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New Approach, Old Drug Show Promise Against Hepatitis C, Research Shows

".....The advance involves two new discoveries. One is that a protein called NS4B is instrumental in binding some of the genetic material, or RNA, and allowing the hepatitis C virus to replicate. The other is that the former anti-itching drug clemizole hydrochloride could hinder that protein, resulting in a tenfold decrease in virus replication with no apparent harm to infected liver-like cells. Because the drug has already been used by people, it is eligible for human testing....."

See: http://www.sciencedaily.com/releases/2008/08/080831151350.htm

Mike
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48 Comments Post a Comment
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Avatar_f_tn
Interesting article.  Thanks Mike.

jd
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476246_tn?1310999221
Some interesting stuff
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Avatar_m_tn
thanks so much for this valuable info.

If I to do tx again before Teleprevir comes out, it sounds like this would be a great add-on to SOC, maybe even with alinia. It might be a good add on with teleprevir.
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232778_tn?1217450711
It is intersting to me that many of the drug candidates poping up, are not new drugs, but rather existing ones. Ribarvirin was like this also, and it makes one wonder if there isn't even more out there which would help. I guess it is logical per all the cocktail ideas, that if you throw enough poison at this virus, it will die. It is a bit frustrating though, that there seems to be little prospect of removing Riba from the mix, IMO riba is the drug that makes treatment the ordeal it is. I had few problems when I was on mono-therapy, but Riba seems to be the symptom magnifier per my experience anyway.
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92903_tn?1309908311
The goal is to improve on the current treatment, a combination of the general antiviral drugs interferon and ribavirin. Those only work about half the time, but have uncomfortable, flulike side effects.

>uncomfortable, flulike side effects.
That would be one way to describe it.
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439539_tn?1233469415
Thanks for that.Interesting stuff.
Tammy
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338734_tn?1377163768
Thanks, Mike. Very interesting.
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Avatar_f_tn
Thanks for posting Mike.  This is great news, especially the new lab technique that facilitates more efficient and faster research.

dointime      
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223152_tn?1346981971
It is all greek to me but I agree, Goof - I think we could embellish the uncomfortable fullike symptoms a tad
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233616_tn?1312790796
cool stuff. this kinda reminds me of the new stuff on the P450 chromosome and how stimulating it increases fibrosis. Soon they'll have much better antiviral/antifibrotics combos and we can all get well!!

Learning which chemicals to stimulate and suppress.....sheesh, what a complex world our bodies are!!

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233616_tn?1312790796
after several attempts, I think the Nature Biotech article must have been delayed, can't find it anywhere.

also can't find any current RX dosing info for this....is it that obsolete that no rx's are available?

I did find a bulk source for it at Spectrum chemicals, but would still need to know dosing info to try it that way.

It might be easier to just do it that way than to try to convince my doctor, after the battle to get on Alinia it would be a hard sell...although it is his buddies at Stanford doing the research...and that's what won him over finally last time...

hmmm...as far as flu like....heck, taken at night, I may be able to eliminate one or both sleep aides. Besides, with all the current sides, like one more would matter?

If anyone finds out more info on this please post it, I would think a ten fold reduction in viral replication should put it at the top of any treaters points to ponder.
It's getting the chemical into the cell that concerns me....how well does it do that.

If anybody finds the original research of Aug 31 please post it here.
and thanks Mike for finding this one....really a plus.
mb
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233616_tn?1312790796
Article abstract

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Nature Biotechnology
Published online: 31 August 2008 | doi:10.1038/nbt.1490


Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis
Shirit Einav1,2,5, Doron Gerber3,5, Paul D Bryson2, Ella H Sklan2, Menashe Elazar2, Sebastian J Maerkl3,4, Jeffrey S Glenn2 & Stephen R Quake3



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AbstractMore effective therapies are urgently needed against hepatitis C virus (HCV), a major cause of viral hepatitis. We used in vitro protein expression and microfluidic affinity analysis to study RNA binding by the HCV transmembrane protein NS4B, which plays an essential role in HCV RNA replication. We show that HCV NS4B binds RNA and that this binding is specific for the 3' terminus of the negative strand of the viral genome with a dissociation constant (Kd) of 3.4 nM. A high-throughput microfluidic screen of a compound library identified 18 compounds that substantially inhibited binding of RNA by NS4B. One of these compounds, clemizole hydrochloride, was found to inhibit HCV RNA replication in cell culture that was mediated by its suppression of NS4B's RNA binding, with little toxicity for the host cell. These results yield new insight into the HCV life cycle and provide a candidate compound for pharmaceutical development.

Top of page
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Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR 3115A, 269 Campus Drive, Stanford, California 94305, USA.
Department of Bioengineering, Stanford University and Howard Hughes Medical Institute, Stanford, California 94305, USA.
Present address: School of Engineering, École Polytechnique Fédérale de Lausanne, Building BM 2111, Station 17, 1015 Lausanne, Switzerland.
These authors contributed equally to this work.
Correspondence to: Jeffrey S Glenn2 e-mail: jeffrey.***@****

Correspondence to: Stephen R Quake3 e-mail: ***@****


the whole article costs 32 bucks....don't think it would help me with dosing info at this stage of their research so I'll pass.

Looks like I need a really OLD PDR to discover what dosages were used.
the research on this is all from the sixties. Old stuff.

Also, it looks like several repatent searches are being applied for, which means the price will skyrocket. Probably Burroughs doing that and a competitor or 2.  It's tempting to just get bulk from Spectrum while it's still generic, sounds crazy, but hey...maybe I've still got a PDR in the attic...hmm

mb
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179856_tn?1333550962
I would think a ten fold reduction in viral replication should put it at the top of any treaters points to ponder.
-----------------------------------

It would be very important to factor this in to the "how long do I need to treat for" questions that's for sure as it would make a 2 log drop by week 12 obsolete but perhaps not be a true indicator of ones real condition.

