SVR Eradicates HCV

[mremeet]

Not sure if this has already been posted, if so it bears repeating:

http://www.natap.org/2008/EASL/EASL_77.htm

"SVR Eradicates HCV

SUSTAINED VIROLOGICAL RESPONSE IS ASSOCIATED WITH ERADICATION OF HEPATITIS C VIRUS AND DECREASE IN ANTI-HCV TITER IN PATIENTS TREATED FOR CHRONIC HEPATITIS C

Reported by Jules Levin
43rd Annual Meeting of the European Association for the Study of the Liver April 23-27, 2008, Milan, Italy

M. Martinot-Peignoux1, S. Maylin1, N. Boyer2, A.C. Cardoso1, M.P. Ripault2, N. Giuily2, C. Castelnau2, M. Pouteau2, P. Bedossa3, P. Marcellin1,2 1 INSERM, U-773, Centre de Recherche Biomedicale Bichat-Beaujon CRB3 Hopital Beaujon, Clichy, 2 Service D'Hepatologie, Hopital Beaujon, Clichy, 3 Service D'Anatomie Pathologique, France

ABSTRACT

Background-Aim: Hepatitis C virus (HCV) eradication, in patients with chronic hepatitis C who achieve a sustained virological response (SVR), is still controversial. In this study performed in patients with chronic hepatitis C who achieved an SVR, HCV-RNA was measured in serum, peripheral blood mononuclear cells (PBMCs), liver and anti-HCV antibodies titers were assessed, during follow-up.

Methods: 278 patients with an SVR after treatment with IFN alpha-2b or PEG-IFN alpha-2b+ribavirin, were studied. HCV-RNA was tested: in serum for all the 278 patients every year and at the time of PBMCs or liver collection; in PBMCs in 71 patients 3.9±3.4 (0.5-10) years after treatment; in liver 38 patients 3.2±1.6 (1-5) years after treatment. HCV-RNA was detected with the VERSANT HCV-RNA Qualitative assay (TMA). In 142 patients HCV antibody titers were measured with the Axsym HCV 3.0 (Abbott), and with the third-generation HCV recombinant immunoblot assay (RIBA) (CHIRON RIBA HCV 3.0 SIA), before therapy and 4.7±2.2 (0.5 to 11) years after treatment. Liver histology was assessed in 92 patients with paired biopsies 1.4±1.9 (0 to 10) years.

Results:

Patients were followed up for a mean of 3.5±2.4 years (range, 0.5-17) years.

Serum HCV-RNA remained undetectable in all the patients (1050 samples).

None of the patients had detectable HCV RNA in the PBMCs or in liver.

The mean anti-HCV titers were 93±19 IU/ml and 45±21 IU/ml, before therapy and on the last serum sample available, respectively (p < 0001).

The most significant decrease was observed with anti-NS5 antibodies (p = 0.001); anti-c22 antibodies remained unchanged.

Normal serum ALT levels were maintained in 94%, fibrosis stage was improved in 57%, stable in 32%, deteriorated in 11% of the patients.

Regression of cirrhosis was observed in 7 of 10 patients.

Conclusion:

In our 278 patients with chronic hepatitis C and SVR, evaluated up to 17 years after treatment cessation, none demonstrated late relapse or the presence of HCV RNA in serum, PBMCs or liver.

HCV antibody titers showed a marked decrease. These results demonstrate a durable response to IFN alpha 2b or PEG-IFN alpha-2b+ribavirin and indicate that SVR is associated with HCV eradication and progressive decrease of anti-HCV."

[moahunter]

Wow - talk about opening up an old and bitter (but enjoyable) thread...

I think Hep C is gone for good on SVR, but heck, what do I know? That's what I want to believe anyway, since I am SVR. To me, it is a totally academic question, because there is no real possiblity of relapse, so why bother studying or worrying about it?

[debfromoakland]

I'm 3 yrs svr, doing great.  But, there's still the new new experiments where they are subjecting sero-neg, post inf, svr, immune cells to a "cocktail of mitogenic" stuff, and finding they are getting 100% of the subject samples to express some HCV RNA, and I think it's the neg-strand relicative stuff, and it's in the various immune cells, with different people having it in diff types of immune cells.  It seems that the reassuring stuff from Maylin, et al is not the same testing process, and suggests future immunocompromise or whatever cou;d wake the dragon.

