New Occult Hep C paper from Pham et al

[TnHepGuy_]

Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles.

"Hepatitis C virus (HCV) replicates in immune cells in both chronic hepatitis C (CHC) and occult HCV infection, but the extent of virus replication in this compartment in these opposing infection forms varies greatly. It was unknown whether this could be linked to HCV genotype or to differences in host gene expression shaping the immune response, and whether HCV replication in immune cells is sensitive to endogenous antiviral cytokines. In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C. Moreover, PBMC from individuals with occult infection transcribed significantly greater levels of IFN-alpha, IFN-gamma and TNF-alpha, but less interleukin (IL)-10 than those from CHC. In CHC, PBMC with low HCV load expressed significantly more IFN-gamma but less IL-12 than did cells with high virus content. In occult infection, HCV RNA detection in PBMC was associated with much lower IFN-alpha and IL-12 expression. Further, HCV replication in T lymphocytes could be completely eliminated by activation of endogenous IFN-gamma in CHC, but of IFN-alpha in occult infection. In conclusion, CHC and persistent occult HCV infection are characterized by clearly different profiles of antiviral cytokine response in circulating immune cells which are also different from those of healthy individuals. Higher expression of IL-10, combined with lower transcription of IFN-alpha, IFN-gamma and TNF-alpha, is associated with a more robust HCV replication in immune cells."

http://www.ncbi.nlm.nih.gov/pubmed/19215578?ordinalpos=1&itool=Email.EmailReport.Pubmed_ReportSelector.Pubmed_RVDocSum


TnHepGuy

[susan400]

I wish that this would translate into the researchers developing a drug for those of us who seem to be failing at every treatment that's been tried!  AND, I don't want to have to wait another 10 years for that to take place, since I've already been doing treatments on and off since 1997...12 yrs!!!   I'm just a wee bit impatient.  :)

Susan400

[apache1]

Thanks for posting this brand new study from feb 09. It coincides with past studies.

Need some help here guys.
So, not sure I have interpreted this study correctly.

g1 infects the plasma more than g2 g3 which favor residing in the pmbc instead of plasma both AFTER SVR ?

Does it mean only g1 gets the occult HCV and g2 g3 do not get occult hcv ???

confused

apache

[mikesimon]

I believe this is the sentence that you are referring to.
"In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C."

I understand that to mean that in CHRONIC HEPATITIS genotypes 2 & 3 show greater viral load in PBMC's but not in plasma. In OCCULT HEPATITIS C genotype 1's after SVR shows the same profile - greater viral load in PBMC's but not in plasma.

I didn't understand it to say that GT 2 & 3 do not get occult virus.

That's the way I read it and, as always, I could very well be wrong. The good thing is that if I am wrong someone will correct me shortly.

Mike

[Bobby1952]

  For us lay people what exactly does it mean ??

I understand that to mean that in CHRONIC HEPATITIS genotypes 2 & 3 show greater viral load in PBMC's but not in plasma. In OCCULT HEPATITIS C genotype 1's after SVR shows the same profile - greater viral load in PBMC's but not in plasma.

??

[apache1]

Thanks Mike. Yes that is the sentence. A lot of info...

For a lowly engineer, that sentence is hard to understand. To me, that sentence needed a little clarification. Still not real sure of the conclusion of this study, or its relevance to us.

=========================================================
In this study, we uncovered that significantly greater HCV load in peripheral blood mononuclear cells (PBMC), but not in plasma, coincided with HCV genotypes 2 and 3 in CHC, but with genotype 1 in residual occult infection after clinical resolution of hepatitis C.
==========================================================

"but with genotype 1 in residual occult infection after clinical resolution of hepatitis C"
This is the only reference I see to SVR
( or in their terms "clinical resolution of hepatitis C"),
and it looks to only refer to  Genotype1.... maybe ?

apache

[mikesimon]

The title of the article and it's conclusion pretty much sums it up - that occult hep c and chronic hep c have different cytokine expression profiles.

Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles.
                                              
"In conclusion, CHC and persistent occult HCV infection are characterized by clearly different profiles of antiviral cytokine response in circulating immune cells which are also different from those of healthy individuals. Higher expression of IL-10, combined with lower transcription of IFN-alpha, IFN-gamma and TNF-alpha, is associated with a more robust HCV replication in immune cells."

It's relevance to us is probably purely academic. This article assumes that persistent occult hepatitis is real. We can and have argued about the issue of whether occult hepatitis truly exists. But the topic most vigorously discussed/debated has been: if it does exist what does it mean for SVRs in terms of liver health - ongoing damage -  and health in general and is there the possibility of recurrence or re-emergence of detectable virus.

