Likda K's Thread cont/hepatitisresarcher/Willing/Ina/Others

[jmjm530]

Willing: Perhaps this seems like quibbling over many RNAs fragments can hide on the head of a pin
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Probably more HCV RNA on the head of a "needle" as opposed to "pin" per the Talmudic expression :)
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Anyway, Thought I'd open this up to continue the interesting dialogue with hepatitisresearcher and others. Hopefully, Linda K's original question got answered along the way :)

[jay1975]

OK, I understand, Thank you

[jmjm530]

Willing: As Jim said, we have danced this dance many times before on this forum, have gone over all the main research papers and editorials, but have never really gotten past the "there's something suspicious about their methods" argument.
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I think "there's something suspicious about their methods" argument has been only one piece of the previous exchange of differing theories. The other pieces have to do with what I believed was described as the "integrity" of the virus found as well as what clinical implications, if any, this all has. This seems to be very much key and another reason why many of the clinicians aren't overly impressed to date. I pretty much knew HR's position from previous threads, so I realized bringing it up here would add fuel to the occult fire. Just wish I could get several like him in the same room with some of those who think otherwise. Jerry Springer maybe :)
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Willing: Like Jim, I'm curious to hear any comments you have about the variability of VL readings. For example, how different are variances of multiple assays on the same vial of serum, multiple vials drawn from the same patient on the same day and multiple vials drawn from the same patient over long separations.
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Did you see Shiffman's recent slide presentation at the Clinical Options site. If not, I'm sure you would find it interesting. I think I pinpointed the exact slide in the original thread. The variances Shiffman describes are so great that it becomes understandable why a two-log drop is considered important to demonstrate tx is working. Not so much because of how much virus is being killed but to show that in fact ANY virus is being killed, at least according to the way I read his variance numbers. Of course, being non-detectible by sensitive PCR or TMA takes the variablity component out of the equation. While you're on the site, there's a nice little audio message by Dr. A in Boston on emerging treatments.

Willing: sorry, I didn't mean to go too californian on you. I just think if these results are true it redefines the tx goal somewhat.
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As someone who spent time in CA, I understand you can't help it:)
But seriously, if by "californian" you mean the virus is less of an evil spirit than the condition of the liver, we're pretty much in agreement. I put off treating as long as I possibly could. three years to be exact after they explained that my biopsy put me between stage 3 and 4. In fact, it wasn't until I started treating that I found out my actual stage at that time was probably closer to 2-3. If I had known that pre-tx, I would not have treated.

So what's with your search for the holy biopsy reader? I've had my slide read five times now but it will be frozen at five since I'm now SVR. Can you beat five :)

Be well.

-- Jim

[jmjm530]

My doctor uses the word "SVR" and "Cure" interchangeably, as do many doctors in the clinical sense.

The discussion here is mostly regarding the microbiological aspect of SVR which to date have no proven clinical implications.

The microbiological aspects of SVR is a very important topic and researchers like HR should be commended for their time and efforts. Still, as an SVR, IMO this should be of no practical concern in your day-to-day life. It certainly isn't in mine.

As the song says, Don't worry...Be happy. You're SVR!

Be well.

-- Jim

[jmjm530]

I guess the second sentence should read in part "clinical significance" not "clinical implications".
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And speaking of "dancing", anyone watch "Dancing with the Stars" last night?

I knew Joey was going to leave, but who do you think's going to win? Mario's obviously the better dancer, but the fact that Emett beat Joey (also a better dancer) leads me to believe there just might be an upset in the making.

Who do I think should win? I'll take Mario's professional dance partner Katrina. Talk about HOT HOT HOT :)

-- Jim

[Hepatitis Researcher]

The size of the viral inoculum is certainly important in the transmission route, but maybe more import might be the fact that surfaces -skin and mucosa are typically equipped densely with innate response cells like dendritic cells and macrophages that can quickly educate class II lymphocytes.All that before the virus can even enter the circulation. We have watchdogs where the invaders typically come.
Also consider HCV is more cytopathic than HBV thats probably why it is not " silent". The first cells infected quickly "feel the pain" and signaling starts right away, but you need containment in local tissues.

The reason why these type of immunological studies are not popular research activities of hepatologists is simply that they are more clinically trained and educated. For these studies you need trained immunologists  ( like Dr. Rehermann) and a spezialized laboratory with emphasis on advanced immunological methods. Elispots, tetramers, peptide arrays are all still relatively young techniques. But look at all these studies by Vincente Carreno - he goes a long way of explaining the vexing complexities of anti HCV T cell responses. Tcells are at the heart of antiviral defenses, not Antibodies. They work in HBV also only when already present when infection takes place.

I will look at Dr Shiffmans slides another time.

[willing]

many thanks for  your assessment of the  the Castillo methods. As Jim said, we have danced this dance many times before on this forum, have gone over all the main research papers and editorials, but have never really gotten past the "there's something suspicious about their methods" argument. The authors of Castillo'06 seem to go to great pains to establish the reliability of their results, so presumably they expect to be challenged on them.

Regarding the "senescence" argument, did you see any evidence in the phylogenetic analysis included in Castillo that indicated the residual virus was somehow less fit? Given the sloppiness of HCV's polymerase and the rate of HCV replication it wouldn't seem to take very long for it to mutate out of any lack of fitness. However the long-term follow up data seems unanimous in reporting the durability of serum-UND status. Also I thought the "mutation-catastrophe" explanation for riba's synergy with ifn was still very much in question whereas you seem to imply it's the accepted mechanism. Is this the case ?

Like Jim, I'm curious to hear any comments you have about the variability of VL readings. For example, how different are variances of multiple assays on the same vial of serum, multiple vials drawn from the same patient on the same day and multiple vials drawn from the same patient over long separations.

I recall that Shiffman's comments (which also appear in a review he wrote a while back) are based on some fairly old data on VL variability and wonder if there are any more recent measurements of variability. Serum-VL may not correlate with fibrosis-inducing inflammation, but the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed&cmd=Retrieve&dopt=abstractplus&list_uids=16847959">Quiroga'06</a>
paper seems to suggest it correlates with intensity of the HCV-specific T CD4/8 T-cell response, which presumably helps explain why low serum VL is a good predictor of SVR outcome.

jim: sorry, I didn't mean to go too californian on you. I just think if these results are true it redefines the tx goal somewhat.