Why does the virus come back with vengeance after

[geterdone]

a relapse occurs in most patients and what could be done differently to change the out come?

[BThompson4]

Thanks everybody for your encouragement.  I've had hep c 35 years, and though not always very good times, my new liver is still in pretty good shape (F1 fibrosis) seven years after transplant.  I am blessed to be in this position, having seen a couple of  friends' transplanted livers eaten up quickly by the virus.

Mr Liver: maybe your new liver will do better than the old one with a future tx with SOC or a new cocktail .  I used to be kind of upset that I got an "old" liver at transplant (I am 52; the liver is 60); but the transplanted liver sure did respond nicely to only 36 weeks of SOC (went from F2 in June 2005 for F0-F1 on March 6, 2007,  which was week 36 of treatment).  This disease can have unpredictable outcomes.  I hope you have great results with your new liver!

[willing]

OK,  as a fellow relapser,  it's my turn to get my a** off the bench and do a little cheerleading dance. True that this past year was somewhat of a  disappointment on the new drug front. As someone waiting  for combo tx that includes  both  protease and polymerase inhibitors I'm not sure '07 made any reduction  in my projected 10 year wait. However...recent progress on the anti-fibrotic front is really impressive.

Focusing on eliminating the virus can get compulsive but is a bit like obsessing over a bad video game. If fibrosis is sufficiently contained, there's a reasonable chance one can happily cohabitate with the virus indefinitely...and while that road is not as straightforward as signing up for soc, there are pretty good indications to follow per hr's recent posts.

[Mr Liver]

I am sorry to hear of your relapse. I'm on the waiting list and needless to say this circumstance is of great concern to me. I have failed tx twice and I am hoping newers meds will come to my rescue,as well. I wish you well and I hope the newer meds can make a difference for all of us who need something more that SOC.
regards,
Mr Liver

[sfbaygirl]

Interesting thread...but since most of us are way past that acute stage, I had to skip some of it.  Wish I had tx'ed then,  but there were no tx's when I was acute.  

Just wanted to add to my list of what I would want next tx.  I would double dose, besides tapering.  Get rid of those virons quickly at first. I think this is important, perhaps my take, but it is.   I wasn't clear at week 12, had a VL of 6 mil. It is the same now and when I relapsed.  Not sure I would want to do the infergon route,  but maybe.  I am layed out on tx anyway, why not?  When I saw HR, he went into more detail about tapering.... I would do this. There are ways to get Alina from other countries, while expensive, I would sure do it if I could.  

BT; So sorry about your relapse!  Susan;  you hang in there girl, something will come along to get you to SVR.  

Hugs to all!
Linda

[sfbaygirl]

I remember HR saying it was not good to just stop interferon, it should be tapered. Since I had to stop ASAP, I didn't get to do this. Still afraid of the stuff!  

I know if I retreat with the same drugs, I will find someone to get me the Alina. Hopefully the VX will be around by then too.  Thinking about re treating is hard, I still get chills just thinking about doing this again.  John would kill me, so maybe I wouldn't last long anyway! lol  I like Jim's low VL statements. It would be great if my ins. would pay for lots of PCR'S  pre tx.  

I haven't read the whole thread yet. Wow is it long.  I guess I won't be bored tonight!  

All of us relapsers have a tough call and I hope we all SVR soon!  

Best to all!
Linda

[willing]

interesting points indeed, however:

- as noted in the reply to the Berg letter, and as is routinely posted here, SVR is durable but not impregnable. I know of no reason to assume the recovery obtained spontaneously differs in that respect from that obtained via tx. As  noted in the reply: the recurrence observed by Berg "appears to be an infrequent event" and "Viral recurrence may also occur after successful viral elimination by antiviral treatment.".

- Both the medscape article and the  "may take up to 18 months, or possibly even longer" summary by Liz Highleyman seem to refer to  

M Micallef, JM Kaldor, GJ Dore. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. Journal of Viral Hepatitis 13(1): 34-41. January 2006.

a meta-study that simple collected previous publications. In turn their finding of prolonged post acute infection seems to go back to

Larghi A, Zulin M, Crosignani A et al. Outcome of an outbreak of acute hepatitis C among healthy volunteers participating in pharmacokinetic studies. Hepatology 2002; 36: 993– 1000

which tracked an unusual outbreak of HCV among volunteers participating in a study via in-lab PCRs.  As noted in the letter by Oldach accompanying that paper,

"It is striking that viremia was still detectable at 8, 13, and 24 months, respectively, in 3 of their patients who nonetheless went on to achieve spontaneous viral clearance."

