Will VX-950 and other Protease Inhibitors stop viral replication in our livers?

[miked]

The following was recently published that HCV patients who attain SVR through standard tx (INF + RBV) still have viral replication in their livers even though their bloodstream is virus free.

"Chronic hepatitis C patients who achieve a sustained virological response (SVR) to interferon-based therapy - continued undetectable HCV RNA 6 months after the completion of treatment - are widely considered to be "cured."
However, according to a report in the November 15, 2006, issue of Clinical Infectious Diseases, the hepatitis C virus (HCV) may continue to replicate in the livers of such individuals.

-Positive-strand HCV RNA was found in 19 of 20 liver biopsy specimens (95%).

-Negative-strand HCV RNA was found in 15 of the 19 samples (79%) that had positive-strand HCV RNA.

-Liver necro-inflammation was still present in the post-treatment liver biopsy specimens of 15 patients, and fibrosis was present in 7.

-Liver damage improved in all but 2 patients.

HCV persisted and replicated in the livers and peripheral blood mononuclear cells of most sustained responders," the authors concluded. "Thus, these patients did not experience HCV infection clearance, despite apparent clinical disease resolution."

Are any of the clinical trials for VX-950 or other PI trying to evaluate if the PI kills the bug, even in our livers?  Because the PI interrupts viral relpication this sounds like it should be true.

If it is true does this mean that all who have attained SVR through SOC will have to re-treat with VX-950 or other PI?

I'm curious to see if this is a goal of PIs.

[mremeet]

Actually I slightly misspoke in my earlier post when saying "My doctor mentioned to me that these test methods were under suspicion by many within the medical community." He didn't really say "the method" was in doubt as in the test itself, but if I understood him properly it was a suspicion that the researchers themselves had not handled/managed/manipulated the samples and/or test properly, perhaps leading to cross contamination. Anyway, that's my rough understanding, just thought I'd clarify.

[mremeet]

I don't know if you've been following this whole low level viral persistence thing vs eradication/cure issue raised by various researchers in the past year or so (starting with Castillo et al). I imagine you have, and I know you're an expert on the various testing methods. What do you think of this whole situation? Do you have confidence in Castillo's findings? It's discussed in the referenced link below "HCV Persistence: Cure Is Still A Four Letter Word":

http://www.hivandhepatitis.com/hep_c/news/2005/010305_b.html

The viral persistence crew claim viral remnants were identified in long term SVR liver tissue samples using "...highly sensitive reverse transcription-polymerase chain reaction (RT-PCR)-nucleic acid hybridization assays..." and "...highly sensitive RT-PCR and in situ hybridization..." Are these methods reliable? My doctor mentioned to me that these test methods were under suspicion by many within the medical community, and that these finding are being contested (as evidenced by RTS's reference in this thread). My doctor mentioned something about the possibility of contamination in their sampling/handling methods, which might account for their (apparent) positive HCV findings. What do you think about this whole shebang? And is the TMA test referenced in the link provided by RTS in this thread (which found no viral remnants) comparable in sensitivity to the more specialized tests mentioned above (as used by Castillo et al)?

Thanks in advance...

[jmjm530]

What still hasn't been shown to me is -- assuming for a minute that persistent virus exists and replicates -- is why then with the exception of perhaps one or two rare cases, does it not break through the tissue/lymphatic wall and become detectible in serum? Or perhaps does this so-called persistent virus only mimic replication in a harmless way as might be argued by the benefits of SVR including improved histology.

[APKhaos]

Jim said, "Eventually, they should get together, but didn't they say the same with VHS and Betamax?"

ROTFL. Thanks Jim, I needed that.

[jmjm530]

Mre: It'll be interesting to see how this report is received and responded to by the viral persistence originators. But is the TMA assay they reference using for liver tissue testing as sensitive as the test used by the originators of the low level viral persistence theory? I thought they were using a very special and extremely sensitive test, that's not commonly used for normal patient screening, and is far more sensitive than what's currently used in a (non-research based) clinical setting? Anyone know if that's right?
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Our posts crossed or I would have more directly addressed your question. But yes, you've hit it on the nail. Two different types of tests/procedures -- one (TMA) widely accepted in the clinical community, and the other (used in the persistent virus studies) not so widely accepted and in fact disputed by some. Eventually, they should get together, but didn't they say the same with VHS and Betamax?

-- Jim

[returntosender]

Here is an SVR study from the 2006 AASLD conference which I didnt see mentioned here but it is quite optimistic in terms of the durability of SVR and it seems to cast some doubt on these other smaller studies that show such high numbers of viral remnants in SVR patients:

http://www.hcvadvocate.org/news/reports/AASLD_2006/Abstracts/Monday%20Posters_HCV%20Therapy_%20Pre-clinical.htm#preclin_927

"LB9. Sustained Virologic Response Is Associated with Eradication of Hepatitis C Virus and Fibrosis Regression in Patients Treated for Chronic Hepatitis C. S. Maylin; M. Martinot -Peignoux; N. Boyer; M. Ripault; D. Cazals-Hatem; N.
Giuily; C. Castelnau; C. F