I would really stop and think about it UNTIL somebody tested and knew - be careful.
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233616_tn?1312790796
Point well taken, my theory would be if cell permeation is the number one hindrance (as HR has suggested many times) then an antihistamine that even eats into the silicone it's been tested on might mean its ten fold effect is because of it's ability to break through cell walls and lipid shells on the virions, probably both.

For me already being UND there's less to worry about, although it is those lingerers that have half of us relasping.
For those treating for the 2, 3, or 4th time, I'd be on this like white on rice. If it could cut down your tx time, and remember every round of tx does it's own damage, then it would make sense of find out what you could.
The human trials have already been done for heart, and skin problems so the safety is well established. It seems to stabalize certain heart rhythms, so heart patients would need more monitoring, and perhaps less of their current meds but that would depend on which kind of arhythmia they have, since only one is effected by this drug.

I'll continue to look into this, and see if an rx could be obtained and report back what I find.
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Avatar_dr_m_tn
The Clemizole paper is quite detailed and does give hints what to expect in a clinical use for HCV.
The concentration at which a 90% inhibition of viral replication in the cell line used occurred was 20 micromoles - that is fairly high and not easy to achieve with an oral drug unless for example 1 to 2 grams a day are used. This of course depends on the pharmacodynamics factors and needs to be measured in the early clinical development stages.

The concentration needed to inhibit the NS4B binding to HCV RNA by 50% (IC50) however is only 24 nanomols, almost 1000times lower.

Thus the drug inhibits its molecular target very well, but does not enter the cells in sufficient amounts, therefore huge extra doses are needed to bring enough of the drug to the site of action. The researchers hope to develop modifications that will increase intracellular bioavailibility.

Resistance development was also tested and found to occur. Therefore a meaningful  use of this compound could only be envisioned as part of a multidrug approach, or at extremely low viral loads.
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408795_tn?1324939275
Well TY for chiming in with that information, now that I know that it would take too much orally I can get back to my reality and stop trying to locate it.  What interest me is they had just mentioned a couple months back two drugs that are already on the market and are already in trials.  That would be the fluvastatin and alinia, hope I spelled those right and I'm not mis-informed.  Is there anything that a person could take that would "decrease in virus replication with no apparent harm to infected liver-like cells"?  It's difficult to accept that this virus has been around, for me dx'ed in 92 and nobody has come up with a semi-cure so that one could safely use until they have all their ducks in a row to tx.  They gotta be close...  thanks again  
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315996_tn?1321809719
thanks, too.
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233616_tn?1312790796
Hi HR, glad to see you still stopping in from time to time.

so 1000th of a gram or 2. isn't that like ten or 20 milligrams? Not a phamacist so not sure of my math here.

those dosages are quite safe are they not?

I'm drawn to the idea that cutting back on the two sleep aides I'm currently on to deal with this disease and the Riba-mania....namely Ambien and Remeron might be lowered were I to have this on board, and getting an inhibitory bump in the process makes more sense.

I'm concerned also about the remeron as it has some action on the P450 chromosome, though I haved been able to find out much about how much safer tetracyclics are than SSRI's the whole family is these classifications has me concerned.

So wouldn't an antihistamine be a better choice from that standpoint as well, as far as P450 goes?
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Avatar_n_tn
always good to see you posting..I was curious to hear your thoughts on two topics, both related to HCV in PBMCs, that have come up recently.

The first concerns mitogen culturing of PBMCs to stimulate viral replication prior to PCR.  Three studies over the past few months have refuted detection of post-SVR/spontaneous clearance HCV in PBMCs as documented in the earlier Pham,Radkowski,Castillo reports:

http://www.ncbi.nlm.nih.gov/pubmed/18593587
http://www.ncbi.nlm.nih.gov/pubmed/18220272
http://www.ncbi.nlm.nih.gov/pubmed/18448695

None of the above applied mitogen culturing of cells, though the Pham/Michalak protocol description makes it clear that this is a key part of reliable detection in lymphoid cells:

http://www.medscape.com/viewarticle/563337_1

"In the case of occult HCV infection, culture of PBMCs for 72 h with phytohemagglutinin (5 µg/ml) to stimulate T cells, pokeweed mitogen (5 µg/ml) to induce B and T cells and/or lipopolysaccharide (1 µg/ml) to activate monocytes and B cells, led to the identification of HCV-RNA in the vast majority of individuals who were otherwise seemingly HCV-RNA nonreactive."

I just noticed Pham/Michalak wrote a comment to the Bernardin study raising the issue and the authors, though claiming a more rigorous dilution calibration, don't seem to dispute the omission.

Also, another very recent study
http://www.ncbi.nlm.nih.gov/pubmed/18594984
which did apply mitogen/cytokine culturing reports finding post-SVR PBMC HCV RNA.

Do you think failure to apply cell culturing is simply an omission,  or that this is being intentionally resisted (eg as a source of possible contamination?)

The second topic is commercial availability of PBMC-detecting tests. Surely, current technology for detecting RNA in serum is very near its limit. Furthermore, most SVRs clear HCV from serum somewhere between weeks 4 and 12 leaving absolutely no guidance about progression of the fight for the rest of tx. If in fact infected cells, in lymph, liver and elsewhere, die/clear at a much slower rate, as one would expect and as suggested for example in

http://www.ncbi.nlm.nih.gov/pubmed/18712814

the availability of PBMC tests would give patients a good, though not definitive, correlation to gauge where they were in the fight (and provide additional support for tapering, for example).
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Avatar_dr_m_tn
The use of mitogens will stimulate numerous components of the replicating machinery, including some that "remnant HCV" might need to proceed though is very hampered molecular machinery. Thus a positive test/find under mitogen conditions is much more likely. Furthermore there is the remote possibility that some, at least partial, integration of the HCV genome, by some spurious reverse transcription, as supplied by our numerous genomic transposons, is leading to PCR detectability of those sequences under these conditions.
The whole issue is however a bit on the philosophical side, since the stability of SVR , even under immunosuppressive regimens, is testimony to the fact that these remaining sequences do not have the power to mount a renewed high level of replication.

