more interesting vl info

[cruelworld]

i just called the NGI division of labcorp to ask about the ultra sensitive
vl tests down to less than 2.
my question was: do they commonly see results in the  2 to 50 range.
they answered in the affirmative, they do get many results
between 2 and 10. they also said that they get plenty of results
between 10 and 50. she didnt have to look this up. she said it was a common occurence.

even though we have never seen such results on this forum, apparently it is more common than we thought. maybe for general purposes throughout treatment the lesser sensitive tests are fine
but i wouldnt want to end  treatment with a vl of 3 or 4. of course the only way you would know you had that vl is to take this test and only this test. i had previously assumed that these "in between"
vl's are a rarity but apparently not. something to think about for eot.

[Ginger12521]

Seems this this type of testing would be more accurate to see if the HCV is truly eradicated from the host after SVR? Anyone have input?


Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C.
Bartolomé J, López-Alcorocho JM, Castillo I, Rodríguez-Iñigo E, Quiroga JA, Palacios R, Carreño V.

Fundación Estudio Hepatitis Virales, Madrid, Spain.

Occult hepatitis C virus (HCV) infection of patients with abnormal liver function tests of unknown origin who are anti-HCV and serum HCV RNA negative but who have HCV RNA in the liver has been described. As HCV replicates in the liver cells of these patients, it could be that the amount of circulating viral particles is under the detection limit of the most sensitive techniques. To prove this hypothesis, serum samples from 106 patients with occult HCV infection were analyzed. Two milliliters of serum was ultracentrifuged over a 10% sucrose cushion for 17 h at 100,000 x g(av), where av means average, and HCV RNA detection was performed by strand-specific real-time PCR. Out of the 106 patients, 62 (58.5%) had detectable serum HCV RNA levels after ultracentrifugation, with a median load of 70.5 copies/ml (range, 18 to 192). Iodixanol density gradient studies revealed that HCV RNA was positive at densities of 1.03 to 1.04 and from 1.08 to 1.19 g/ml, which were very similar to those found in the sera of patients with classical chronic HCV infection. Antigenomic HCV RNA was found in the livers of 56 of 62 (90.3%) patients with detectable serum HCV RNA levels after ultracentrifugation, compared to 27 of 44 (61.4%) negative patients (P < 0.001). No differences in the median loads of antigenomic HCV RNA between patients with an those without serum HCV RNA (4.5 x 10(4) [range, 7.9 x 10(2) to 1.0 x 10(6)] versus 2.3 x 10(4) [range, 4.0 x 10(2) to 2.2 x 10(5)]) were found. Alanine aminotransferase and gamma-glutamyl transpeptidase levels, liver necroinflammatory activity, and fibrosis did not differ between both groups. In conclusion, HCV RNA can be detected in the sera of patients with occult HCV infection after circulating viral particles are concentrated by ultracentrifugation.

PMID: 17475654 [PubMed - indexed for MEDLINE]

[geterdone]

and Oh BTW they did follow your suggestion and moved the "Back to Forum" to the top of the Post Comment Box so it can been seen. Improvement,eh!

jasper

[geterdone]

in short, blew it with the change over with insurance company at the beginning of the year, my fault.

INF at this point 0
Just doing Mono Riba at this point, 2x am/3x pm continuation / had extra riba from reduction back at week 20.

No Procrit at this point either, as this is the hold up with the meds delivery.

Game plan now, ride the Riba wave until INF comes in.

There are several other options and scenarios at this point but have not specifically nailed one down as of yet but am considering one as suggest by Joshua.

The thyroid has been flip flopping for some time even with the meds and was not happy to hear that this may be a permanent side effect of the interferon but will see when all said and done.

jasper

[cruelworld]

i would expect that concentration to be zero, but thats just a wild guess. i tried to look up you eot plan on that thread you pouinted me to.   with so many  pages and pages of responses  i never found out whats happening. sounds like you are already finished. whats the story? oh by the way thanks for the simplified explanation, i would have a headache too but
the fog keeps me safely and completely locked out of most
of those better discussions. also whats happening on your thyroid situation?

