Not sure if this has already been posted, if so it bears repeating:
"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
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.
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.
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."
Eradication of Hepatitis C Virus in Patients Successfully Treated for Chronic Hepatitis C.
Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, Giuily N, Castelnau C, Cardoso AC, Asselah T, Féray C, Nicolas-Chanoine MH, Bedossa P, Marcellin P.
Université Paris VII, Hôpital Beaujon, Clichy, France; Service de Microbiologie, Hôpital Beaujon, Clichy, France; INSERM U-773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Hôpital Beaujon, Clichy, France.
BACKGROUND & AIMS: It is unclear whether hepatitis C virus (HCV) is eradicated in patients with chronic hepatitis C who achieved a sustained virologic response (SVR). METHODS: In this long-term follow-up study, including chronic hepatitis C patients who achieved SVR after interferon-based therapy, the presence of residual HCV RNA in serum, liver, and peripheral blood mononuclear cells (PBMCs) was assessed, using transcription-mediated amplification (sensitivity, <9.6 IU/mL). The benefit of SVR on liver fibrosis was evaluated using the METAVIR score. RESULTS: A total of 344 patients were followed up for a median duration of 3.27 years (range, 0.50-18 y; interquartile range [IQR], 1.68-5.35 y). A total of 114 patients had a posttreatment liver tissue (median, 0.50 y; range, 0-14 y; IQR, 0-3.5 y), 156 had PBMCs (median, 3.0 y; range, 0.50-18 y; IQR, 1.25-5.50 y). Serum HCV RNA remained undetectable (1300 samples), indicating that none of the patients had a relapse. HCV RNA was detectable in 2 of 114 (1.7%) liver specimens, and in none of 156 PBMC specimens. Histologic analysis of 126 paired pretreatment and posttreatment liver biopsy specimens (median, 0.50 y; range, 0-14; IQR, 0-3.5) showed that fibrosis stage was improved in 56%, stable in 32%, deteriorated in 12%. Regression of cirrhosis was observed in 9 of 14 (64%) (CI, 39-89) patients. No cirrhosis decompensation was observed, and 3 patients developed hepatocellular carcinoma. CONCLUSIONS: In this large cohort of chronic hepatitis C patients, SVR was durable up to 18 years after treatment cessation, in addition to fibrosis stability/improvement (88%) and cirrhosis regression (64%). The presence of residual HCV RNA was observed only in liver tissue (1.7%). This result strongly suggests that SVR may be considered to show eradication of HCV infection.
Thanks for the abstract mike, interesting. You you have a link and a date for that study? Just curious when it was completed, thanks...
Also here's another one from last year. Probably already been posted before, but in the spirit of eradication/cure, here it is again. And yes - I know one of you out there is just seethingly CHAMPING at the bit reading this info. And you know who you are cybersquatsch! ;-)
Pegasys Study Authors Conclude that Patients Successfully Treated for Hepatitis C Can be Considered ''Cured''; Mitch Shiffman says 'you can cure HCV', Eugene Schiff says 'get treated'.
Reported by Jules Levin
DDW, May 22, 2007, Washington DC
The findings were to be presented Monday at the 38th annual Digestive Disease Week conference, in Washington, D.C. (They were presented first at EASL last month).
"This paper strongly suggests, for the first time, that hepatitis C is a curable disease," said lead researcher Dr. Mitchell Shiffman, a professor at Virginia Commonwealth University School of Medicine and chief of hepatology and medical director of the school's Liver Transplant Program. "After treatment, 99.6 percent of the patients remained virus undetectable for over five years," he added.
"This is the first long-term study that confirms what we believed for many years that these individuals are truly cured of hepatitis C," Shiffman said.
Most people who have hepatitis C don't know they have it, Shiffman said. "Of those who have been diagnosed, only about 25 percent have received treatment, because of the side effects of treatment," he said. "The reason why you should treat it is because you can cure hepatitis C, and we finally have the data to definitively document it."
Dr. Eugene Schiff, chief of the division of hepatology and professor of medicine at the University of Miami Miller School of Medicine, agrees that most cases of hepatitis C can be cured.
"In contrast to hepatitis B or HIV, this virus can be totally eradicated and cured," he said.