On the other hand that recent Afdhal study I noted above, to avoid treating patients who might already have cleared, followed their patients quite closely to detect clearance point: "  To avoid unnecessary treatment of those patients who might achieve spontaneous recovery, all eligible patients were enrolled and screened for an initial observation period of 8 to 12 weeks. During the observation period, biweekly serum ALT HCV RNA analyses were performed"
and they observed "No patient in the no-treatment group had spontaneous resolution after week 14. Of the 131 patients who consented to therapy, 29 (22%) achieved spontaneous resolution of HCV infection during the observation phase and did not receive treatment. "

that is spontaneous resolution, when it happened, was by week 14 or earlier.

Overall, the Afdahl'06 and Largi'00 studies seem at odds. I tend to believe the former because of the larger sample, regular testing  and reliance on a well-calibrated  test (COBAS AMPLICOR TM HCV, version 2.0, Roche, lower limit of detection of 50 IU/mL), and OK , I just trust stuff out of Harvard.  However, I have to agree that Larghi'00 definitely raises the possibility of a much longer window for spontaneous clearance.

[susan400]

Short of a miracle, I'm not holding out for any spontaneous clearings of my HCV.  I've been chronic active for too many years now and I think its more likely to NOT happen, than to happen.  

Susan

[jmjm530]

"...(HCV Spotaneous) Clearance, if it occurs, usually happens within 4 months, but may take up to 18 months, or possibly even longer..."

http://www.hivandhepatitis.com/hep_c/news/2007/121107_b.html

"...Although viral clearance generally occurs within the initial 6 months of infection, recent studies have suggested that spontaneous clearance extends beyond this point.[7,34,35]"

http://www.medscape.com/viewarticle/521187_4

[jmjm530]

This letter from Berg may be of some interest in the unpredictable nature of RNA testing in the acute stage. While not matching up to the previous study -- a positive followed by an UND, then positive, then UND -- Berg does talk about postiives following negatives (viral relapse in spontaneous clearers) in a couple of patients where no prophlthiouracil type of treatment was present. Since we know that SVR is durable as measured in serum close to 100%, then these acute relapsers point out some of the differences between let's call it a spontaneous acute cure and a drug-induced chronic cure, suggesting that we can't make the "cure" call for an acute too quickly, as the authors of the first study apparently did in order to contrast it with what they contend is a  prophlthiouracil-induced relapse. No cure, no relapse.

-- Jim

http://www3.interscience.wiley.com/cgi-bin/fulltext/106595829/PDFSTART

[jmjm530]

Willing: Your interpretation, if I understood it, is that the infection did not resolve spontaneously until at least week 26 and that the 2million,UND,140,000 readings prior to that are inconsequential fluctuations.
-------------------------------------------------------------
In part yes, except that I wouldn't consider the 2 million an "inconsequential fluctuation" since that was week 1 baseline, therefore only the 140,000 IU/ml and week six UND appears relevant as inconsequential fluctuations until an unreversable UND took place. True, the propylthiouracil was administered at week six with a following viral load of 140,000 at week 21, but this can be argued more than one way. The author's argue propylthiouracil-induced relapse, but equally plausible is that the acute process wasn't complete at that point and/or simply delayed by the propylthioracil in this elderly patient.

Willing: Of these, none achieved spontaneous clearance after 14 weeks so assuming this guy only cleared after 21 would be quite a stretch.
------------------------
The 14-week figure seems a bit short, but I'll have to accept it until I do some more digging. But note that this patient was genotype 3A who I believe have higher rates of spontaneous clearance and therefore might clear later than the 14 weeks stated.

But to a prev point, with most certainty none in the study were treated with propylthiouracil and developed leucocytopenia which could have changed the normal acute clearance curve.

I'll get back if I come up with more relevant acute studies. Thanks for the discussion. I mean, who really knows.

-- Jim

[willing]

well I suppose it depends on your hypothesis about the underlying mechanism that accounted for the measurements observed. The study authors seem to believe the infection had resolved spontaneously by the week 6 test only to resurface on a week 21 test, quite possibly because of the immunosuppressant meds, and to then disappear again, permanently.

Your interpretation, if I understood it, is that the infection did not resolve spontaneously until at least week 26 and that the 2million,UND,140,000 readings prior to that are inconsequential fluctuations.  I couldn't see the data that backed that slide 9 from Friedman's presentation, however, the course of acute infection seems quite well studied,  though obviously there's less data on it that for chronic. See for example,

Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, El Gohary LA, Ramy AH, Madwar MA, Rasenack J, Afdhal NH.

Duration of peginterferon therapy in acute hepatitis C: a randomized trial.
Hepatology. 2006 May;43(5):923-31. Erratum in: Hepatology. 2006 Oct;44(4):1055.
PMID: 16628640

In their study of 173 patients "with proven acute HCV infection", the overall spontaneous resolution rate was 23%, on target with expectations. Of these, none achieved spontaneous clearance after 14 weeks so assuming this guy only cleared after 21 would be quite a stretch.