[geterdone]

let me ask you this or anyone else, my last INF shot was 18 days ago, given the peak and down curve of the INF what would be the INF concentration level be in the serum at this point?
Thanks!
jasper

[geterdone]

your killing me here,

Right, the circulating virions in the blood serum and extracellular fluids can only infect the uninfected hepatocyte pad of the liver. Yet, the floating virions circulating in the serum and extrecellular fluids are either dieing or dead on their own and triggers the “natural INF” response of CTL’s and helper T cells or killer cells that attacks the invader virions and or decaying virus cells, which is over come after the initial infection process begins and ongoing process. Thus reducing the viral load of the virions with in the liver caused by the induced therapy of the combo treatment but there are few who survive either because of their stronger (DNA) for lack of words, and or because of their thicker lipid coats makes and its way back to the liver through the serum to a virgin hepatocytes pads.

Through combo treatment, the infected hepatocytes pad or pads are helped eliminated by CTL target killing of the pad cells and sometimes neighboring cells accentually, eating the cell or cells which may be in the process of inflammation or the possibility of promoting inflammation with in the liver cell pads as seen by the biopsies in the various stages of fibrosis and or bridging.

I think thats what was said and am glad everyone else understood it , I gots a headache

jasper

[Hepatitis Researcher]

Jim
"Maybe I'm reading this wrong, but my understanding is that the reason newly transplanted virgin (non-hcv infected) livers become re-infected is because the host (us) is infected with HCV floating around in serum, etc, and the virus simply circulates from serum into the liver. If the liver transplant was done after SVR, there should be no re-infection in most cases, although I'm not 100 per cent on this"


This is exactly the scenario. At the moment the new liver enters the transplantee, there are large amounts of virions floating around, interstital fluid and circulating blood space - they will reinfect.
If transplanted after SVR ( rare)  - reinfections very rare, about as rare as relapse after SVR and immunesupression.

The reinfection after transplantation  will typically run a faster course due to the immunocompromised state in many individuals, but after all, the liver is virgin and will take a lot of beating until cirrhotic again.
And reinfection can now be treated with a decent chance for success - as Mikesimons case well demonstrates.

[alagirl]

No, I mean, that question was asked by me, I think, out of my ignorance of the status of most people who are transplanted.  For whatever reason (unfortunately probably due to the fact that my blood count is falling into the toilet again and I can't think straight), I was thinking that people are transplanted after SVR.  Which doesn't even make any sense when you think about it...

[jmjm530]

As I mentioned earlier, I'm not entirely certain on how the tranplantation process and drugs used could affect someone who had a transplant after SVR which I assume is a small population compared to those who receive a transplant while HCV infected. But to those who are HCV positive at transplant, my understanding is that they will remain HCV positive and therefore by definition their new livers will start to become infected.

[alagirl]

I hope that's correct then (that the transplantees are HCV+ at transplant and not SVR and that this is why they infect) - I absolutely don't have this data since I'm so newly infected and haven't had time to study it yet (Truly, I suppose I've hoped that I will clear the virus on my first treatment, and I treated so shortly after becoming infected that I felt there were some things I may not have to intensively study I suppose.  Really, its terribly lazy on my part though...)

[jmjm530]

Ala: Sure, purportedly, the newly transplanted "virgin" liver is reinfected because of the immunosuppressed status after surgery due to the meds, and steroid boluses, and different things, etc, but there are many reasons for short periods of difficulties with the immune system.  So how long do we need to worry about these "virions," which prior to this evening, I didn't realize I needed to add to my list of things about which to be paranoid...
---------------------------------------------------------------
Maybe I'm reading this wrong, but my understanding is that the reason newly transplanted virgin (non-hcv infected) livers become re-infected is because the host (us) is infected with HCV floating around in serum, etc, and the virus simply circulates from serum into the liver. If the liver transplant was done after SVR, there should be no re-infection in most cases, although I'm not 100 per cent on this.

As to immune system difficultties after SVR, it's a compelling theory, but my understanding is that it's just a theory and not universally embraced by clinicians. At least not by two I have spoken to. Their theory is that SVR is "set" when the treatment drugs are stopped. In other words, at that point, assuming you are UND, you will either SVR or relapse, regardless of post EOT events  or regardless of how you come off the drugs such as tapering. Statisics seem be bear out the former as SVR is extremely durable with only a handful of reported relapses after 1 year of SVR.

-- Jim

[geterdone]

It is amazing when one puts oneself in with the virus that one will begin to slightly understand the surface of the 5 w’s of the virus and the correlation between the meds and their functions in combating the virus and virions and what roll each plays in the evolution being played out in our bodies. HR hope you stick around here for a while may have some question after deciphering your last post. If anything my family room wall will have a nice mural design when finished, may be I should have lined it with white paper first tho, lol!