But, many patients find the side effects of treatment off-putting. Those side effects can include fever and chills, Shiff said. "You feel pretty lousy. After treatment starts, you feel worse the day after your shot, but it tapers off over the course of the week," he said. "Along with that anxiety, irritability and depression can develop. And we are quick to use antidepressants to allow these people to stay on the medication."
Additional side effects include a drop in the production of white blood cells and anemia. Often patients are giving additional drugs to combat these conditions, Shiff said.
Treatments can go on for as many as 72 weeks, depending on the reaction to therapy Shiff said. "Some people are reluctant to get treatment, because they heard that the treatment isn't so pleasant," he said. "But they should come out and get treatment."
Schiff noted that new antiviral drugs to treat hepatitis C are being tested. "It is hoped that these new antivirals will be more effective and have less severe side effects and may even be used without peginterferon alfa-2a or ribavirin," he said.
WASHINGTON--(BUSINESS WIRE)--May 21, 2007 - Results from a new study, presented at the 38th annual Digestive Disease Week (DDW) conference, showed that more than 99 percent of patients with chronic hepatitis C virus (HCV) infection who were treated successfully with PEGASYS(R) (peginterferon alfa-2a) had no detectable virus up to seven years later - validating the use of the word "cured" to describe these patients, according to study authors. Currently, the best indicator of treatment success is a sustained viral response (SVR), defined as undetectable hepatitis C virus in the blood six months after the end of treatment. The results announced today are from a long-term follow-up study to determine whether the virus re-emerges in patients who achieve an SVR. (Studies show that, overall, about half of patients with hepatitis C monoinfection can achieve an SVR with PEGASYS and ribavirin treatment, the current standard of care.)
"The results announced today are encouraging because it is rare in the treatment of life-threatening viral diseases that can we tell patients they have the chance for a cure," said Dr. Mitchell L. Shiffman, Professor of Medicine, Chief of Hepatology and Medical Director of the Liver Transplant Program, Virginia Commonwealth University Medical Center, and study author. "But in hepatitis C today, we are able to help some patients achieve an outcome that effectively enables them to put their disease behind them."
About the Study (Abstract ID #444)
This study monitored 997 patients (either mono-infected with chronic HCV or co-infected HCV and HIV) who achieved an SVR following treatment with PEGASYS monotherapy or combination therapy with PEGASYS and ribavirin. Serum levels of HCV were monitored on an annual basis for an average of 4.1 years (range 0.4 to 7 years) following successful treatment. Of the 997 patients, 989 (greater than 99 percent) maintained undetectable levels of HCV; the remaining eight patients tested positive for HCV, at an average of two years following the completion of treatment. The study found that these eight patients exhibited no consistency in age, gender or HCV genotype, and it has not been determined if these patients experienced a relapse or if they were re-infected with HCV.
"We at Roche are proud to be able to offer some hepatitis C patients the prospect of such a positive outcome with our currently-available therapies, but we also recognize the urgent need to further improve response rates," said Tom Klein, Vice President, Hepatology, Roche. "In addition to ongoing research with PEGASYS, Roche has the most comprehensive pipeline in the area, with four compounds currently in human development that target the virus in a number of different ways. The development of R1626 and partnerships with InterMune, Maxygen and Pharmasset, all underscore our long-term commitment to finding effective new therapies with the goal of successfully treating more patients with chronic hepatitis C."
I am not as confident as you that every trace of HCV is necessarily eradicated once SVR is achieved. I believe that in some SVRs that may be the case but I suspect that in many SVRs HCV traces remain. The fact that I do believe this in no way suggests that I do not think SVR is a very very good thing. I think the evidence is clear and convincing that once SVR is achieved the vast majority of patients' liver function improves and their liver architecture stabilizes or improves and they decrease significantly their risk of developing HCC.
If people equate SVR with "cured" and "complete eradication" I think that's fine and I don't see a risk in believing that. I just think otherwise. I rarely see biopsies post SVR that would convince me that it is likely that the virus is absolutely eradicated.