My personal opinion is that SVR is durable and confers a great benefit and may improve liver histology. I think that is pretty well settled..
For my purposes anything beyond that is purely academic. I suppose it's nice to know that the anti viral cytokine response in immune cells are different for CHC and occult hepatitis but I don't really know what to do with that information

Mike

[Hepatitis Researcher]

here is the conclusion of the authors;

In summary, our study revealed that HCV replication in lymphoid cells in CHC and occult persistent infection is accompanied by evidently distinct expression profiles of the genes involved in antiviral and proinflammatory cytokine responses. Expression levels of some of the genes were found to be closely related to the virus loads in circulating immune cells.

The fact that the gene transcription profiles in low-level HCV infection were different from those of healthy individuals also argues that the virus replicating at low levels in immune cells is not ignored by the cell innate defence but continues to trigger its response for many years after clinically apparent clearance.

Further work is required to determine whether the status of virus replication in immune cells and the expression profiles of the genes induced, including those identified in this study, could serve to predict the patient's response to antiviral therapy and the likelihood of establishing CHC.


My note; this is further evidence that in some SVR this ongoing innate immune stimulation will have the consequence of increased inflammation, over the level that this person would have had, as a simple age related phenomenon, if never HCV infected. There is not much that can be done about this. It most likely serves to stabilize SVR.

[Rockerforlife]

Although occult HCV infection generally appears to be mild, some patients have shown evidence of serious chronic liver injury. In addition, occult infection raises the possibility of disease spread via blood donations, hemodialysis and other procedures. Fortunately, the study also suggests a minimally invasive approach to detect occult infection.


http://www.innovations-report.com/html/reports/medicine_health/report-24439.html

[TnHepGuy_]

Very good to see you here again!  And thanks for taking the time to comment on this paper.

"My note; this is further evidence that in some SVR this ongoing innate immune stimulation will have the consequence of increased inflammation, over the level that this person would have had, as a simple age related phenomenon, if never HCV infected. There is not much that can be done about this. It most likely serves to stabilize SVR."


As 'mikesimon' mentioned above, and what you have stated, this is the practical 'crux' of any discussion re occult: the potential negative effects of having an ongoing immune response to replicative RNA. The price some (all?) SVR's may have to pay to remain so is a chronic increase in their immune system - but at what cost?


So I would ask you (HR) this:

- In general terms, what are the known clinical consequences of patients w/ similar such long-term conditions (i.e. - chronic over-stimulation)?

-  Increases in autoimmune concerns?

-  A lowered or lessened ability of the immune system to properly respond when called upon to do so?

-  Would it be a reasonable assumption that in this particular type of chronic immune response (to occult Hep C) a fibrotic response would not be unusual?


And while there may not be much that can be done in regards to having and 'treating' an overly stimulated immune system, I believe a patient in such a circumstance benefits greatly when knowing what their current condition truly is. Such knowledge can eliminate unnecessary testing, false diagnoses and wrong treatments to symptoms and ailments that might otherwise be incorrectly attributed to unrelated sources.


TnHepGuy

[DoubleDose]

HR, thank you very much for your clarifying comments on this research study.  I also concur with your conclusion, and feel that this post-SVR, cytokine reaction to the now suppressed, persistent virus after SVR, may just be the missing link in our pursuit of just what causes so many post-tx, long term after effects.  Certainly the Interferon itself may be responsible for a good portion, but my contention is that much of the ongoing, and often 'auto-immune' in nature responses that many of us experience, is exactly this phenomenon...a post-tx cytokine response to low level virus.  So we are SVR, but still a little like smoldering coals....or maybe like radio-active, half-life victims....  Thanks for being a part of the forum again!!!

TnHepGuy - Thanks for your follow up questions and comments regarding HR's reply.  I also second your questions!!!  This subjest still deserves much attention, and not to be 'blown off' by those that would prefer to assume that it is a very benign phenomenon...or even a non-existent issue.

DoubleDose

[Rockerforlife]

Im pretty sure a large % people who SVR will go on to live normal lives...providing they dont go on and party like its 1999....my nurse says in her 28 years of treating patients that all are still SVR...and in good health...who knows if the "occult patients,"  (who show the slow  progression of damage) is not caused by life style or even things we dont even know...just my thoughts....ill take the SVR  if a can and from then on....just do the regular check ups for damage...to me im not too worried about no occult bug....yet

[Hepatitis Researcher]

To the questions;
In general terms, what are the known clinical consequences of patients w/ similar such long-term conditions (i.e. - chronic over-stimulation)?

-  Increases in autoimmune concerns?