As to the PBMC tests after serum UND results, those might not reflect the truly important variable which is likely to be the further shrinking of the genome pool size of HCV in the liver after UND and even less the gradual remodeling of this remaining quasi-species pool into a more immunogenic/less epitope avoiding/less speedy and efficient replicating variety - deeply hidden facts that might be the truly deciding factors in achieving SVR in the end, aside from simple quantity of total number of remaining "HCV" genomes reduction...
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Avatar_n_tn
thanks -  seems a bit odd that someone setting out to measure residual HCV in PBMCs, as those three papers did,  wouldn't either include that step or discuss why they had not done so.

Re  PBMC-based VL, I was thinking successive readings would  provide some indication of changes in cellular-level infection whereas currently, after serum-UND is reached, there's nothing. True, this is not what one really wants to measure, but if there's even rough correlation it would be an improvement over guessing. Post-svr resurgence is not a realistic concern, but decisions about extending, tapering and dose adjustments have to be made every day and seem to turn on the extent of remaining infection and  fitness of the remaining virus.

Interesting twist about partial integration - a major gap in the 'occult infection' claim is that so far only the 'occult' and not the 'infection' has been shown.
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Avatar_m_tn
Very good to see you here again. And always great to read of your thoughts and insights.

"The whole issue is however a bit on the philosophical side, since the stability of SVR , even under immunosuppressive regimens, is testimony to the fact that these remaining sequences do not have the power to mount a renewed high level of replication."


What do you make of the following papers, then?

http://www3.interscience.wiley.com/journal/121382474/abstract?CRETRY=1&SRETRY=0

http://www.amjmedsci.com/pt/re/ajms/abstract.00000441-200807000-00025.htm;jsessionid=LHTPYt312czWMM5v1GbWKdjVhMmtKpG3dvx9yTs1dyxKzhpjGvjz!609209752!181195628!8091!-1?index=1&database=ppvovft&results=1&count=10&searchid=1&nav=search

http://www.ncbi.nlm.nih.gov/pubmed/16107964?ordinalpos=62&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


And in transplant settings?

http://www.ncbi.nlm.nih.gov/pubmed/12927925?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/15964345?dopt=Abstract

http://www.ncbi.nlm.nih.gov/pubmed/15589744?dopt=Abstract


Separately, what are your thoughts on this finding of occult in kidney tissue?

http://www3.interscience.wiley.com/journal/120091231/abstract


TnHepGuy

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Avatar_dr_m_tn
Thank you for the links. I am am aware of these reports and also that there is, as expected a grey zone of reactivatibility, since there will be a great variety of types of leftover HCV genomes with different fitness from  none (so that immunosuppression CANNOT REACTIVATE IT)  to quite fit ( SO THAT NOTHING WILL HAPPEN WHILE IMMUNE SURVEILLANCE IS HIGH but recurrence at strong immunosuppression), that need to be considered combined with their epitope inherent Tcell immunogenicity.

The emotional need for a feeling of total safety from recurrence is understandable and thus these topics need - in the context of this forum- presentation in a somewhat simplified, black and white format. In that sense: SVR is stable, do not worry. If you have immunosuppressive treatment - worst case scenario you can retreat.
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Avatar_n_tn
Now I am a little bit confused.  Since this has been a very volatile subject on this forum, as you may be aware from prior threads, I want to try to clarify what you are saying just a little bit more.  You state that SVR is stable, but at the same time it seems to me that you also indicate that SOME HCV genomes, leftover after SVR in the body, with greater levels of fitness, actually can re-activate or recur, thus causing an active HCV infection again.  You indicate that if this were to happen, one could retreat, so I interpret this as meaning that, while rare, it is possible to trigger an active infection again in some SVR's, under extreme immunosuppression.  

If the above is accurate, would this then imply that HCV is placed in a state of virtually permanent remission when SVR is achieved, but that it is not  ever totally eradicated in SVR's?  I do want to try to get some expert opinion from you on this, because this issue has inflamed tempers in the past, and been the cause of  lengthy, and often rancorous threads.
I suspect personally that SVR is extremely durable and stable, BUT that the virus is still present in differing forms, and at extremely low levels in most SVR's....thus leading to a situation best described as long term remission.  Even though virtually a permanent state, this remission could in rare cases allow for relapse, and NOT just re-infection.  This is my interpretation.  (might extreme, chronic alcohol abuse also provoke a potential relapse in some rare cases, just as immunosuppressive drugs could do??)

What would be the best way to characterize it from your perspective?  Thanks for your input.

DoubleDose
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Avatar_dr_m_tn
The molecular/biological reality in individual SVR patients is likely dramatically different after SVR and what is left is most of the time not really the HCV virus as we know him ( already a huge variety of forms, even within a genotype)  but some vastly mutated/truncated remnant that one cannot really call HCV, without making the real HCV virus community blushing with shame, In some selected cases these remnants do better for themselves both in terms of quantity and quality and those are able to re surge once the immune pressure is off or vastly lessened where it matters...

One has to realize that these "remnants' are the end-products of a gigantically accelerated evolution process during IFN/riba treatment with the utmost strange creatures in a wide variety of shapes, molecular functional capacities  and quantitative amounts being created....with some having at least however the HCV PCR flag rescued from their glorious ancestors, with sad memories when they were a proud and powerful population...
Therefore to quote from my above post:

there will be a great variety of types of leftover HCV genomes with different fitness from  none (so that immunosuppression CANNOT REACTIVATE IT)  to quite fit ( SO THAT NOTHING WILL HAPPEN WHILE IMMUNE SURVEILLANCE IS HIGH but recurrence at strong immunosuppression), that need to be considered combined with their epitope inherent Tcell immunogenicity.

