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Medical Forum / Diseases and Disorders / Hepatitis / November 2006

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New paper w/ overview of occult  Hep-c

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smith21347@msn.com - 17 Nov 2006 15:41 GMT
http://www.wjgnet.com/1007-9327/12/6922.asp

Are people cured from hep-c ?    I don't think so.

                                               Ron
greyhackles - 17 Nov 2006 22:00 GMT
>http://www.wjgnet.com/1007-9327/12/6922.asp
>
>Are people cured from hep-c ?    I don't think so.

And you are entitled to your opinion, no matter how demonstrably incorrect it
may be.

Painting with broad brushes usually results in sloppy results...

/greyhackles
kjoh - 17 Nov 2006 22:22 GMT
Hi Ron.  This is a stinky rotten piece of news you posted.  It sure weighs
heavy on my thoughts about re-treatment.  Findings like this have been
floating around for a while, but nobody seems to want to make much of it
(?).  This isn't the kind of information that will make Roche and Shering
Plough smile.  What are the implications of these findings?  Maybe this
new "form" of geno 1b HCV RNA just hangs out quietly in liver tissue and
peripheral blood cells and doesn't do a lot of damage.  Or as much
damage...

Here is a link and excerpt for a similar article from the same author(s).
Notice that in both articles they are careful to point out that combo tx
does improve liver damage.

Using the search window at www.pubmed.gov turns up lots of unreadable
science.  For example, type in "peripheral blood mononuclear cells + hcv"
FYI, pubmed.gov is the U.S. National Library and National Institute of
Health database of summaries from all major (and a zillion minor)
peer-reviewed medical journals.

Also, I scrounged up a couple definitions in  Wikipedia that might be
helpful to people trying to make sense of these articles.

Not cheers
kj
1b :-(

Hepatitis C virus replicates in the liver of patients who have a sustained
response to antiviral treatment.   November 2006 Clin Infectious Disease

"...Results: Positive-strand HCV RNA was found in 19 (95%) of 20 liver
biopsy specimens, and negative-strand HCV RNA was found in 15 (79%) of the
19 samples that had positive-strand HCV RNA...Conclusions: HCV persisted
and replicated in the livers and peripheral blood mononuclear cells of
most sustained responders. Thus, these patients did not experience HCV
infection clearance, despite apparent clinical disease resolution."

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstra
ctPlus&list_uids=17051492&query_hl=11&itool=pubmed_docsum


A couple definitions from Wikipedia::

"Peripheral blood cells are the cellular components of blood, consisting
of red blood cells, white blood cells, and platelets, which are found
within the circulating pool of blood and not sequestered within the
lymphatic system, spleen, liver, or bone marrow...

A Peripheral Blood Mononuclear Cell (PBMC) is a blood cell having a round
nucleus, such as a lymphocyte or a monocyte. These blood cells are a
critical component in the immune system to fight infection and adapt to
intruders. These cells are often extracted via centrifuge from whole blood
samples for use in clinical trials...

An occult infection is medical terminology for a "hidden" infection, that
is, one which presents no symptoms..."

http://en.wikipedia.org/wiki/Peripheral_blood_cell
http://en.wikipedia.org/wiki/PBMC
http://en.wikipedia.org/wiki/Infection
Thomas Wagner - 18 Nov 2006 01:46 GMT
>Hi Ron.  This is a stinky rotten piece of news you posted.  It sure weighs
>heavy on my thoughts about re-treatment.  Findings like this have been
[quoted text clipped - 4 lines]
>peripheral blood cells and doesn't do a lot of damage.  Or as much
>damage...