Very likely in some SVR, but the individual variability precludes definite conclusions for any particular patient:

1. Remnant HCV ("PseudoHCV, since most will be crippled mutants") will vary widely in amount.

2. Innate response to this remnant amount will vary and the types of remnant will matter as well.

3. Any increased innate stimulation that persists is typically followed by counter-regulative measures "immunosuppressive regulatory machanisms' if you will, that are just as complex as the activations of the defense machinery and badly needed for the stability of the organism. Thus the degree of these "response suppressive" mechanisms is itself genetically variable and typically starts to deteriorate with age, that is among the reasons why so many older people are chronically inflamed.
Thus some counterbalance their HCV remnant induced cytokine elevations fairly well and feel good, others suffer dearly.




-  A lowered or lessened ability of the immune system to properly respond when called upon to do so?

Chronic innate induced inflammation is both a call to action for the immune system as well as a reason for exhaustion and chronic molecular damage to the delicate machinery needed to properly and optimally operate the adaptive immune responses. Thus a decrease for example in Bcell diversity can be caused by chronic inflammation.
This is however a very broad concept. For example myocardial fatigue and insufficiency/failure can be hastened/caused by chronic Gingivitis/Periodontitis, because the inflammatory signals sent out body-wide activate the hidden defense system/eg TNFalpha production of the cardiomyocytes themselves, causing long term molecular damage to the contraction machinery. Similar mechanisms are likely at play in the immune system, but much harder to separate in the setting of ever variable activity.

-  Would it be a reasonable assumption that in this particular type of chronic immune response (to occult Hep C) a fibrotic response would not be unusual?
NOT LIKELY, SINCE THE FIBROTIC RESPONSE REQUIRES A FAIRLY STRONG LIVER SPECIFIC INNATE RESPONSE.

Again the actual degree of a system-wide cytokine level elevation caused by HCV remnant stimulation as described in that paper would need to be investigated in each individual by cytokine level measurements, serially, since these tend to fluctuate. Unfortunately these tests are not yet well standardized and the prime example, TNF alpha, is not even typically used by rheumatologists to test their patients before initiating anti TNF alpha therapy - which is used in increasing numbers lately for various immune mediated disorders.

[DoubleDose]

You just commented on something which connects with another problem which I have developed in the past year, now that I am 5 years post-tx, and SVR.  I have developed Peyronies Disease, which is in effect, a fibrotic, or scar tissue affliction in the penis, causing a curving.  In recent research studies published by the Urologists Association, it seems that increased levels of circulating cytokines, and specifically TNF-Alpha, have recently been correlated to a very high degree with those who have Peyronies.  This is a disease with no currently understood cause, and only lately is getting lots of research attention.  Of course, I have to consider my post-tx auto-immune reactions, and plethora of symptoms after SVR, in thinking about the potential catalyst for this Peyronies condition.  I am certain there is a relationship.

My question to you is:  Should I consult with a rheumatologist about the TNF-Alpha therapy that you alluded to, as a possible treatment for the Peyronies???  If an increase in this cytokine is indeed responsible for the PD, as some new research suggests....might there be a way to mitigate this ongoing imbalance in TNF-Alpha???

Your comments above really 'turned on a light bulb' for me.  I would bet quite a large sum that my cytokine levels are grossly out of whack since treatment, just by the numerous autoimmune like sx that I seem to display.

Thanks for any thoughts you might have on this possibly related issue!!

DoubleDose

[Rockerforlife]

Dont know if this is any help,but there is a natural product out there that modulates and balances the immune system....its called 'moducare"

[Hepatitis Researcher]

While TNF alpha might have a role in the progression/promotion  of Peyronie's disease it does not seem to be the primary player. This fairly frequent syndrome (5%) might be caused by a genetically predetermined propensity of excessive TGF beta expression under conditions where the body tries to heal by scarring even minor traumatic injuries. Thus minor traumatic injuries to the tunica albuginea are responded to with excessive progressive scar tissue formation. TGF beta is a critical 'cytokine' or tissue hormone that acts to "heal" injuries by promoting scar formation

Certain cytokines levels will have a promoting role in that setting, however the effect of inhibiting specific ones like TNF alpha is hard to predict and you will have a difficult time finding a doctor prescribing one of the TNF alpha inhibitors for this purpose, since regression is - even if there is a positive effect- going to take substantial time. There will also be the argument that TNF alpha inhibitors shall not be used in patients with hepatitis, even if SVR, I presume.  There is literature describing an inhibitory effect of trans Resveratrol on TGF beta expression and Curcumin might be useful in reducing the intensity of the profibrotic pathway signaling that results from increased TNF alpha levels, but of course there are no trials to prove any effectiveness of these in this particular disorder.