Also please remember, there is a huge margin between none and even small amounts, so that for instance a few thousand crippled "HCVlike" remnant genomes in the liver total  would literally mean nothing to the carriers biology.

In summary most of these remnants are not able to resurge under immunsupression, while some would, owing to a wide spread of genomic powers leftover. Betters statistics to that might emerge over time, but the individual SVR patient will never know if he has any remnants or how fit they could be if he would need to be immunosuppressed
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Avatar_n_tn
Thank you for that follow up elaboration on the subject.  I like what you are saying, and believe that the odds of any sort of resurgence appear to be very low, from my read on your passage.  I also note your comment that it would be impossible to determine whether or not you were one of the SVR's that harbored a potentially resurgence-capable
remnant of the virus.  I guess time will tell how many of the SVR's actually experience something like this.  I would expect few to occur, since extreme immuno-suppression is not common, and the remnants would also have to be highly 'fit'.  

Another consideration is the question of what changes have already taken place in the body and cellular immune mechanisms, both as a result of chronic HCV infection, and as a result of the intense immune system activation during tx, and whether they are reversable to any extent, or if they continue on their own, to contribute to malfunction and negative symptoms over time.  The practical question that I have to put forth is : why do so many of us (SVR's) continue to feel so poorly, long after tx has ended?  Some of us are feeling worse in some ways than before tx, I would venture to say.  Future treatments will need to set goals beyond just eradicating the virus, I believe....like preventing exacerbation of symptoms after SVR, and maybe even reversing some biological problems or disturbances as a consequence of achieving SVR.  

Just a few thoughts.  Thanks again for your timely and detailed input!

DoubleDose
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Avatar_m_tn
HR all let me see if I get this? So what you’re saying is that after a rigorous treatment of inf and riba the virions are more or less so mutilated that the chemistry of them has changed gradually during treatment and that the structure of the virions during the onslaught of the meds are incapable of reconnecting or replicating due to the structural changes and that it had morphed from its original fitness to different sizes and shapes to where they are no longer able to produce an effective positive or negative chain and therefore the t cells recognize the deformity of these cells and attack them as an invader, hence the evolution of change had started with the introduction of the inf and riba. So as all these billions and billions of virions are replicating during the first few months of treatment they are also changing as the evolution advances even in their cleaving and that the remnants segment circulating in the liver as well as in the PB that the t cells kill them off in time except for the most fit and that being just before the heightened onslaught in which a few hearty virions were able to adapt to the fast changing chemical environment going on and were able to do so for the duration of treatment to where their original dna coding still remains intact and in a “rare” possibility after treatment has ended or perfect storm, are able to re-infection?

jasper
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Avatar_n_tn
"the real HCV virus community blushing with shame"  : it's good to see the  fundamental truths, like prejudice, carry on right down to the viral level "goodness,  that  degenerate quasi-species has let themselves go so low we stopped sharing sequence with them generations ago".

However, as best I can tell, we know  very little about these survivors, which is why I tend to believe the subject of occult should be of great interest to everyone interested in getting to SVR.   I hope someone will correct me if I'm wrong, but as far as know we don't have full sequence for any post-SVR/spontaneous virus.

More to the point there is scant data on the $64K question of whether residual/occult virus is infectious. There is the interesting case of

http://www.ncbi.nlm.nih.gov/pubmed/17456153

in which a blood donor who showed up serum UND on most (but not all) replications of individual, non-pooled, commercial PCRs, including high-sensitivity ones, *was* able to infect a recipient. An isolated case, but one that suggests that even virus unable to flourish is capable of damage.

A key experiment, which I don't think has been done, would be to inject a chimp with a cell extract of post-clearance PBMCs in which HCV RNA had been detected. This may never be done however, as it seems chimps are no longer available for hcv studies - probably a good thing in the larger scheme of things.

Also, not all evidence of residual HCV is based on nucleic acid tests : in
http://www.ncbi.nlm.nih.gov/pubmed/15722526
detection of viral NS3 protein was by flow cytometry, which should help dispel some of   PCR contamination anxiety.
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Avatar_m_tn
".....there will be a great variety of types of leftover HCV genomes with different fitness from  none (so that immunosuppression CANNOT REACTIVATE IT)  to quite fit....."

I'm surmising (please correct me if I am wrong) from your answers to above questions that varying HCV genome post-clearance fitness levels would exist. For example, in some SVR's there may be nothing 'leftover' except totally unfit (i.e. - not able to mount a replicable 'attack'), while others may have versions that do have fit replicable HCV genomes (as would seem to be evidenced in the three re-activation papers referenced). These latter patients (w/ fit genome) would therefore then be the ones susceptible to potential reactivation under extreme stress conditions (e.g. - immunosuppression, etc).

All of this would then point to an ongoing post-SVR immuno-stimulation to 'keep things in check' (as it were), be the HCV genome remnants under immune attack be fully fit or anything less-than. Could having this chronic ongoing immunostimulant response in-and-of-itself present any potential long-term concerns for patients? Also thinking long-term, would the immune system be expected to eventually reduce and/or possibly eliminate the remnants given enough time? Or would a 'truce/balance' be expected, with replicable remnants remaining indefinitely?