1) SVR = cure has never been seriously challenged; residual virus clearly does not trigger anything like the damage of unchecked infection. Which does not mean it triggers no damage - there is some evidence of this, but it's scarce
2) SVR is durable has also never been seriously challenged though again there is scant evidence of occasional resurgence
3) SVR=viral eradication is a much more open ended and controversial issue. We now have 3 recent papers refuting detection of post-SVR HCV RNA is PBMCs. The one above along with
vs the collection of papers, mostly out of the Pham, Radkowski, and Castillo labs collected in TN' health page. As best I can tell, the discrepancy is mostly due to technical issues related to different detection methods. The Pham/Michalak lab's discussion of methods is quite insistent that mitogen stimulation of PBMCs is essential to bring the trace levels of occult-HCV up to detectable levels. I Haven't read the most recent Maylin'08 paper in detail yet, but neither of the other two papers above applied that part of the protocol (Bernardin acknowledged the omission). Some response from the Pham/Michalak lab to the recent refutation is presumably forthcoming; at this point there's still much more evidence against total eradication than in support of it, and that's where I'd place my bet (note that even the Maylin'08 paper found post-SVR RNA in 2/114 liver samples)
As scientific skirmishes go, it's very interesting stuff, but whether eradication or lack of it has any significant bearing on one's health decisions seems unlikely.
I've never seen anything in Pham's papers that rule out the presence of HCV Rna particles due to adsorption. This is a critical step to further any hypothesis about residual HCV rna particles.
HR talked some time ago about the lenghts one of his labs went through to prevent cross contamination resulting in false positives on sensitive TMAs, even to the point where different steps were performed at two different labs which were physically apart and where I even believe workers were not supposed to socialize with each other.
Perhaps then, what Mr. Liver is suggesting, is that some of Pham's findings may be the result of some sort of contamination/lab procedure, as opposed to an actual finding of HCV.
Before the flame throwing begins :) I'm not suggesting in any way, nor do I of course have any knowledge that this is occuring, but I imagine that as your testing becomes more and more sensitive, contamination would become more of an issue. Perhaps Pham's procedures are bulletproof, really dont know.
Well, at least I have an idea of what he was referring to. I never get upset with different opinions about this stuff Jim. SVR/Cure/Complete Eradication isn't a trigger point for me. It's a complex issue.
I concur with you completely. I have no real conviction one way or the other, but would like to see more rigorous studies, and get a better consensus down the road from ALL the top researchers regarding this issue. They all seem to be at odds with each other, and I want to keep an open mind, and just find out the real truths about eradication/persistence. I feel no attachment to either point of view, and in fact would LOVE to see 'eradication' fully, finally, and unanimously be proven and acknowledged by the entire research community.
Why do some people tear these positive reports apart, do you guys know of people after many years of SVR, it returned, or was it a reinfection?...oh ..no!!!!
You can if you want, find evidence for anything if you dig deep enough, relax and try to think positive, look for positive studies to brighten our day, now that would help...eh!
Matthew Hoare 1,
William TH Gelson 1*,
Simon M Rushbrook 1*,
Martin D Curran 2,
Tracy Woodall 1,
Nicholas Coleman 3,
Susan E Davies 4,
Graeme JM Alexander 1.
1. Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
2. Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke’s Hospital, Cambridge, UK.
3. MRC Cancer cell unit, Hutchison / MRC research centre, Hill’s Road, Cambridge. 4. Department of Pathology, University of Cambridge, Cambridge, UK.
Background: It is unclear whether HCV has been eradicated or persists at low level in HCV-antibody positive HCV-RNA negative individuals; the natural history and liver histology are not well characterised.
Methods: 172 HCV-antibody positive, serum HCV-RNA negative patients underwent diagnostic liver biopsy between 1992 and 2000 and were followed a median 7-years (range 5-12). Patients with any possible cause of liver injury other than HCV were excluded. A single histopathologist scored sections using Ishak criteria. Characterisation of the inflammatory infiltrate in selected cases used a novel semi-quantitative technique and compared with HCV-RNA positive patients and healthy controls.
Results: 102 patients were excluded because of a risk factor for liver injury other than HCV. 70 patients met study criteria; 4 (5.7%) became HCV-RNA positive during follow-up. 66 cases remained HCV-RNA negative; 5 (7.5%) had a normal liver biopsy; 54 (82%) had fibrosis (stage 2 or 3 in 16 (24%)). Non-viraemic cases revealed expanded portal tracts (p < 0.05), with fewer CD4+ (p < 0.05) and more CD8+ cells (p < 0.05) than healthy controls, but were indistinguishable from HCVRNA positive cases for these parameters. Lobular CD4 staining, absent in healthy controls, was noted in both HCV-RNA negative and positive cases and was more marked in the latter (p < 0.05) with a sinusoidal lining cell distribution.
