a significant correlation existed between  NKG2A expression on CD8+ T cells and HCV serum levels supports the concept that reduced expression is linked to HCV replication or to changes in the cellular microenvironment induced by HCV replication."</em> so this looks like another of HCV's devious, immune-evading, squatting strategies, but maybe there's more to the story.

That was an interesting conversation with Hoofnagle; he;s certainly one of the big names in the field. The reason I suggested asking about AIH or thyroid disorder is that those clearly cannot be waved away by "everything goes back to normal". Understanding what happened there might give a clue as to what can happen in less obvious cases. Scott, did your Dr. explain the mechansim that triggered AIH  and why it didn't revert ? Hoofnagle's most likely correct about the hgb, but it still might be interesting to check whether lower hgb is associated with any of the conditions on that laundry list of ifn-associated immune problems.

As to  occult/persistent  bein a crock, as we've discussed extensively, it could be a crock because (1) the PCRs are somehow flawed and  the RNA they're detecting is contamination/error or because (2) the RNA is real but not associated with viable, infectious virus. He seems to be suggesting (1). When Pham first came out I remember us discussing the possibility of "dueling PCRs" and that's why I ran that literature search recently seeing if anyone had refuted the findings. Nobody has, or at least nobody I've been able to find in the standard citation data bases, and a half dozen labs have corroborated them. It's really hard for me to believe that so many peer-reviewed journals could be independently publishing nonsense. If it is a crock because of (1), why hasn't anyone published rebuttal data?

[TnHepGuy_]

Just for fun, this morning I called and spoke w/ one of the lead researchers from <a href="http://www.isicr.org/">the International Society for Interferon and Cytokine Research (ISICR)</a>.

I asked about concerns in regards to any long-term potential consequences of having been on interferon. He said that as a researcher, he has seen very little in the way of studies/information out there on patient experiences long-term - that most of what is in print relates to sx's during tx. He said my best hope would be to speak to a particular research doc over at NIH. (It turns out that I had spoken with this doc years back w/ questions about the future of PI's). I placed a quick call to him but was tripped over to an answering service. So, I'll try again sometime in the future.

When I explained to the researcher at ISICR about the very slow recovery/rebound of my Hg (and to a lesser extent my WBC's), he speculated that the interferon was most likely the culprit. I asked about autoimmunity and his belief is that interferon tx itself is responsible for a small number of cases, that it may exacerbate existing/underlying conditions. But he went on to say that very little is truly known. He stated that little is known about what genes interferon reacts with and the "how's" and "why's" of those reactions. One area he mentioned that they are studying is natural killer cells (NK) and their interactions with various interferons (natural and man-made). He wasn't familiar with the study(s) showing sub-responding NK cells to post-interferon Hep C SVR's, but speculated that this would be a particular sub-set of NK's. When I asked if this might leave a person more susceptible to other infections as a result of these "sub-responders", he said NK's are only one small part of a larger defense system and he didn't think that a patient would be at any greater risk.


His belief is that in terms of future tx, small molecule rx's will minimize and eventually eliminate the need/use of interferon in Hep C tx'ing. He thinks that 5 years or so is a reasonable time guess to begin the switch-over.



My bottom line take away is that in the 50 years since interferon was first discovered, precious little is still known about how it truly works on a cellular level. And even less is known what it's consequences are.



If either of you would care to speak with him - and he is very happy to talk shop with anyone who is interested - please let me know and I'll e-mail you his name and phone number.



TnHepGuy


And no, I didn't bring up the subject of occult. I'll save that for the doc at NIH.

[TnHepGuy_]

<u>DD</u> - The impression you write of is the exact one I got while on the phone with him - that he fully tows the orthodox line of Hep C research and tx'ing. He didn't want to hear or consider any deviation from the party line on any of the questions that were posed. One thing that I found particularly disconcerting was when I asked him if he had read or heard of any of the information out there connecting riba w/ bone loss - and he drew a complete blank. Me thinks he may be a bit too comfortably isolated inside the federal NIH bubble there in Maryland. Though I can't paint completely with that broad of a brush. The researcher I spoke w/ over at ISICR (also federally funded) seemed much less rigid and dogmatic.


<u>willing</u> - I didn't get to ask him, but one thing about occult Hep C "not existing" I find interesting is that occult Hep B has been discovered and accepted as fact for some time now. Therefore, why would it be such a huge leap to think that a version could also exist for Hep C? Also, when I spoke w/ my GI last year about occult Hep C he said: "Yeah, we've known about it for years now - just don't know what, if anything, it means". Now, my doc keeps up on all-things Hep C but is more-or-less a "traditionalist" - by no means "out-on-the-fringe", as Hoofnagle undoubtedly believes Pham and the rest must be. The impression I took from Hoofnagle was that he was just going to stand his ground come hell-or-high-water - and throw darts at their testing methodologies.


I think the question you have about a lack of peer rebuttal is a damn good one. Care to pose it - along with a few others - to the source?


TnHepGuy

[DoubleDose]

You hit it right on the head!  This institutional isolation, and elevation to 'god-like' stature causes many of these 'gurus' to think : just because I say it, it must be true.

I have noticed that many of these nationally known 'experts' are neither good listeners, nor exhibit ANY of the characteristics of an even fairly decent scientist.  They don't question, they do not observe, they don't probe, they don't even read most of the leading-edge research.  They just bombastically lecture and describe only what they wish to be true, and simplistically believe to be true.  They are in many ways completely indoctrinated by the 'party line' as you said, and by the big, prestigeous institutions of which they are a fixture.

It is very disappointing that WE, the patients and subjects of all this illness, medication, experimentation and treatment, end up being the ones who come up with novel insights,who ask tough questions, who scour the research and put 2 and 2 together, and who try to objectively listen to and observe the manifestations of HCV and of treatment.  Everybody else is too preoccupied with trying to act like they already know it all.  Gee, sounds like I just described doctors!

Ultimately, I think the true research scientists will have their day, and the weight of the data will slowly push opinions in the medical community to newer and more accurate understandings.

In the meantime:  Y'all is CURED son!!!!! Now git on outta here!!!!

DoubleDose