'willing' also brings up a good point of concern: the potential for occult infect-ability. While one patient's post-SVR, newly modified/trained immune system may be able to keep it's own 'personal version' of fit HVC remnants in check, another person (e.g. - a patient newly exposed via transfusion, dialysis, etc) may not be able to mount a defense against those particular remaining fit genomic remnants and possibly end up going full-blown primary HCV or having chronic occult (with the other possibility being complete clearance). Without full clearance, odds are that this particular patient would then have a ~33% chance of not being diagnosed (via lack of detection from not having elevated liver enzymes) in the first scenario (full-blown primary HCV) - and ~100% not being detected in the second scenario (chronic occult). Assuming all of this to be true, it would seem to point to a certain percentage of new primary HCV cases occurring via this avenue. And this might also point to a time where occult could end up being the majority form of HCV-type infection due to it's lack of detectability (i.e. - not being tested for in the general population nor the blood supply) and having the same modes of transmissibility as primary HCV.


TnHepGuy
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Avatar_n_tn
Your concern about the potential for increasing numbers of people contracting and transmitting the Occult version of the virus has been one of my thoughts as well.  Right now we have no idea how many are out there already, chiefly because there are no 'red flags' or markers to alert these individuals to their infection.  Undetectability of HCV in serum, while simultaneously carrying the infection, is the key trait of Occult HCV, and is still very little understood, and little studied.

The above comments and posts, by HR, willing, yourself, etc., all open a 'can of worms' as far as considering what might not be visible to individuals through testing and medical exams.  If liver enzymes, and antibody tests, and more important PCR's do not expose an active infection, then how do we ever identify those with this 'silent' form of infection, and how large is the pool of infected individuals out there?  I do not think there are any answers.

I also think that trying to ascertain who among the SVR's might harbor 'fit' forms of the virus, which might continue to attempt to flare into chronic infection, under immuno-suppressive circumstances, or might just 'mess with' our immune function by provoking constant responses, is at best a 'guess-timate'.  We really don't have clear insight into the percentages of SVR's who have more fit, or less fit residual virus. (Or do we, HR?)

And, maybe the scenario that HR deescribes, is exactly what 'remission' of a virus is all about.  Maybe the mechanics of the potential for re-activation, as HR describes, have to do with:  1. levels of more fit residual virus, and,  2. the degree of immunosuppressive incident.  Could we then conclude that we indeed are in a state of 'very strong remission', with nonetheless a potential for relapse in many, dependent on the previously mentioned factors?

Couple this information with my other concern, that spurious HCV virions, transmitted in atypical ways, through sexual fluids, saliva, etc., might have THEIR OWN infective behavior and pattern, which may also be virtually undetectable, and remain isolated in specific tissues or organs, while being held in-check by CELLULAR immune responses, rather than humoral responses. (thus there is no response on typical HCV blood antibody tests)  More than a few studies have zeroed in on this 'cellular immune respones' finding, often found in close contacts of those with HCV.  No real clarification yet as to what these 'cellular responses' might mean, and how long they might persist.

Lots of issues for scientists to explore and clarify.  I am very interested in the answers to all of the above.

DoubleDose
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Avatar_n_tn
While I completely agree that this whole area is (a) poorly understood and (b) interesting it's hard to ignore the presence of two very large elephants in the room (no, this is not a McCain/Palin thread)

Elephant 1 is that the incidence of new HCV cases due to transfusions has dropped dramatically since AB and RNA testing of donations. Elephant 2 is that the there is a huge, and growing, population of SVRs who never look back and go on to live happily and die of something else  entirely.  ( (too lazy to dig up evidence so I'll plead judicial notice on these). Both support the view that, most of the time,  if you've got serum RNA you're infectious and sick and if you don't you're not. The special cases reported definitely make it unwise to replace 'most' by 'all' but their scarcity justifies 'nearly all' ( that poor woman with the 8 year resurgence gets dragged out as often as Jim's poor old anemic Swedes).

Anyway, here's some excerpts from the serum-UND but in kidney case TN posted above :


"A 46-year-old Caucasian man presented with lower-limb swelling and was found to have stigmata of chronic liver disease and abnormal liver biochemistry. Hepatitis C serology was positive, as was an 'in-house' serum polymerase chain reaction (PCR) assay for hepatitis C virus (HCV) RNA (lower limit of detection, 50 IU/ml). Liver biopsy revealed features of established cirrhosis secondary to chronic hepatitis C infection. His only known possible risk factor for HCV was a course of dental treatment in southeast Asia 30 years earlier. He was initially treated with two 12-month courses of interferon-a monotherapy with normalisation of alanine transaminase (ALT) and negativity for HCV RNA by the same 'in-house' assay. However, he became PCR positive 3 months after cessation of interferon therapy. Three years later he was given a 12-month course of pegylated interferon-a and ribavirin with similar results (PCR negativity during treatment with relapse 3 months afterwards) and also started on treatment with atenolol for mild essential hypertension. Given the increasing evidence in support of maintenance interferon therapy, 2 years later he was given a further course of pegylated interferon–ribavirin combination therapy, with withdrawal of ribavirin after 6 months. Pegylated interferon-a2a 90 mcg weekly was continued over the next 3 years, during which he remained in good health (other than the occasional episode of gout treated with colchicine and allopurinol) and had a normal ALT and undetectable HCV RNA on repeated testing with the previously described assay. Baseline creatinine was normal and there were no documented episodes of renal impairment. He did, however, on one occasion, develop a rash on his lower legs, which was typical of that seen in cryoglobulinaemia. At this time he was found to be positive for serum HCV RNA and on further questioning explained that in the preceding month he had been injecting interferon that he had inadvertently left inside a hot automobile rather than stored in a refrigerator.