Conclusions: Non-viraemic HCV-antibody positive patients have a liver biopsy that is usually abnormal. Fibrosis was present in most with similar inflammatory infiltrate to viraemic cases. The presence of a CD8+ rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV-RNA negative cases.
In hindsight I wasn't very clear, but in essence Jim's 'take' is close to what I was referring to. Adsorption in this instance refers to the phenomena whereby viral particles adhere to the outside of cells, in this case, PBMC. Once the cells are cultured in vitro, broken up, and tested for HCV rna particles and their properties related to propagation
( e.g., both + and - strands, etc) , they would of course, be present. If adsoprtion is not ruled out, the conclusion of replicating HCV in PBMC could very well be in error.
thanks for the clarifications but either I'm misunderstanding or we're equating two unrelated issues
contamination is in fact the bane of anyone running PCRs. A google search will quickly confirm that there are scads of support groups for frustrated lab workers who run into this. However, it is fairly easy to detect by running controls, which is standard practice (if your PCR is amplifying DNA/RNA in a water sample it's not what you're interested in).
The issue of contamination is a much more serious problem in the context of clinical testing that HR was discussing where you're basically going to run the PCR once and make serious decisions on the outcome (that whole batch of pooled donated blood has to be tossed because we found some HCV RNA in it). On the other hand in an academic lab setting, you're running the same PCRs over and over, with controls, and your final conclusions are based on the overall results. For contamination to creep in it would have had to systematically evade the controls on all of those runs. Possible, but unlikely, and all the more so once your results have been replicated by other labs.
The Pham/Michalak protocols are set out in the article: "Molecular Diagnosis of Occult HCV and HBV Infections "
( free access n medscape, need to register)
which includes the comment
"All steps, beginning with the acquisition of samples and their storage, followed by nucleic acid isolations, preparation of amplification cocktails and performing reactions, to retrieval of amplicons for NAH analysis, are conducted under strict contamination control conditions using appropriate contamination and reaction controls throughout."
see also Fig. 1 and the 72 hour mitogen incubation of PBMCs, the step not done by the labs that are failing to detect RNA in PBMCs.
Re adsorption, if some HCV virions are on the surface of the cells, or even in the process of cell penetration and bound to the membrane, they are present! I don't see how this invalidates the reported detection.
Thanks for the reply and sorry for such a slow response.
I wasn't referring to cross-contamination in my post above. I know the great care they excercise when working at the molecular level. I've seen inferences made when conflicting results are obtained in studies
but the possibility is fairly low, especially when results are repeated.
I really don't have a dog in this hunt, but the topic is interesting. Theoretically, HCV can enter any nucleated cell and use it for reproduction, so its presence in blood cells other than red blood cells or hepatocytes is expected. The issue is whether it can exist and replicate in vivo while in these types of cells (PBMC) after the virus can no longer be found anywhere else in the sera or liver . If infective HCV is found years later in PBMC it suggests PBMC is a viral reservoir for HCV. This implies the virus may become inactive or dormant, or it exists through low-level replication. Again, the researchers have worked hard to show just how fast and effective HCV can grow from PBMC in vitro, yet from my readings none seem to be able to duplicate this "low-level reproducing" state convincingly. Even low level replication would eventually result in the release of virions into the surrounding sera due to apoptosis, if for no other reason, would it not ? Even with low level replication (I don't believe I've ever seen it actually quantified) what exactly prevents the virions that are released from seeking out their favorite habitats-red blood cells and hepatocytes ?
For reasons yet unknown PBMC may well be the last type of cells that become virus-free when one rids the body of HCV. And its certainly not far-fetched to envision re-emergence (relapse) to have its genesis from infected PBMC if that were true. Its an interesting topic, one that still has detractors on both sides of the research that has been done.