[DoubleDose]

The above article alone is reason to be open to the concept of both 'occult' HCV as well as 'compartmentalized' HCV, both after SVR, in spontaneous resolvers, and maybe even in a portion of the population who have no apparent signs of HCV, such as antibody negatives, PCR negatives on serum testing, etc.  There are still riddles that are unsolved, and more to learn about HCV.  I continue to believe that the concept of either totally eradicated or 'infected', one or the other as our only descriptions, is both simplistic, given what we know, and is a limiting concept as far as future research.

DD

[mikesimon]

Tn,
my thoughts exactly.

mremeet,

Role of nucleic acid testing in cadaver organ donor screening: detection of hepatitis C virus RNA in seropositive and seronegative donors.
Aswad S, Khan NS, Comanor L, Chinchilla C, Corado L, Mone T, Mendez R, Mendez R.

National Institute of Transplantation; Los Angeles, CA, USA.

Hepatitis C virus (HCV) transmission by both seropositive and seronegative cadaver organ donors has been documented, yet nucleic acid testing is not routinely used to identify active infection in these donors prior to transplantation. Between November 2001 and February 2004, we screened 1445 cadaver organ donors for anti-HCV antibodies with either HCV EIA-2.0 (Abbott Diagnostics, Chicago, IL, USA) and/or Ortho HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ, USA) and confirmed seropositive samples with Chiron RIBA3.0 SIA (Chiron Corporation, Emeryville, CA, USA). Samples with sufficient volume (n = 726) were tested by the VERSANT HCV [transcription-mediated amplification (TMA)] Qualitative assay (Bayer Healthcare LLC, Tarrytown, NY, USA) which can be performed in approximately 5 h. Those with detectable HCV RNA and sufficient volume were quantified by the VERSANT HCV 3.0 (bDNA) Assay (Bayer Healthcare LLC) and/or the HCV RNA TMA Quantitative Assay (n = 23) and genotyped (n = 57). Seventy-seven of 1445 (5.3%) donors were seropositive, reactive by either one or both anti-HCV assays. Fifty-two of 63 (82.5%) of the seropositive samples had detectable HCV RNA and were genotyped. Seventeen of these samples had quantifications ranging from 128,123 to >7,692,307 IU/mL. Six of 663 (0.9%) seronegative samples had detectable HCV RNA. Their quantifications ranged from <9.3 to 1,464,799 IU/mL, and five of these six were successfully genotyped. As HCV RNA was demonstrated in samples from both our seropositive and seronegative cadaver organ donors, we are now incorporating nucleic acid testing into our donor screening/diagnostic algorithm.

[TnHepGuy_]

As one who gets to ingest extremely powerful anti-rejection meds on a daily basis, I'd imagine that you (or anyone else in similar circumstances) and your docs would be very interested to know if low-level replication were taking place in your liver. For example, in the case of an occult+ liver PCR - the attending physician would most certainly want to know if there was a chance of the virus roaring back when making dosage level decisions and/or new or differing anti-rejection med choices. Undoubtedly there are other scenarios where this could be the case also: lagre doses of steroidals, etc.


TnHepGuy

[mremeet]

"I apologize for the fact that I will not investigate that issue. I've had enough of that stuff for a while."

LOL Well I'd say you're off the hook, and I don't blame you for not bothering to check. But if (1) you've consistently tested serum UND with heptimax for more than 4 years running, especially (2) considering you've probably been taking immunosuppressants of one type or another during all this, and (3) you have teen-like enzymes, I'd say that should be good enough for just about anyone.

As another aside, I wonder if the donor liver or blood is tested using PCR? Normally I think of PCR results as having a rather long turn around time, and considering the shelf life and dispersion of donor livers (i.e. they may not all be located in a place where timely PCR testing can take place) it might not be feasible. Wouldn't surprise me if they simply check the donor's serum for HCV antibodies, and if + the liver is assumed to be HCV+. Especially considering the ongoing controversy about viral persistence anyway (similar to how HCV antibody positive people can't donate blood).

[mikesimon]

I was HCV positive prior to transplant. I was transplanted in June 2000 and I was diagnosed in January 1995 after a major variceal bleed.
I received an HCV negative liver. I saw that pathology report.
I treated within 2 months with regular interferon 3 x per week and low dose ribabvirin for 1 year. I didn't clear.
6 months after stopping my first treatment I retreated with standard dose Peg-Intron standard dose and low dose ribavirin for 53 weeks. I cleared late and relapsed immediately.
I treated a third time within 3 weeks of my second treatment. I treated for 73 weeks with standard dose Pegasys and weight based dose ribavirin. I cleared at week 12 or possibly week 11 and stopped in June 2004. I first tested undetectable in April 2003 and have never tested detectable since that time and I have tested every month since stopping in June 2004 with Heptimax <5 IU/ml.
I do not recall the particulars of the pathology report on my donor's liver. Since it was a cadaver liver I assume a PCR was performed on the tissue since no serum was probably available at my center. That is a good question though. I apologize for the fact that I will not investigate that issue. I've had enough of that stuff for a while.
Mike