Two weeks later he presented acutely with a 10-day history of general deterioration, abdominal and leg swelling and then development of a florid blistering erythematous rash over his lower limbs. Pertinent investigative findings included low serum albumin, raised serum creatinine, low C3 and C4 levels, positive urinary dipstick testing for blood, raised urinary protein at 1.5 g/24 h and the presence of a monoclonal immunoglobulin (Ig) M ? band on cryoprecipitate and Ig electrophoresis. Hepatitis C IgG was positive while serum HCV RNA was undetectable on this and subsequent occasions using a COBAS Amplicor qualitative assay (Roche Diagnostics Limited, Burgess Hill, UK; lower limit of detection 50 IU/ml). A computed tomography scan of the chest, abdomen and pelvis showed features of cirrhosis with splenomegaly and ascites, but no lymphadenopathy. His remaining liver biochemistry and prothrombin time were normal. A liver biopsy (obtained via the transjugular route) was also negative for HCV RNA by the same PCR assay and histologically showed advanced cirrhosis with minimal interface hepatitis. Skin biopsy was consistent with bacterial cellulitis and this responded to ongoing treatment with intravenous antibiotics, leaving a residual (minimal) rash of purpuric appearance. Renal biopsy confirmed a membranoproliferative glomerulonephritis (MPGN). PCR assay of renal tissue was positive for HCV RNA, in contrast to simultaneous serum and cryoprecipitate samples that were negative. The HCV genotype was not determined. In view of the diagnosis of HCV-associated cryoglobulinaemic MPGN, treatment with pegylated interferon-a2a 90 mcg weekly was continued and his condition slowly improved with normalisation of serum creatinine and albumin. Unfortunately, he was subsequently readmitted to the hospital with an episode of severe septicaemia and multiple organ failure secondary to spontaneous bacterial peritonitis, and died despite aggressive therapy including ventilatory and inotropic support."

After 3 years of IFN I wouldn't be able to remember where my car was, let alone to take the ifn out of the car.

Like the German blood donation case, there's an eery sense of now you see now you don't (contamination or barely detectable? and none left in the liver - though clearly relapsed twice?)

PS   - re

>More than a few studies have zeroed in on this 'cellular immune
> responses' finding, often found in close contacts of those with HCV

would appreciate the reference for that  Egyptian familial transmission study if you have it.
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Willing: that poor woman with the 8 year resurgence gets dragged out as often as Jim's poor old anemic Swedes).
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Or as often as Palin's tired explanation of why she first was for and now against...opps.. meant Willing's tired explanation of why he was first against and now for early and sensitive viral load testing.
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Relapsers or null-responders.  While you're waiting around for the next time you can tx, or you seek help by a drug I am gonna leave the written word on fluvastatin.  Of course you would want to talk to your doctor to see what his take is on taking some of this drug as I haven't read about the sx's.  Also, this is not an alternative tx as there isn't one.  The important part is that the drug inhibits HepC replication of the virus with no known down side.  God Bless

Fluvastatin inhibits hepatitis C replication in humans.
Bader T, Fazili J, Madhoun M, Aston C, Hughes D, Rizvi S, Seres K, Hasan M.
Veteran's Administration Medical Center, Oklahoma City, OK 73104, USA.

BACKGROUND Hepatitis C viral (HCV) infection is the leading cause of death due to liver disease in the United States. Currently, pegylated interferon and ribavirin produce sustained viral remission in only 50% of patients. Additional agents are needed to increase the cure rate. In vitro experiments show strong antiviral effects of fluvastatin against HCV. OBJECTIVES: To assess the safety and antiviral effects of fluvastatin in chronic HCV carriers. METHODS: 31 veterans with chronic HCV were prospectively given oral doses of fluvastatin, 20 to 320 mg/day, for 2-12 weeks with weekly monitoring of HCV RNA and liver tests. Reductions of viral load (P < 0.01) versus a control group were considered suppressive. RESULTS: With 80 mg a day or less, 11/22 (50%) patients responded by lowering HCV RNA. The first lowering occurred within 4 weeks (9/11, 82%). The greatest weekly change in HCV RNA level was a 1.75 log(10) reduction. When lowered in responders, the viral load remained relatively constant for 2-5 weeks (7/9, 78%), or on the next test rebounded immediately to a non-significant change from, baseline (n = 2). Continued lowering of virus was seen in 2/19 (22 %) patients when the study ended. We found no evidence of liver tests worsening. CONCLUSIONS: FLV used as monotherapy in vivo showed suppressive effects of HCV clinically that are modest, variable, and often short-lived. These findings support "proof-of-concept" for pilot trials combining fluvastatin with standard therapy. Statins and fluvastatin, in particular, appear to be safe for use in hepatitis C.

PMID: 18410471 [PubMed - indexed for MEDLINE
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Here is a link to one of the Egyptian studies regarding familial transmission of HCV.  
Please note all comments in the discussion section of this study.  I think they raise more questions, and then even doubt some of their own explanations for the high transmission rate, in this discussion.  

http://www.ajtmh.org/cgi/content/full/75/1/16

Here is another similar study, with a focus on cellular immune reactions in familial settings.  I will let you distill the relevant discussion and results commentary, and relate them to us in layman language here on this thread.  I am not going to try to translate this one.  It does seem that they also raise lots of unanswered questions.  I am also struck by the amount of detailed study and testing that was done in this study.  Are we doing the same here in the US?  Or just ignoring these topics?  Here is the link:

http://www.ajtmh.org/cgi/content/full/73/1/44

By the way, how do you make these links 'live' links.  Can we do this on the forum?  

Enjoy the reading!!

DoubleDose
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Thanks for painting such an extraordinarily vivid picture of SVR, from a viral perspective. I will be watching for further posts on the subject with great interest…truly fascinating.

Greencharles
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"Elephant 1 is that the incidence of new HCV cases due to transfusions has dropped dramatically since AB and RNA testing of donations."


I guess a 'mouse' in the room that I am positing for consideration would be a scenario where occult (as 'defined' by HR above being in the majority cases/patients composed of unfit genomic remnants) is passed on (transfusion, dialysis, etc.) and never becomes full-blown HCV, instead remaining in chronic occult state. This type infection would go undetectable in nearly every case (as things stand today). And my question then becomes: what, if any, long-term negative effects might having this low-level chronic infection and commensurate immune response possibly cause?