For me it becomes rather a moot point after one is 3 years post SVR. For nine years now I've made the challenge that no one could find a verifiable, documented case from a reputable, professional source detailing relapse beyond three years post-SVR. In those 9 years no one has yet to provide one. If HCV can exist for any amount of time post SVR it must either be in its death throes and incapable of infection, or
what is being detected does not represent a complete particle in the first place. If this were not true,the medical records would be brimming with documented relapses beyond 3 years post SVR and we know that this simply isn't the case. This area has been researched now for 15 years or so, so the data is vast, yet none exist that shows late relapse 3 yrs post SVR. Heres a study link that mentions adsorption, briefly, and shows concurrent corresponding drops in viral amounts in sera, liver, and PBMC.
You're talking about "relapses 3 years post SVR". "Occult HCV" may be a different matter. The replication rate with occult hepatitis C may be too low for HCV to be detected with the current serum tests used to determine SVR. I never see biopsy samples of post SVRs analyzed with immunohistochemistry, InsituHybridization Assays (ISH & FISH), Molecular Anatomic Pathology, and Immunofluorescent Testing. If after this type of testing no trace of HCV was detected I would be much more inclined to view SVR as complete eradication. But, once SVR is achieved it's understandable why the patients don't volunteer to undergo follow up liver biopsies.
> no one could find a verifiable, documented case from a reputable,
> professional source detailing relapse beyond three years post-SVR
I believe that's the case, or at least I'm not aware of such a source, though there are at least two cases of documented recurrence after spontaneous clearance:
and the ever-popular
Long term SVR follow ups tend to report numbers close, but shy of 100%, but to get something published I'd expect you'd need sequence data from the original and recurrent infection to rule out re-infection - and there's not (yet) much of that about.
> none seem to be able to duplicate this "low-level reproducing"
> state convincingly.
A number of the studies on TN's page document detection of both + and - strand RNA in PBMCs etc. so the virus is definitely replicating.
Whether failure to overwhelm the immune response, as happens when chronic infection first gets established, is due to lack of fitness in the virus or to an improvement in the host response ('fooled me once...') is not yet clear - and one of the main reasons to keep studying occult HCV, IMHO. If I was handing out NIH grants, I'd get the Pham/Michalak lab to collect specimens from a large tx group at EOT, sequence all HCV clones, and later compare the SVRs with the relapsers.
>Hep C replicates, yes??? If there was some trace left, it would replicate and then be detected in the RNA tests
Overall, it seems a bit like a cat and mouse game. You start with a house full of mice, then you get a cat. The fact that you rarely, if ever, see another mouse doesn't mean they're not there; it does mean you probably no longer care.
I also don’t know for certain what happens when the vast majority of us SVR in terms of eradication (or not). Mikesimon you said “I am not as confident as you that every trace of HCV is necessarily eradicated once SVR is achieved.” Just to set the record straight, I’m not “confident” every trace of HCV is eradicated (nor did I ever say so). Just wanted to clear that up before going on any further.
But I do feel that it’s very possible, and perhaps even the most likely explanation of what happens when we SVR. I do not buy hook, line and sinker, these fairly recent low-level test results that suggest we are persistently infected with viable virus long after SVR-ing. It’s not that I don’t acknowledge that it might turn out to be true that there is true viral persistence, but I think there are many very significantly unanswered questions that remain. And these unanswered questions in my view tend to favor the eradication outcome as the more likely end product of SVR.
Unfortunately, I am not educated in the biological sciences. Nor am I educated in the test technology that is being used to produce these controversial results. So I am not in a position to directly judge whether or not these tests have been run properly or if these results can really be trusted to be what they appear to be. But I am educated in the sciences and have been involved in test measurements using sophisticated scientific instrumentation for many years. And if there’s one thing I have learned, it’s that there are many potential pitfalls that can beset scientific inquiry when sensitive instruments are being used to measure very tiny or trace amounts of just about anything. Sensitive test instruments and methodologies can easily become corrupted with the slightest unintended interference, even in the face of extreme caution and dutiful attendance to scientific principles when extremely low levels of the test stimuli are being measured. Extremely high levels of amplification are almost always vulnerable to noise and other factors that ordinarily would be negligibly small to consider. When you’re amplifying the tiniest trace of a signal to the levels of detection that are being attempted in these controversial test results, without knowing anything more about it, all I have to say is that you better damn well have your p and q’s straight. My assertion is that it seems like there’s plenty of room for error here, and so far at least, not all reputable scientists who *are* educated in these test methodologies are accepting of these test results – yet, anyway. And there have been some recent inquiries (like the ones posted on this thread) that certainly appear to cast doubt on the persistence camp. Hence, I think most reasonable and objective observers acknowledge that so far the issue remains unresolved.