[mremeet]

Thanks for the clarification on the biopsy PCR results. I don't recall your entire history, I know it has many twists and turns though (this being one of them). One thing I was curious about though: Did you have HCV prior to your transplant and managed to SVR shortly thereafter? (via SOC) Or you did have HCV but managed to SVR just prior to your transplant? I can't remember what exactly happened. And the thing I'm wondering about, is that since people who have HCV (or test + for HCV antibodies) can and do donate livers upon their death - and considering that you would probably show up in the transplant recipient database as either having or had HCV, would that mean that you might (or would) get a liver from an HCV+ (or antibody +) person? Maybe you didn't and received a liver from a "clean" person never infected with HCV (SVR or otherwise). But considering the relatively close sequential timing of your treatment, SVR, and transplant combined with some possible bureaucratic chaos in how you may have been classified in the transplant database, I might be a bit concerned about the possibility of getting an infected liver, or perhaps a liver from an SVR which may have "persistent" virus in it.

But maybe not and you know for an absolute fact that your new liver was clean - just a thought I was curious about that may play into the whole confusion. I also wonder how new livers that become available for transplant are screened prior to transplant. Do they perfrom a PCR for HCV on them? Or simply measure for HCV antibodies? Or....???

[mikesimon]

Well we agree on that. I wouldn't have had a biopsy if I didn't have a problem. And that's why I won't run out and get one now. I don't mind them that much but it's not my favorite way to spend an afternoon either. And, you're right. Regardless of the results I cannot do anything about it. The point is I had the biopsy because my enzymes were elevating and I was also an SVR. Let's agree that a PCR of my tissue should have been done. If it ruled out HCV then it would have been far more likely that I was experiencing "some minor component of rejection" as the chief pathologist put it. And that would have been useful to know for many reasons not the least of which is to shed light on my chances to wean myself off of all the AR meds. Mike

[jmjm530]

As stated in probably what were crossed posts, I do agree with your decision and might do same in your shoes. But no, personally, I would not do it for myself for reasons originally stated nor in fact would I have another biopsy unless the docs felt my liver was acting up.

[jmjm530]

Our posts probably crossed but that's pretty much what I said in my last post to Mike.

[mikesimon]

Well Jim, I'm not running to get a biopsy so it's not an urgent matter. I am only saying that if I got another biopsy I would definitely insist that the tissue be tested for HCV. If you were to have a biopsy wouldn't you want the tissue tested? I think most of us would like to know as much as we can even if there isn't anything we can really do about it.
I want to know this stuff and what better place to learn than my own liver - particularly with my history. I would have thought my surgeon would have wanted to know for certain whether HCV was active in my liver. Looking back I think I was rejecting and it was as simple as that. Distinguishing acute rejection from HCV on biopsy is very difficult because they look the same. So how could the pathologist have known what was causing my inflammation and fibrosis? All the pathologist had before him was my age, my underlying disease and the date of my transplant. So he called it HCV. Perhaps if he had in front of him my serum undetectable tests since April of 2003 and my recent AR dose reduction he might have called it acute cellular rejection. I think that would have fit just as well as HCV.  
Basically we get a biopsy to learn about the state of our liver. A PCR of the tissue just adds to that information so it should have been done without question.
Mike

[nygirl7]

Jim

I think it might be easier for you or I to let bygones be bygones but with someone who's been transplanted it might be a bit more of a pressing concern.  We haven't dealt with nearly the physical or mental aggravations and pain - personally if they were gonna be in my liver I'd feel like what the heck you might as well but if I'd been through the whole mess that he has...I'm pretty CERTAIN I'd want it done.

[jmjm530]

Let me take that back. In your very specific case -- liver transplant -- maybe the data could become useful in some very specific scenarios where a decision to use interferon again might come into play -- such as what happened last time. In other words, if they didn't find HCV in your tissue then it might make less sense to use interferon, but I'm way over my head in this area so please take this as speculation from someone that really doesn't understand the transplant and post transplant process.

[jmjm530]

My main point was what would you do with the info once you had it?

To my knowledge there are no tx protocols for people who are serum UND but liver tissue positive.