Thanks again!
jasper

[alagirl]

Exactly how long after treatment can these "virions" shack up in one's "intracellular spaces" or "interstitial fluid" and what does that do for the theory that SVR is a cure?

Sure, purportedly, the newly transplanted "virgin" liver is reinfected because of the immunosuppressed status after surgery due to the meds, and steroid boluses, and different things, etc, but there are many reasons for short periods of difficulties with the immune system.  So how long do we need to worry about these "virions," which prior to this evening, I didn't realize I needed to add to my list of things about which to be paranoid...

[Lady Lauri]

Cruelworld.... this post has been very helpful :}, may I impose on it with another question?

I still don't quite understand on the testing! Can anyone explain this one that Human Genome Sciences is using?


COBAS Ampliprep/COBAS Tagman HCV test with a dynamic range of 43 IU/ML-69 million IU/ml and a lower limit dtection of (LOD) of 10 IU/ML.

Thank you, LL

[Lady Lauri]

Quoting APK.....Your last post here was a revelation to me.

My God, I understand all that! Finally, on a tx brain dead night!
I am going to print and read over about 5 times!
THANK YOU!

LL

[APKhaos]

Your last post here was a revelation to me.

After almost three years of reading, I was still muddled about the specific mechanisms of SOC therapy. I'm sure I'm not alone in that. Then along comes your last post and the drachma definitely dropped, for me at least. Many thanks for the clarity of that description. It really helped demystify the central issue here. Much appreciated!

[Hepatitis Researcher]

Surprisingly, the circulating or otherwise existing in the extracellular fluid virions are only of relevance insofar as they can reinfect new, uninfected hepatocytes , from the blood passing though the liver.
All virions that do not reinfect are of importance only insofar as they (or better their processed remnants, taken up by macrophages and dendritic cells.) act as a trigger to the peripheral immune system to produce cognate CTLs and helper T lymphocytes.

The immune system and IFN or riba does not have any direct effect on circulating virions ( with the minor exemption in the case of HCVs minor neutralizing antibodies), nor would such an effect be of any importance in the fight against the infection, unless it would reduce the number of circulating virions to such numbers that reinfections could not occur anymore, (which is a very small number).

There is really no "virus killing' going on outside of the liver in the sense of an active, therapy induced destruction. Circulating virions have a short life and die by themself in huge numbers, a small number only makes it back to the liver and finds a fresh hepatocyte to infect and to start a new virus producing intracellular machinery.

The therapy is directed against and works by:
1. Eliminating  Infected hepatocytes by CTL mediated killing
2. Noncytolytic elimination of the intracellular virus machinery by induction via CTL produced gamma IFN or therapeutically induced IFN alpha.
3. Killing of hepatocytes, infected or not, by unspecific "bystander" inflammatory mechanisms caused by the unspecific proinflammatory intrahepatic infiltrate ( In the biopsies seen as portal infiltrates and "necroinflammatory" activity).

4. The prevention of reinfection by anti HCV antibodies binding to circulating virions is not of major importance in the dynamical fight of the immune system against HCV. For that reason hyperimmunserum "HCIG" does not effectively prevent reinfection after transplantation. Currently, two companies are trying to develop a pair of strongly binding anti HCV monoclonals in the hope to improve upon this mechanism to prevent reinfection after transplantation. Transplantation BTW is the one moment in which the  extrahepatic virons DO come into play, becuse they reinfect the new, vrgin liver.

[geterdone]

So what has changed is, is in the initial up dosing of the combo it has or should have eradicated all most all of the virions in the first 12 weeks of TX for (responders speaking) as UND, and for the remainder of TX is for the remaining TX time is for the body compartments and or organ components in which the virus may or may not find their way back into the blood stream and this is why the post PCR are needed to see if any remaining virions have reentered the blood stream which leads us back to the taper down Theory, at least for me anyway.

MH must be working on the site because it is sure slow tonight.