Also, test method vulnerabilities aside, lets assume for a moment these test results are legit…at least partially legit. Maybe they really are picking up on something that is, or is related to, the HCV virus that once dominated that “biosphere?” What I mean by that is, where does the virus go when we SVR? And what I mean by that is, when we are actively infected we have trillions upon trillions upon trillions of these virii swarming through our blood, bone, skin and organs. Constantly processing in and out, in an out. We are literally soaked and dripping in the virus to our very core. And for most of us, it’s been there for many, many years (almost 25 years for myself). Constantly reproducing, dying off, reproducing again and again ad infinitum generation after generation after generation into simply astronomical numbers over the years it spends inside our bodies. So my point is, lets assume there really is total eradication. Does eradication really mean “eradication”? Does it mean your body is truly expunged of every single trace, every single vestige of the virus? Every little speck is now gone and somehow magically flushed out to the nth degree so that not one single viral particle (viable or not) remains?? Considering the *astronomical* scenario described above, that just seems fantastically unlikely doesn’t it? Especially considering that part of the virus’ game is to actually hole up inside of cells, thereby provided a strong measure of obvious shelter, containment and perhaps preservation.
Or does eradication really mean that the virus is simply choked to death by being largely flushed out (but not completely) and utterly denied the ability to replicate so that it effectively “dies” (considering it’s not even alive to begin with). By “die” I mean all functions die off, the reproductive processes that normally take place during its very short lifespan are sufficiently interrupted so that the cycle of life and reproduction is halted for good throughout the entire body. And the vast majority of the physical inactive/dead virus that remains in the bloodstream is swallowed up by the immune system and disposed of. But what about the dead/non-viable virus that ends up trapped inside certain cells? What really happens to it? Do the viral particles, which are essentially strands of proteins, disassociate? Do they disintegrate and disappear altogether? Not the slightest vestige remains? That seems unlikely doesn’t it? Again, I’m not educated in the biological sciences, so this may seem like naïve and ill informed speculation, but doesn’t it seem very likely that some tiny vestige of the dead/inactive particles would remain warehoused inside of at least a small number of cells?
And what about the inside of those cells? When the virus was active within the body inside those cells, it was replicating. Inside the cells is where the replication takes place. The cell is the manufacturing factory for the virus. If the virus effectively dies and becomes permanently deactivated inside the cell, wouldn’t both + and - strands remain? Sort of trapped in protoplasmic amber? Both + and – strands are both coexistent within the cell during the reproductive process, no? (remembering that the presence of negative strands supposedly implies ongoing replication) I think of it a bit like an old bombed out factory with broken parts and the manufacturing dies that made them laying on the floor – smashed, rusted and no longer producing anything. The vestige of the manufacturing process remains, but the manufacturing itself stopped long ago. The mere presence of the old broken parts and the dies that made them does not prove or imply that manufacturing is ongoing.
And although I don’t know how often liver (or other) cells “turn over” inside the body (i.e. die off and are replaced), even if the cell dies and its membrane ruptures, I could see where some of the dead viral particles are disgorged and possibly absorbed or otherwise taken up by the new cell, or perhaps they could even end up being trapped between the cells, sort of squished and immobilized between the outer surfaces of the membranes. And maybe others are slowly, continuously picked up and end up inside PBMC’s or lymph fluid? Doesn’t that seem like a perfectly reasonable possibility? Or are we to believe the human body is such an incredibly orderly and perfectly sterile environment that even this level of infinitesimal and benign contamination is 100.000000000% cleaned out? That just doesn’t seem reasonable, does it? (cont...)