Personally, I would leave my SVR as SVR until someone showed me the clinical relevance of looking beyond, i.e. to leave well enough alone.  Not so much that "ignorance is bliss" but that more data without underlying clinical relevance doesn't really get you anywhere.

That said, I respect your desire to know "the real facts", and do let us know what you find out if and when the time comes.

-- Jim

[mikesimon]

I figure that if they are going to take a tissue sample of my liver then they should test it for HCV. That seems so obvious to me I wonder whether I am understanding your question. I like to know as much as I can about me, my liver and HCV.
If your point is that there are more specific tests then the PCR that would probably be used I agree with that. But, if that is the threshold for testing why do we even get serum tests? We used them in the past when they were less sensitive than they are now and the current tests will likely not be as sensitive as they will be in the future. You use what you have. Mike

[jmjm530]

Willing: "...You might ask (your doc) was the last time he picked up a pipetman.
-------------------
But he's both married and straight. Maybe a pipetlady in his younger days.

[jmjm530]

Mike: He said "don't trust anyone" and I replied "except you, right?" and he said "no, not even me".
------------
Are you sure your surgeon isn't James Bond? Daniel Craig uttered similar to "M" at the end of "Casino Royal".
----------
Thanks for the detailed summary but curious why you would want a PCR of your biopsy tissue, esp in lieu of no other clinical problems.
]
If it's UND, that's great, but as DD will probably tell you , it still doesn't mean you are UND if  using ultra sensitive testing (in serum and/or tissue) that has been used only in studies, should you be in that camp.

And if it's positive, so then what? How would that alter treatment or your life? I doubt they would put you back on interferon if serum UND, unless you had other clinical issues. I personally see it as a lose-lose proposition until there is more understanding of what these things actually mean if they mean anything. Anyway, that's just my personal take, I'm sure you have your reasons.

-- Jim

[willing]

>my specialist works at the main pond
no matter how good you are, it's hard to be in two places at the same time. If you're seeing patients, you're not at the bench, no doubt part of the reason pathologists are so hard to reach. Next time you  see him, you might ask when was the last time he picked up a pipetman.

>make you stubborn as a mule
I suppose I should be grateful it's not a horse joke, but yes, I've already been warned in that regard... and thanks for the h pylori tip!

[mikesimon]

My surgeon thought it was HCV before even seeing my biopsy report - just by seeing the enzyme history.

I really don't know what to think about me and HCV. I can tell you that I was really surprised when the chief pathologist gave me the story. I just wanted to know the specific molecular test that showed HCV. I was floored when he told me there was no test. If I gave you the pathologist's name and you Googled him you would be amazed at how much he publishes and the complexity of topics he addresses. This man is one of the preeminent pathologists in the country so when he told me that "negative serum HCV RNA testing does not mean that the liver tissue is negative for HCV" I have to believe that he has seen it in his lab on more than one occasion.

To be clear about this I never asked my surgeon this specific question. I haven't even seen him since the biopsy results so I cannot say that he intentionally or negligently misled me. Maybe hes seen so many serum undetectable patients show HCV on biopsy that he just accepted the results as accurate. When I first posted the story about my biopsy Jim and willing wanted to know what test was used and I started investigating. When I saw the disclaimer regarding molecular tests which were not FDA approved but were developed at my center I figured that one of the listed tests was the one that was used. At the time willing and I were in touch with one another and it was willing who called my attention to the fact that immunochemistry-based detection of HCV proteins in biopsy samples is possible and that the language on my biopsy report contained references to those types of tests. That's what I thought the pathologist was going to tell me - which specific test was used. Suffice it to say that I am not happy about this. Since I have been serum undetectable since 2003 and stopped TX in June 2004 I think a PCR of my liver tissue in June 2006 would have been more than reasonable - it should have been mandatory. My surgeon was out of the country when the biopsy was ordered so I can't necessarily blame him for the order although I don't completely absolve him of responsibility either. But after he saw the results he should have sent me immediately to get another biopsy with a tissue PCR to be certain about what was causing my enzyme elevation. There's nothing to biopsies as far as I'm concerned  - except the results that is. I really don't know exactly how many I've had because I have had a bunch. And they sure aren't anything to the surgeons - they order them all of the time at the drop of a hat. I think a PCR should have been done on my tissue without question. The fact that it wasn't does trouble. I am reminded of what my surgeon told me just 2 or 3 days after my transplant. He said "don't trust anyone" and I replied "except you, right?" and he said "no, not even me". It does seem that the older I get and the longer the relationship the greater the likelihood of disappointment. If I have learned anything through this is that my surgeon was right when he told me not to trust anyone. And the mistake I made was to trust. When my AR dose was being reduced (it was a weaning off process of all AR drugs) I thought that the reduction that triggered my problems was too drastic. I also thought that testing every two weeks following the dose reduction was not frequent enough. I thought I should be tested every week.  I did question the 2 week testing interval but I finally acquiesced to it because I trusted my team despite the fact that it just didn't seem like the prudent course. I will try very hard never to make that mistake again. I believed that I was too seasoned a patient to allow something like this to happen to me. And, I know that I am far more experienced than most patients and I cringe when I think of what other less experienced and less knowledgeable patients might permit and acquiesce to. It's a jungle out there and particularly so when you're sick.