[geterdone]

Laymen here,

So what you are saying is that while treating the virus with high doses of interferon these strands of RNA are cleaved up, but all are not totally destroyed by the t cells and are floating around in the peripheral blood and organs and are still giving off a signal in a mutated state by which the now altered natural interferon is still attacking anything with its signature in an undetected state?

Could it be that during the duration of treatment with the synthetic interferon and its “additives” that it by some chance altered the natural gamma interferon from its natural state in which it has left it in an overstimulation state there by causing just as much long term damage as the virus itself but on a lower chronic level?  

jasper

[DoubleDose]

Thank you so much for your informative reply.  You have provided more specifics and insights on how PD works than the specialists that I have seen.  I may conduct my own trial with the Curcumin over a long period.  I have already added daily Vitamin E, Acetyl-L-Carnitine, Primrose Oil, L-Arginine, L-Citrulline, and assorted other supplements, for the last nine months....and am seeing some slight improvement which may or may not be a result of the supplements.  Thanks again for your interest.

DoubleDose

[geterdone]

Laymen question here and maybe on the boarder of deep space but here goes.

Can the in coded gamma interferon and immune system changed over time to be stronger in fighting the virus as it evolves and changes its tactics to evade the immune system?  Does the immune system become even stronger while fighting the evasion or is there a Plato which is reached and the immune system is unable to get stronger?

If our immune system has been fighting this virus for the last 20, 30, 40 years and the immune system is “adaptive” to the ever changing tactics and evolution of the virus with in our bodies and the immune system gets stronger as time goes on while fighting the virus then the immune system has to change also to meet the needs, right? Then when the synthetic interferon is added to that for a long duration, what happens when the synthetic interferon is gone and the gamma interferon dips below the natural threshold what ever that may be because I am sure it has lost its original coding level of 20, 30, 40 years ago. So is it possible that the new level of the gamma interferon after the prolong use of the synthetic interferon has changed or altered the immune system to a higher level than that of a more suitable level for our biological needs and if this is the case, would it be more sensitive to pick up on the signaling process of the persistent mutated virus causing it to stay in the attack mode causing much of the post treatment symptoms experienced?

jasper

[Hepatitis Researcher]

The molecular structure of the natural Interferons does not change or adapt with time. The huge functional network of cells that produce IFN and numerous other molecules that interact with virus infected cells changes, becomes more activated with external Interferon added. HCV producing cells then die off in huge numbers, some might be cleared of the virus without cell death (noncytolytic clearance). At all these phases the large number base of the virus will contain certain variants that are less visible to the critical Tcell response by having, by chance, changed their critical recognition epitopes. Such mutants, albeit much less fit, might be able to survive the immune elimination process, but have lost their power to rapidly replicate or turn off the innate responses in the cell that they infect to some degree. Thus some very slowly replicating and otherwise functional incapacitated HCV mutants will stay in the system, but elicit enough recognition to trigger the production of cytokines in the dendritic and macrophage cells that they still infect. This is essentially the finding of the above paper. But this cannot be interpreted as a now stronger immune system. It is a response to a remnant antigenic trigger.

[geterdone]

Appreciate the follow up and as with the rest here and glad to see you post, Thanks! I do have one additional question that being does polyethylene glycol, ethylene glycol used to extend the half life of the interferon have any adverse effects on the body long term or is it in such a low state that there are no effects to worry about?

I am one year post as of March 12th and considered a SVR’er < 2, < 2, and < 5 insurance change, lol! For me, the taper worked tho slightly modified, thank you!

jasper

[Hepatitis Researcher]

The Polyethylenglykol (PEG) that is attached to the IFN molecule exists in minute amounts only and you can expect no negative effects from it.

[apache1]

HR, got a few questions, if you got the time.

How large does this mutant occult infection does it take to elicit cytokines response ?
Or will one incapacitated HCV mutant viron in one dendritic or macrophage cell make that cell produce cytokines.
And how much cytokines production does it take to effect a patient ?

What was the significance of the genotype differentiation in the above paper ?

Is it possible for occult mutant infection to blossom into a full blown HCv infection ?
Or is it probable to intermittently test positive at very low levels (50 IU/mL) then negative on a follow up test from remnant replicating occult... all years after SVR,  ?

Sorry for all the questions HR, I find this part of microbiology extremely fascinating. And you have a way of making a laymen understand. I really appreciate you being here for us.

Thanks
apache

[geterdone]

Recht schönen Dank!

jasper

[alagirl]

this is further evidence that in some SVR this ongoing innate immune stimulation will have the consequence of increased inflammation, over the level that this person would have had, as a simple age related phenomenon, if never HCV infected. There is not much that can be done about this. It most likely serves to stabilize SVR.
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Fabulous.

Good to see you btw