Well, I don't know. First of all, even the authors of the study clearly
point out that this "occult" HCV doesn't do as much damage (if any) as
normal chronic HCV. Second, it's not at all clear that HCV persists in
ALL successfully treated patients. As we've discussed regarding similar
previous reports, there are a number of possibilities:

a) what persists in (some of?) those who achieved SVR is not a
"full-blown" HCV virus, but rather one that is severely crippled, as can
be deduced from the fact that it doesn't replicate at any significant
rate above barely keeping "alive". Given that practically all patients
with SVR experience a significant and sustained positive effect on
fibrosis and even cirrhosis, what remains of the virus obviously is
pretty powerless to do damage. The incidence of cirrhosis and liver
cancer in sustained responders is significantly reduced.

b) a small subset of patients achieving SVR may have remaining pockets
of the virus in their system that are kept in check by the immune
system, but could potentially rebound if there is a severe immune
deficiency. Since there is no test that can prove the absence of the
virus with complete certainty, this is certainly a possibility.

c) all of us who achieved SVR are ticking time bombs. This is simply
absurd. There is no indication that any significant number of patients
are in danger of relapsing 5, 10, or 20 years down the road. There have
been a number of long-term follow-up studies, none of which found any
such thing.

So... I don't know why the results of this study should keep anyone from
initial or re-treatment. The authors found clear evidence of the
treatment improving liver status. There is some conflicting evidence
about viral persistence, and this should be investigated further. But
there certainly is no reason to panic.

Thomas
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kjoh - 18 Nov 2006 03:40 GMT
"But there certainly is no reason to panic."

Who panicked? It's just one more piece of information we must factor into
our decisions.  I do wish Big Pharma would step up to the plate and fund a
few SVR biopsies and PBMC tests to help us figure out what this means.

Cheers
kj
Thomas Wagner - 18 Nov 2006 05:29 GMT
>>"But there certainly is no reason to panic."
>
>Who panicked? It's just one more piece of information we must factor into
>our decisions.

When Ron writes "Are people cured from hep-c ? I don't think so." then
that sounds pretty panicky to me. And how is that information relevant
to a treatment decision? Are you basing your decision on the word "cure"
or on the clearly positive effects of treatment?

> I do wish Big Pharma would step up to the plate and fund a
>few SVR biopsies and PBMC tests to help us figure out what this means.

Since neither Roche nor Schering have ever used the C word, I'm not sure
why they would be obligated to pay for this somewhat esoteric research.
It's obviously being done, and somebody must be paying for it. But as
the outcome of that research appears to have more psychological than
physiological relevance (I don't care whether I still have a few
crippled virions in me as long as they don't harm me) it doesn't look
that high priority to me. There's more important stuff, like the
development of better treatments, that they should be (and are) spending
their money on. If against all odds we find out in 10 years that even
folks that have been clear that long can relapse, I sure hope there will
be better stuff available then.

Thomas
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kjoh - 18 Nov 2006 18:16 GMT
"Well, I don't know. First of all, even the authors of the study clearly
point out that this "occult" HCV doesn't do as much damage (if any) as
normal chronic HCV."

Hi Thomas. Thanks for your input, as always.  What the authors "clearly"
point out is that the occult form of infection is a milder form of
disease, but certainly  not harmless or passive:

"...liver necroinflammatory activity and fibrosis were observed in a
significantly higher proportion of patients with occult HCV infection than
in those without intrahepatic HCV-RNA."

..Thus, it was concluded that occult HCV infection is a milder disease,
with less liver damage than chronic hepatitis C. Nevertheless, as patients
with occult hepatitis C may present dyslipidemic disorders, studies on the
natural history of occult HCV infection should be performed to prove the
role of occult HCV as the cause for liver injury in these patients...

..Therefore, it seems that occult HCV infection may play a role in the
development of HCC however, as discussed above, more studies on this issue
should be performed.

.. In summary, although these patients are serum HCV-RNA negative they
could be potentially infectious as HCV is replicating in their PBMC, thus
preventive measures to avoid HCV spread in hemodialysis units must be
considered.