And this doesn't have to be limited to HCV, of course, either. Other viral occult infections exist (HBV, etc) that can and do also fly under virtually all screening radar - each producing it's own particular immune response.


TnHepGuy
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AMEN!!!  That's what I have been suggesting for a few years now.  Infection can pass in different ways without setting off a chronic, full blown HCV infection, and without triggering blood antibodies.  Hence it is invisible to the medical community and to the patient!

DD
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willing:  I think that I can also find links to a few more of these sorts of studies, if you are interested in looking further into this subject.  Are these the articles you were referring to, by the way?  

everyone:  What are the opinions on these two issues:  potential intra-familial transmission, and cellular immune reactions to the virus, and other atypical means of either being infected or maybe just reacting locally to the virus.  Other studies would be appreciated.  There are a few interesting ones out there on both subjects, I believe.

DoubleDose
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DD : yes, the 2nd of those was the one I was looking for - many thanks! (and, no I don't think there's any way of making links active; that feature dates back to the bad old, pre-ads,pre-glitz days)

I think your claim under AMEN above is  pretty solidly supported, eg by the results of this study and references it cites.

Basically,  in both chimps
http://www.ncbi.nlm.nih.gov/pubmed/14554088
and humans
http://www.ncbi.nlm.nih.gov/pubmed/10352286

there seems to be a threshold of exposure sufficient to activate  the CMI side of immunity, as evidenced by HCV-specific CD8+ and CD4+ T cells, without ever kicking the humoral, AB generating, side of immunity into play.

Once you move above the level of QM, black and white certainty seems hard to come by, and everything turns to shades of gray. One, very pale gray,  shade seems to be that living near someone with HCV-AB(many of whom presumably were also PCR+)  exposes you to enough virions to raise the hackles of at least part of the immune police. In that study, kids living with at least two HCv-AB +family members, had a much greater frequency and diversity of CD4+ and CD8+ cells specific to HCV epitopes than kids living without anyone with HCV ABs in the house.  Mine have all moved out now, but I used to routinely ask for, and fret over, their AB tests. They always came back neg, but  I wouldn't be at all surprised if they have  HCV-specific CMI activity.

However, I think it's a very long stretch to assume that development of this sort of immune response is associated with any health consequences. It just seems an indication of immunity doing its job, and a sign that the trace levels of HCV routinely reported in saliva, tears, mucus, fishbones, etc. etc. are real but not a threat.


jim:
>and now for early and sensitive viral load testing.
you must be thinking of my evil twin (aka 'Test, baby, Test' willing). He thinks the way to SVR is  to drill, er, test, early and often. Me, I still think that as far as guiding soc, one is throwing money away by paying for sensitive tests any time other than w12.
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just a curious question, why do you feel that one is throwing money away by getting a sensitive pcr test before week 12? Is it because there is no relevance in viral load during this period because the meds are not at their fullest peak and that the virus is at its highest and lowest replicating state in which you will not get a true reading of the pcr? Thanks in advance!

jasper
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For the average person treating here what would be gained by having a pcr’s test at week 4 and 8 as apposed to just having a pcr done at week 12? I had a standard test down to <10 at week 8, would it have made a difference if I had one before that? and if I was at the max dosing of (180/1200) from the get go what else could be done to that point, increase more riba? without knowing the true cmax of the inf and riba in my system? May this be the reason why that most doctors do not do pcr testing before week 12? I would hope to think that it is up to the treating doctor to be proactive at week 8 because of the bx and first vl base line before treatment begins and if one has started out on a lower dosage there may be a little wiggle room to increase the riba or inf at week 12 without throwing the patient into toxicity.  

jasper
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Well, first, "Willing" has posted in the past that should he treat again, that he personally would get the most sensitive test available and if I remember correctly would test a week 4, maybe earlier. Therefore, I see his comments as abstract/argumentative and really don't want to continue on with him a conversation that has been going on too long. Not even sure if he takes it seriously any more but I'm afraid some members are and may forgo what are important tests.

Fact is that that senstive week 4 testing is supported by most leading liver specialists as well as by major researchers like Berg, who Willing was very fond of quoting until Berg came out for sensitive and early testing.

Getter: For the average person treating here what would be gained by having a pcr’s test at week 4 and 8 as apposed to just having a pcr done at week 12?
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The word "average" is key because early and sensitive testing is only useful if either you and/or your medical team is above average, i.e. you're treating with a hepatologist who knows his stuff.

And as mentioned in another post, one of the good things about MedHelp is that many of us strive for the highest common denominator in terms of treatment and not the lowest. But even if your doc doesn't know a TMA from the AMA, another doc you may see in the future might. Such as an outside consult, or a new doc if treatment doesn't work the first time. And to those that know, this information is important for a number of reasons.

First, RVR (UND at week 4) is predictive of SVR. This is important information for both doctor and patient in terms of how vigorously to treat in numerous scenarios including significant side effects. It also can help determine treatment length as studies keep coming out giving more refined odds on SVR with different tx lengths for those who are RVR and for those who are not.

It can also help the doctor "tweak" dosage by giving earlier indications of tx response, especially in a more agressive tx program. It can even help both doctor and patient make more informed decisions whether to continue of stop treatment in certain cases.


And lastly, early, more frequent, and more sensitive viral load testing will become part of your medical record that can be useful in future treatments as newer studies come out that may be able to use these numbers in ways we still don't know about. A point, btw that Willing has conceded some time ago, but still persists in suggesting these tests are useless.

Just one example is helping ferret out true responders from non-responders for future PI treatments per a thesis put forth by Dr. Mitchel Friedman where he suggested that was sometimes difficult because most only tested at week 12 and someone may have responded earlier only to then have the viremia turn back on. These people he considers responders but in a sense they are hidden responders and end up being misclassified as non-responders.