Maybe ignorance is bliss in my case but I always do like to know what the real facts are - even if they aren't encouraging or favorable

Mike

[jmjm530]

Willing:...l ike Jim's specialist, who work further downstream (for many Dr's, the personal definition of cured probably comes down to the fact that they never see SVR patients again).
---------------
Actually my specialist works at the main pond and I'm still seeing him two years after SVR. Do watch out for those oats btw, they can make you stubborn as a mule :)

[willing]

CS : thanks for the explanation; yes, given that the study is reporting results on patients who had never undergone tx,  SOC protocols seem irrelevant to the findings

all: interesting twist in a various ways : the assumption that the inflammation is HCV-related and the pathologists' comments, however,  on a personal note, it's got to be good news!

The discrepancies between what reputable specialists have to say on the topic underscores for me that the issue is still very unsettled, hence the ongoing controversy  on this forum and in the published literature is not idle bickering.

Personally I tend to give more credibility to those working at the lab-bench/microscope, like Mike's pathologist, than to clinicians, like Jim's specialist, who work further downstream (for many Dr's, the personal definition of cured probably comes down to the fact that they never see SVR patients again).

[DoubleDose]

Your comments are really good news, especially from your personal perspective.  In the few studies that I have read regarding positive hepatic virus and negative serum virus, after treatment, I do believe that the LFT's were somewhat abnormal in the liver positives.  I can't imagine that with LFT's consistently in the teens that you would have active or chronic virus in the liver.  You sure have a great shot at good news, anyway, since you had no PCR of tissue, and now understand that there was no confirmation of active virus other than some circumstantial inflammatory signs in the liver tissue.  I would think that to be probably typical.

I do think that the issue of persistence probably is a little different from the issue of positive/ or negative hepatic tissues after SVR, in that I would think the persistent viral matter would be sub-detectable (if there is any actually there), and would need extreme amplification to detect.  It would likely be in various other organs and tissues as well.  The real question ends up being one of 'accurate PCR test results with true low level replication, vs. some other manifestation or contamination that shows up as 'replicating virus' on extreme PCR amplification.  I am uncertain if either position has much certainty at this point, which is why I remain open to final determination by scientists.  Although some of us are said to be in the 'viral persistence' camp, I would characterize it as the 'open to the concept of viral persistence, as research has frequently suggested' camp.  At the same time I sense that others are in the 'absolutely sure it is eradicated, and totally cured' camp.  That is just fine with me, and it is their right to hold that opinion.  In fact, I really hope that they are right!

I think the issue of liver infection, with a positive PCR using ordinary testing is another subject apart from 'persistence' and may be related in many ways, or more similar to Occult HCV, or they may all be manifestations of the same thing, just moving on a continuum from very invisible to very obvious.  

I hope that when and if you do the biopsy/ PCR that you end up seeing only a big goose egg!!!  I think you will!  

Thanks for the candid retraction and clarification...it puts everything in a much nicer light for you, and for us!  Your surgeon does seem to see the possibilities for different viral outcomes, and SVR behaviors, and that in itself is another red flag waving toward the need to further study 'occult', AND 'persistent' HCV.  I believe this, anyway.

DoubleDose

[mikesimon]

No - and I was tested 1 or 2 weeks before and 10 days or 2 weeks after. I would have to check to be precise about the time but both the before and after were absolutely positively within one moth of my biopsy.

Yes, there was no PCR or molecular testing of the tissue sample so that question is up in the air - whether there is any active HCV in my liver.

I don't know when I want another biopsy. It's not the procedure that scares me - it's the results. My enzymes have been consistently in the low teens since they normalized and I get a whole lot of labs - every two weeks. So I think I have a clue about my liver healthy without a biopsy.
But, when I do get one you can be sure the tissue sample with undergo PCR testing - without question.

All is well on this end and I hope that you and your family are well also.

Mike