Thanks!
jasper

[geterdone]

So the INF is injected into the body’s intercellular fluid (or makes its way into) and to combat the virus in these fluids and also be absorbed into the blood stream which is why it takes time to build up the INF concentration with in the body. The Riba on the other hand is ingested and absorbed through the intestines and works in reverse by being absorbed into the body. So the virus works in the same way to some extent because some virions make their way through the blood vessel wall in to the body through various channels of the blood vessel which makes it harder for the INF and the Riba to find and explains for the long duration of the treatments.

jasper

[alagirl]

Cruel - How can I put this politely?  Oh what do I care about being polite, I'm sick and hurting and I've had the same migraine for almost three weeks now.  I think the girl at labcorp likely may have lied to you, or at least, "overexpressed" the frequency with which she sees these viral loads quantified at just three and four, kind of like my nurse practitioner lied to me prior to my commencing treatment when she told me that they had a HUGE practice with 400 HCV patients and several "acute" patients (actually, they have only a handful of HCV patients and no acute patients.

If, HR, you are saying that there are areas in the body where viruses could hang out in the blood larger capacity, I suppose I agree with this, but I have to think that diligent repeated and sensitive testing would eventually ferret that out.  I get viral loads at least every four weeks if not more often.  Basically, whenever I begin to feel paranoid.  I test.  

It's mostly for my mental health, less for my physical health, I think.  My doctors know I'm neurotic.  They're either pretty decent about it or they just don't want to argue with me.

[Hepatitis Researcher]

The 30% chance was only referring to the 1ml of serum investigated in the test. You could still have 3000 viruses in the non tested other part of the blood and also there will some be located  in the interstitial fluid - outside of blood vessels but also out side of the bodys tissues. that is at least 10 more liters of fluid where a virus can be, although the concentrations in this interstitial space should be less than in the circulation, since the virus is at least partly confined/blocked off  by the endothelium lining of blood vesels.
Note however that in the liver this otherwise fairly tight endothelial lining has numerous large holes (fenestrations)  - to allow better access of plasma components to the liver cells, that actually for this reason  come in direct contact with the plasma alongside the sinusoids, this way there is no barrier for viruses  in the liver capillaries at all.

[jmjm530]

Difficult to answer, because first of all it's not known whether viral load detection alone can predict SVR, no matter how sensitive a test you use.

Let's say you did a 100 vial test -- or even a 1000 vial test -- and were UND at let's say week 6, does that mean you can stop treatment and be assured SVR? Remember, that most of the predictive stats we discuss assume at least a short course of treatment for geno 1's which is 24 weeks using SOC drugs.

What seems more plausible is that detectible virus via sensitive tests at a certain week suggests relapse, as opposed to UND suggesting SVR, unless a certaincourse of SOC drugs is run.

The viral kinectics of SVR just aren't fully understood as is what happens when the interferon is stopped at EOT, either all at once or in a taper-off scenario. One can only theorize what occurs and the theories are in part colored by whether you believe SVR threatening virus are existent at EOT in an SVR, or not. In the former scenario -- more heavy lifting would be expected by the immune system at EOT. In the former, SVR (or relapse) is more or less written in stone by the time you stop the drugs.

-- Jim

[geterdone]

So, given both of these test and one down to 2iu and if there is a scarce remote possibility that even one lone virion has survived both test, and you still shows undetected in the 2 ml of blood sampled down to 2iu is there still a possibility or (error) rate that one virion has survived in the 2iu test and if the immune system is not fighting anything else it would seem that there would be a very good chance of remaining or obtaining SVR. But there is still that possibility that in a compromised immune system or even a healthy immune system, a one lone virion or virions in the other 3,998 milliliters of blood can still replicate when the trough is created by the sudden stopping of INF at the end of treatment, is there that possibility and giving hr’s 30% chance of no virus left there is still in reality a 70% chance there are in the other 3,998 ml of blood, am I reading all this right?

jasper

[jmjm530]

Results presented in a confusing way, i.e. why say "unable to calculate" when they seem to mean -- and also say -- UND to limit of quant but if both tests were taken at the same time it has to mean you were UND.

Anyway, I agree that the important part is is the qual, i.e. UND to 2 IU/ml. My point before re the inexact quantification between 2 and 40 had more to do with what the tech told you on the phone re the incidence of 3's and 4's since the 3's and 4's are more or less estimated per HR's post while Heptimax appears to be directly quantified but I'm not even sure on that. As to your "89", that was not the TMA part of Heptimax, but the real-time PCR. I don't know the incidence of false positives, but I'd guess less than with the TMA portion. The actual error rate data might be available from the lab itself.