The question isn't "why" get early, frequent, and more sensitive tests, but the real question is "why not". In most cases your insurance will pay for the testing if requested by your doctor. The more points, and the more accurate the points, the more information a top-level doctor has to direct your treatment and the more info in your chart for other doctors both on a consult basis or in a future treatment scenario. But back to the "average" doctor -- even the average doc is starting to use the week 4 tests more and more. Perhaps in another couple of years the average doc will use the week 8 test as well, or even a week 2 test. Remember not everyone clears the first time.

-- Jim
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Meant Doctor Mitchell Shiffman, not Dr. Mitchel Friedman.
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>why do you feel that one is throwing money away by getting a sensitive pcr test before week 12

serum VL does not measure the extent of ongoing infection, however reduction in serum VL does measure response to meds. As a diagnostic tool, serum VL is only useful when there is  suitable comparison data to enable interpretation of the results. For g1s, a large body of data supports SVR odds are negligible if you have any VL at 24 or have not had at least a two log drop by 12. More recent, and well-documented, data suggests that SVR odds with standard 48w soc are poor if you have *any* VL at w12 and that odds can be significantly improved by extending to 72:
http://www.ncbi.nlm.nih.gov/pubmed/18046717

Beyond that, it's mostly reading tea leaves. For example does an UND-w8 result suggest more or less than 48 is advised? Testing at w4 and checking RVR can provide an important psychological boost for enduring the rest of tx if one has made the cut, but decisions about whether to shorten or lengthen based on that test are still very preliminary:
http://www.ncbi.nlm.nih.gov/pubmed/18171217

I do agree with jim that this is for the  most part a non-issue. There's never a reason to not have a high-sensitivity VL test given the option; if you can, you should collect as much data as possible (and I have and will do the same). However, if your Dr/ins.co/national health plan are giving you grief about obtaining tests it's important to distinguish the one that really matters, w12 with currently available data, from the background noise.

As for trusting your Dr's ability to fiddle with the dials by adjusting dosage based on week by week results (in the absence of any data to guide the fiddling) or to decide whether  your w12 result was or was not a breakthrough - well if you believe  that, I've got these mortgage-backed securities I can sell you at an *exceptionally* good price...
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Willing: I do agree with jim that this is for the  most part a non-issue. There's never a reason to not have a high-sensitivity VL test given the option; if you can, you should collect as much data as possible (and I have and will do the same). However, if your Dr/ins.co/national health plan are giving you grief about obtaining tests it's important to distinguish the one that really matters, w12 with currently available data, from the background noise.
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Agreement, hallelulah :) I'd just add that since the week 12 test is more or less a given, the next "push" should be for a sensitive week 4 test. Then go for whatever else you can get. I suppose this then will be your last inserted reference to "Jim's thing about sensitive tests". LOL. No, I would be disappointed if it was and you never fail to disappoint :)


Willing: As for trusting your Dr's ability to fiddle with the dials by adjusting dosage based on week by week results (in the absence of any data to guide the fiddling) or to decide whether  your w12 result was or was not a breakthrough - well if you believe  that, I've got these mortgage-backed securities I can sell you at an *exceptionally* good price...
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I'll pass on any mortgage-backed securites these days (buying the Bklyn Bridge seems a better deal) , but still think tx is part art and part science. Take double-dosing for example. In my case I was told I could stop the double-dose when UND. Only way to find that point more exactly is by frequent testing. Or the riba/hgb issue, which does have some back up. If hgb doesn't drop and VL remains flat, increasing riba is a very reasonable approach. But again, the only way to know what's, what is by frequent VL testing. Today's art by good and experienced clinicians can turn into tomorrow's science. Study data often lags way behind clinical observations.  
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Jmjm, willing as always, like hearing both sides of the isle. It seems that jt57 is having the very problem being discussed here with the sensitive pcr’s. It seems that her doctor is on top of things by getting the 8 week pcr and I’m assuming the reason being is because of her high initial vl and bx data. Jt is on 1000mg riba and not sure of the inf. But has not reached UND at week 8, would she be a candidate for upping here dose to 1200mg a day?

jasper
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geterdone: a big shortcoming with the way VL data is currently gathered and presented is that we now nothing about the serum-UND distribution of a given cohort. For example, in Berg's data, among those reaching serum-und by w12, there was a distribution ranging from w1 to w11. On average that cohort had, say 85%, odds, but  for the w1 crowd the odds were probably 99.999999999% and for the w11 crowd maybe 60%. We know nothing specific about w8, so what does that result mean?

The maddening point here is that while a huge effort goes into looking for silver bullets very little effort goes into better analysis of the data available; and of course public release of the data is nil.

Say you started a large group with (1) weekly or bi-weekly tests to und. and (2) randomized their soc time to 47, 48 and 49 weeks. What you want to now is what's the optimal number of weeks to continue after serum-und and this is probably *not* a constant like the drusano modeled 36. Comparing the small differences in  actual SVR rates for those three arms of a given und-week would start to give you an estimate of the optimal time to eot without running afoul of the ethics boards for prejudicing  participant outcome.

Anyway, anyone interested in this topic, should take a look at Berg's latest review on the subject:
http://www.ncbi.nlm.nih.gov/pubmed/18625426

jim: seems a dangerous time to mention the Bklyn, if Paulson and helicopter Ben hear about the idea, taxpayers will be buying that too. Want to start a pool to see where the deficit gets to by the time W goes back to Crawford? And, OK - I'll try to stifle all comments about sensitive tests if you include a "forward looking statements" disclaimer when touting their value :)
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LOL. I suppose a "forward looking statement" is appropriate for part of its value, but more important we appear to agree to value in the *present*. And, I dare say value in the past, or at least as I see it :) As to the deficit, by the time the admin gets through with this thing there may be no money for those frequent and sensitive tests. Ugh.
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