..Thus, patients with an occult HCV infection had a better immune
response and this could be the cause of the milder disease that these
patients have in comparison to those with chronic hepatitis.  These
results seem to suggest that the clinical differences observed between
occult and chronic hepatitis C are a consequence of the host's
immunological system."

This is important information, based on a growing number of studies.  I am
not panicking - I am not even hysterical :-)  But I do find this
information disturbing.  I prefer not to cast it aside when I make my
decisions about re-treatment.  

Kathy
don't shoot the messenger
Thomas Wagner - 19 Nov 2006 00:56 GMT
>This is important information, based on a growing number of studies.  I am
>not panicking - I am not even hysterical :-)  But I do find this
[quoted text clipped - 3 lines]
>Kathy
>don't shoot the messenger

No intention of shooting the messenger. However, please keep in mind
that this study lumped all groups of "occult" HCV together. There are
just two paragraph that pertain to the subgroup of sustained responders:

"Occult HCV infection has also been identified in a similar cohort of
patients: those with chronic hepatitis C who have responded to an
antiviral therapy with loss of circulating HCV-RNA and normalization of
ALT levels. Several papers have reported the presence of an occult HCV
infection (persistence of HCV-RNA) in the liver and in PBMC of sustained
responders[22-24]. However, other authors have not found viral RNA in
these patients[25,26]. These discrepancies could be due to different
preservation methods of the liver biopsies, to differences in the
sensitivity of the methods employed for HCV-RNA detection, different
geographical incidence, etc. Thus, further studies are needed to know
the real prevalence of occult HCV in complete responder patients. One of
the possible consequences of occult HCV infection is the persistence of
liver necroinflammation in an important number of sustained responder
patients[23,24].
 The case of a patient with chronic hepatitis C who cleared serum
HCV-RNA with normalization of ALT levels in whom HCV infection
reactivated following prednisone therapy after 8.5 years of HCV-RNA
negativity has been published. Thus, occult HCV infection should be
taken into account when these anti-HCV positive patients with normal ALT
levels undergo immunosuppressive therapies[25]."

The references 23 and 24 are indeed disturbing (clickable pointers to
all references are in the original article). But both looked at a very
small sample. Reference 25 OTOH looked at 400 patients with SVR, and
found viral persistence in just 2%. How those numbers can be reconciled
is a big question.

But again, all this information must be viewed in the context of
long-term mortality studies on SVR (and even "transient responder")
patients. There aren't that many, but one is here:
http://www3.interscience.wiley.com/cgi-bin/abstract/72513868/ABSTRACT

"This study included 594 patients with chronic hepatitis C who received
interferon- therapy (Interferon group) and 144 patients with chronic
hepatitis C who did not receive interferon (Control group). The patients
in the Interferon group were classified into the following three groups
based on the response of the serum aminotransaminase level of the
patient during and after completion of the therapy protocol: sustained
responders (n = 175), transient responders (n = 165), and non-responders
(n = 254).

[Note: this was interferon monotherapy, hence the low success rates.
More modern therapies could possibly also contribute to more persistent
viral elimination.]

[...] Multivariate analysis showed that interferon therapy decreased the
risk for developing HCC by 48% compared with that in the Control group
[...] No sustained responder or transient responder in the Interferon
group died of liver-related disease. The cumulative survival rates of
the Interferon and Control groups were nearly identical during the first
5 years following diagnosis. Thereafter, the cumulative survival rate of
the Control group declined, resulting in an 8-year survival rate in the
Interferon and Control groups of 97% and 81%, respectively [...] Our
study demonstrated that interferon therapy significantly lowered the
incidence of HCC among patients with chronic hepatitis C who showed
sustained normalization and among patients who showed transient
normalization of the serum aminotransferase level after completion of
interferon therapy. The survival analyses and determination of cause of
death suggested that interferon therapy improves the long-term survival
of chronic hepatitis C patients who respond to this therapy, possibly by
decreasing mortality from liver-related diseases."

Sounds pretty good to me...

Thomas
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