It's just one case and there's no sense reading too much into it. However, unless you're inclined to throw it out as bad data, it supports the view that even for someone with the "right" CTL response, the virus persists and can be induced to rebound.

[jmjm530]

Here's the Shiffman Slide Presentation -- See Slide 9 -- Free Reg required at Clinical Care Options Site:   http://webcasting.clinicaloptions.com/p41111200/

As to the "bouncing" -- isn't the 140,000 IU/ml  the only relevant number since that is the first Detectible following an UND.

Anway, as I thought I was clear in the first post, I'm not hanging all my hats on the intermittent viremia thesis -- maybe just the Stetson --- but hanging more of them on the understudied nature of the whole acute stage/spontaneous remission process, as explained in a previous post that might have crossed your last post.

-- Jim

[willing]

Mike :  hey, I've always been a fan of the "reasonable man" standard. I'll be happy to sit on a jury with you anytime! Hope you had a good holiday are are well. My reservations about the cause have to do with the fact that the VL was detected almost 3 months *after* he stopped taking the immunosuppressants, but after all this guy was 69 - he's entitled to take his time.

Jim: OK, I'll poke around and see if I can dig up something about VL fluctuations in spontaneous clearance during acute stage (maybe that Scott Alaskan paper?)  but I'm fairly certain bouncing from UND to 2-million (over a range of 6 weeks no less) is *not* part of the normal process. Fluctuations in antibody rates seem well studied so presumably there's something about VL as well. However,   if that were the case I don't see how their paper would have gotten past peer review ( you can get the full text by clicking on the pdf icon in that link you posted)

[jmjm530]

I'd have to take a look at the full-text, but will give it a stab anyway...

Given that the viral load went from DECT  (week 1) to UND (week 6) to DECT (week 21) to UND (week 28) and UND (week 47)...

Given these numbers, isn't it possible that what we're looking at is either: (1) one of a number of "normal" patterns in spontaneous remission, a phenomena that is studied nor understood all that well; or (2) that the introduction of this drug temporarily interferred with the pattern of spontaneous remission which was in progress.

In either case, I don't see how this supports the occult/persistent virus thesis because it's still unclear to me that the virus was entirely eliminated based on a single result of 140,000 IU/ml during the acute stage/struggle. As to the intermittent viremia -- a separate argument -- I would not call 140,000 IU/ml "whopping high" but think it could fit into Schiffman's thesis is intermittent virermia during the acute stage.

-- Jim

[jmjm530]

meant to say in part "....I'm not sure if intermittent viremia during the acute stage necessarily means that the virus can't be  high at times such as presented here"

[jmjm530]

Nah, fell asleep before the ball fell, most be getting old. LOL.  

No, I think the acute stage -- and it is understudied because so few are caught in the acute stage -- taints this whole study, err case history. They simply don't understand the dynamics of how people clear the virus naturally. Does it happen all in one swoosh? Or does it happen in multiple swooshes? Also, I'm not sure if intermittent viremia during the acute stage necessarily means that the virus has to be high. Doc Shiffman explains it more in detail over at the Clinical Options site and btw these are not "false results" but rather viral behavior during the acute stage. Again, not aruging the whole occult thing here, just this one particular study.  But hey, now that the sensitive viral load thing has been put to rest, it's good we have something else to disagree about :)

Oh, how about a tiny link to the full-text free access. Thanks.

Be well,

-- Jim

[mikesimon]

I have to agree with you - of course, you knew I would. Here was what I was working on to post to Jim:
While I am not necessarily disagreeing with your analysis I think that, assuming that your take is right, it does seem odd that this patient tested 2.3 million IU/ml at week 1, then negative at week 6, then 140,000 IU/ml at week 21, then negative at week 28 and negative again at week 47. You can call it quirky and/or acute but to see virus then no virus and then virus and then no virus seems noteworthy. We've seen no virus and then, upon relapse, we've seen virus back but, then it's back to stay. I am not including either false positives or perhaps a few virions hanging on - which we may have seen with a few members here. This guy's 21 week VL was 140,000 IU/ml.

I saw your response and stopped, seeing how much better you did than I was doing.

Be well and happy - both of you guys.

Mike

[willing]

Best wishes for a happy new year (and many more!). I suppose subjective assessment  of the strength of a piece of evidence is why we rely on juries.. but IMHO this is a pretty straightforward case (the whole article is open access BTW)

- the acute stage of infection *is* in fact well-studied; it just doesn't come up much around  here.. we've all gone through of it, this guy, probably thanks to a vigorous CTL response was one of the lucky 20% who cleared on his own.

-  HCV-RNA and other test results are  given at the close of the paper (see their Table 1). The readings indicate that when first admitted for some post-surgical trauma  he had whopping high LFTs and high-end VL of 2 million. Also pancreatitis.

