Article on Occult/Persistence and Other Posts

[TnHepGuy_]

Here's a good, comprehensive article by one of the leads (Pham) on research into occult Hep C:

<a href="http://www.findarticles.com/p/articles/mi_m3230/is_2_38/ai_n16084704">Occult hepatits C virus persistence: identification and characteristics</a>


(from the article):

"<i>Although HCV is considered to be primarily hepatotropic, accumulated evidence clearly indicates that the virus also invades and replicates in the immune system. In fact, the presence of both HCV RNA positive and negative strands has been demonstrated in lymphoid cells in both in vivo and in vitro settings. For example, T cells, B cells, monocytes, and dendritic cells from patients with chronic hepatitis C have all been shown to carry HCV genomes. (2), (10-12) Most recently, by applying assays of superior sensitivity mentioned above, replication of HCV has been seen to persist in lymphoid cells for years after spontaneous recovery or a sustained virological response to IFN-alpha/Ribavirin therapy. (1-3) In addition, low levels of HCV RNA in lymphoid cells have been detected in a significant proportion of patients with persistently elevated liver enzyme levels of unknown etiology. (13), (14) Along the same line, susceptibility of T and B cell lines as well as primary human T cells and macrophages to HCV infection have also been documented. (15-18)</i>"

[willing]

as best I can tell, the following are "true", meaning they are accepted by nearly everyone working in this field :

1. undetectable RNA in serum during tx, regardless of the sensitivity, does not signal the absence of infection

2. undetectable RNA in serum 24 weeks post-tx (SVR) signals either the absence of infection or a tx-induced change in the body's ability to contain residual infection

3. SVR is durable in at least > 95% of patients, probably more

4. the major health impact of chronic HCV infection is fibrosis (->cirrhosis,esld,hcc)

5. HCV is also associated with many non-liver complications, eg cryo

6. attaining SVR significantly improves the outlook of patients with respect to liver impact, extra-hepatic benefeits are not as well proven

the following seems "well established" meaning  that a literature search  in an indexing database (ISI) of all papers that have cited <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15140984&query_hl=7&itool=pubmed_docsum">Pham, et al '04</a> turned up no citations that refuted the finding and at least a half-dozen that corroborated it

7. undetectable RNA in serum post-SVR may not signal complete viral eradication. In particular careful examintion of cells from a variety of tissues shows the presence of both HCV RNA and its replicative intermediate in many but not all patients.

I posted this list of  cites a while back. If this finding were controversial the list would have included papers that challenged it. By itself, the finding doesn't prove that the RNA detected is associated with mature, infection-capable, virus and that even if it is that there is any health impact from the persistent low-level infection. However, a recent small study <a href="http://www3.interscience.wiley.com/cgi-bin/abstract/112595728/ABSTRACT"> Giannini, et al '06</a>  confirmed (7) *and* reported a strong correlation between the presence of post-SVR infection of PBMCs and MC effects :

<em>"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-stimulated11 and uncultured PBMCs were HCVRNA–positive in 5 cases (Table 1). Detection of negative-strand HCV RNA via Tthbased reverse-transcriptase polymerase chain reaction confirmed activecell infection in most cases. Interestingly, isolated lymphatic infection was strictly associated with the persistence of both MC-syndrome and t(14;18)-bearing B cell clones (Table 1)." </em>.

That's only one small study, obviously preliminary, but more than speculation.

Jim: I'd pick either the Pham review or the Giannini paper depending on whether you think (7) or its health implications are more interesting.

[jmjm530]

Thanks! I'll report back if I can lasso his attention long enough for a meaningful response.

[Chriskid]

It

[fishdoc]

When I first started reading the forum, a couple of months prior to tx, it seems to me most agreed the beginning of tx was the "worst" time.  Others seem to feel that last month was by far the worst... I am starting into month 4, and I am dragging NOW.  Would anyone mind a thread where those that have passed before us rate treatment? Just to give us more to worry about...
Mine so far:
Month 1  no problems
Month 2  some fatigue
Month 3  fatigue increasing
Month 4  fatigue is getting to me, some nausea
Month 5
Month 6
Month 7
Month 8
Month 9
Month 10
Month 11

[mikesimon]

Thanks for the article. Mike

[TnHepGuy_]

"<i>Occult HCV infection

In our studies, using the highly sensitive RT-PCR/NAH assays, conclusive evidence was obtained for the presence of replicating HCV in persons who apparently completely recovered from hepatitis C and whose sera were repeatedly negative for HCV RNA by standard assays. We found that more than 80% of these individuals were serum HCV RNA positive at levels usually not exceeding 1[0.sup.2] vge/mL and that 30% to 40% of them also carried HCV RNA in circulating lymphoid cells at levels between 10 and 1[0.sup.4] vge per 1[0.sup.7] cells (see Figure 1). (1), (19)

However, when the cells, including those apparently negative for HCV RNA, were ex vivo treated with mitogens known to activate different immune cell subsets, e.g., phytohemagglutinin (PHA) to stimulate T cells, pokeweed mitogen (PWM) to induce B and T cells, and lipopolysaccharide (LPS) to activate monocytes and B cells, HCV RNA was detected in all of the individuals. (1), (2), (19) Interestingly, in the majority of the cases, synergistic stimulation of T and B cells and monocytes with mitogen cocktails led to a more pronounced upregulation of HCV RNA expression than did single mitogen treatments, suggesting that all three cell subsets are reservoirs of the virus (see Figure 2). This propensity was also found when the same cell subsets purified from hepatitis C patients were analyzed. (2), (19) Overall, the ex vivo synergistic mitogen stimulation of peripheral lymphoid cells allows for a more precise detection of silent HCV infection than by testing either sera or naive (untreated) lymphoid cell samples alone. Our original identification of commonly occurring occult HCV infection has been corroborated by recent data from several other laboratories. (3), (4), (6) This collective evidence challenges the previous notion that resolution of hepatitis C reflects complete virus eradication. Further, the invariable detection of replicating HCV genomes in lymphoid cells from individuals with either occult or symptomatic infection attests to the existence of an extrahepatic compartment for HCV replication.

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, liver biopsies from many of them show evidence of persistent minimal inflammation or even of active chronic hepatitis. (3), (5)

Implications of occult HCV infection

Although investigations on clinical relevance of occult HCV infection have just begun, the data available at this point could help explain sustained HCV-specific T-cell responses observed in individuals decades after recovery from hepatitis C. (8), (20) 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) Along the same line, HCV RNA was also detected in sera of anti-HCV positive patients weeks after acquiring HCV-negative kidney (23) or bone marrow (24) transplants and immunosuppressive therapy. With respect to commonly observed HCV reinfection of liver allografts in patients with end-stage diseases caused by chronic hepatitis C, migration of lymphoid cells, including those carrying not readily detectable quantities of replicating virus, may constitute a main mechanism by which the transplanted liver becomes infected.

In summary, occult HCV infection is a common, if not an invariable, consequence of resolution of hepatitis C when measured by highly sensitive assays established recently in some research laboratories. The availability of assays detecting HCV RNA with a comparable sensitivity in clinical laboratories would improve the precision with which HCV is detectable among patients and in the general population. Furthermore, the persistence of traces of replicating HCV in lymphoid cells, from which viral infection may potentially rebound under favorable conditions, suggests that future treatments aimed at HCV elimination should take into consideration that both the liver and the lymphatic system are the sites of virus propagation.</i>"



TnHepGuy