- he recovers from the perforation and pancreatitis and is discharged. Six weeks later they seem him, quite possibly to follow up on the HCV, and lo and behold it's gone. Note that  LFTs, while still out of range are an oder of magnitude better. But they find another problem, with his thyroid, and start him on propylthiouracil for which documented side-effects are a reduction in white-blood cells.

- sure enough, by week 10 his leukocytes are way down and they stop the thyroid meds

- at the next follow up, week 21, the white blood cells are back in range but now the HCV-RNA is back! (140,000) and the LFTs are way out of range again

- the next two follow ups at weeks 28 and 47 show the hcv gone and everything back to normal.

Arguing for false results on the hcv-rna tests is pretty thin ice : the VL readings are whopping high values, not  borderline . More importantly they correlate well with the LFTs.  Of course none of this is conclusive but their conclusion that suppression of immune function by the thyroid meds led to temporary resurfacing of the VL at measurable levels seems quite sound. See also the other references of immune-suppression HCV rebound they cite.  "It is generally believed that hepatitis C virus is not completely eliminated from the body but is under control of the immune system." The fact that all this happened without the benefit of SOC seems to just underscore that the whole HCVhost "truce" is not limited to SVRs.


Perhaps the champagne fumes are still having an effect??

[jmjm530]

Third paragraph from bottom -- meant to say "...positive following a negative..."

[jmjm530]

I read the abstract here: http://www.jmedicalcasereports.com/content/1/1/169

The patient was diagnosed with Acute Hepatitis C, with classical symptons of elevated enzymes, jaundice, etc. and a positive HCV RNA. Six weeks later he was UND. He was then treated with propylthiouracil and developed leucocytopenia and the virus returned at what appears to be week 28.

To me, this is a very narrow case study -- acute stage, no treatment, etc -- and does not support "old virions never die, they just get clobbered".

In fact, it doesn't even support the author's own conclusions: "his case history shows the risk of recurrence of HCV during leucocytopenia. These findings indicate that patients who are anti-HCV positive but HCV-RNA negative may be at risk of cytopenia-induced HCV reactivation."

The assumption here is that the HCV was REACTIVATED during leucocytopenia, but given the quirky and understudied nature of acute HCV and the dynamics of  spontaneous remission, etc -- it's unclear to me if indeed the HCV indeed every went away. (And you can't have reactivation if the HCV isn't first gone).

Besides again the understudied nature of acute HCV and the viral dynamics is the fact that during the acute stage of HCV, viremia may be intermittent, meaning it can move in and out of the detectible range. This alone could account for the neg following a positive.

I'm not saying that thsi occult stuff doesn't happen-- that's for another time -- just saying that this author's conclusions are not consistent with the author's own data, as often is the case with studies.

Hoping you would start off the New Year with something stronger than this in support of  the "occult". Anyway, hope you had a healthy and happy New Years and many to come.

-- Jim

[susan400]

I wish I knew why it happened, too!  Susan

[willing]

yes, on the basis of only an observed VL measurement I don't see how one could distinguish those two effects. Presumably the presence of neutralizing anti-hcv antibodies and other immune mechanisms for clearing extra-cellular virus could be measured separately and then used to gauge how much of an observed  VL reduction was due to suppressed viral production within infected cells but I don't know of a study that's done this. One of the things I'd like to get around to at some point is understanding hcv cell/blood correlation a bit better...

all: btw, here's another recent data point in support of the "old virions never die, they just get clobbered into silence " occult viewpoint (with free text)

Gruener NH, Raziorrouh B, Jung MC.
Recurrence of hepatitis C virus during leucocytopenia and spontaneous clearance after recovery from cytopenia: a case report.
J Med Case Reports. 2007 Dec 4;1(1):169
PMID: 18053213

[mremeet]

Oops, comp malfunction there. To finish...

To the best of my knowledge, effective antiviral therapy (that's capable of leading to SVR) does also curtail cellular virion production, doesn't it? And if this is true, then wouldn't the measured serum VL be an indicator of both circulating viral clearance and decreased hepatocyte production? I know you wouldn't be able to tell how much the production of new virions had been curtailed, but the measured serum VL would be dependent on both of those variables, no?

[mremeet]

"Unfortunately serum VL is a very poor estimate of  actual cellular infection. What's being measured is only the ability to clear extra-cellular virions from circulation and any damping effect on viral reproduction."

To the best of my knowledge, effective antiviral therapy (that's capable of leading to SVR) does curtail cellular virion production, doesn't it?


Changes in VL are a very useful  gauge of the body's response to  antiviral drugs (which is why they're so critical during the 1st 12 weeks)  but they don't say  much about the extent of  underlying  cellular infection.