Otherwise, lets look macroscopically at what we can simply observe about the treatment of HCV when SVR occurs. Without necessarily concerning ourselves with all of the intricate and complex antiviral dynamics that no one really fully understands (yet). If eradication really is taking place, what would it look like? Well, I think it would look an awful lot like it looks right now. Lets look at some very obvious treatment scenarios that strongly suggest eradication:
1. For example, we know that genotype 1 has a roughly 50% SVR rate with 48 weeks of existing SOC. But what does that mean? Of course it means that after tx ends, about 50% will SVR and 50% will relapse. This is very similar to what we would expect to see if someone was infected with a tough strain of bacteria that was resistant to antibiotics and underwent a lengthy tx with AB’s. Some people would clear, some wouldn’t. Those who treated longer and/or perhaps who took higher doses of the antibiotics would be more likely to clear, same as HCV tx.
2. People who are treated and achieve UND status during treatment for longer periods of time are much more likely to achieve SVR than those who remain UND for shorter periods of time. This seems to occur for a very obvious reason doesn’t it? The patients who go UND earlier and stay UND longer during treatment seem to be beating the virus. The virus is being subdued more thoroughly within those people and certainly appears to be pressured onto the path of eradication. Conversely, someone who goes UND late and/or only remains UND for a relatively short period of time during tx, is more likely to relapse. This again seems to suggest that eradication is taking place when SVR is achieved. Just as you would intuitively guess, the virus appears to exhibit behavior that directly resembles that of bacterial eradication, which I assume is widely believed to be truly eradicative (when successfully treated). In other words, it’s as if the virus (like a bacteria) is a stone that’s being rolled up a hill during treatment. Successful treatment entails keeping constant pressure on the virus and rolling that stone all the way to the top of the hill and then finally casting it down the other side. And once it’s cast down the other side it won’t be coming back even after the drugs are stopped. If the treatment is unsuccessful, the stone does not make it the top of the hill before tx ends. Pressure is then released and it quickly rolls back to the bottom of the hill after tx stops – relapse, and the virus returns usually in full force shortly thereafter. What we see in HCV tx in this sense, looks just like an eradicative process.
3. If the virus really is eradicated when SVR is achieved, you’d expect it wouldn’t come back. Simply because, well, it’s eradicated. It’s GONE. And again, what do we see in the vast, vast, VAST majority of SVR’s now numbering in the 100’s of thousands and almost certainly exceeding a million all told (including naturally cleared)? We see that the virus does NOT return in them. We see that as long as we have known the virus to be in existence and measured/detected, that SVR is durable. It is DURABLE and LASTING under a very wide variety of conditions, including in the presence of very significant disease and drug induced immunosuppression, old age and in the presence of other serious concomitant diseases. It just doesn’t come back – again, which is exactly what we’d expect to see if eradication was taking place.
4. If the virus was eradicated in SVR, we’d expect HCV antibodies to slowly diminish over time. Perhaps even disappearing altogether, given enough time in some. The reason we would expect this is because the body is constantly stimulated to produce antibodies when there is an ongoing, active infection. But typically after an active infection is thwarted and resolved (be it bacterial or viral), antibody levels once very high during the peak of infection, then slowly decline and constantly decay after the threat has been eradicated and time goes by. And so what do we see in HCV SVR patients? We typically see their AB levels drop off over time, and given enough time some people even become UND for HCV AB’s once again (as if they were never infected). Why does this happen? If there was even a small viral persistence, or if the immune system was “quarantining” the virus as some online theoreticians have postulated, wouldn’t we expect to see AB persist at reasonably high levels? Normally it only takes a tiny viral presence to stimulate a large production of antibodies in response. But that’s not what we see, is it? Again, yet another phenomena that smacks of eradication.
5. Although somewhat more controversial because of factors/complications associated with post tx effects and possible autoimmunity issues etc, we also would expect resolution of most or all symptoms of HCV after SVR. And in most people there is substantial (or whole) resolution of the most significant symptoms - namely the advance of liver fibrosis. Post interferon side effects aside, achieving SVR usually means a very significant resolution of HCV related symptoms, again what we would expect to see with eradication.
Anyway, not to go overboard here, but I think the “big picture” quite clearly points towards eradication. There are so many obvious and clear facts surrounding the treatment and follow up performance of a huge number of SVR’s that supports an eradicative conclusion. On its face, eradication seems like the most likely probability in my view. And if it’s not true eradication and some kind of ongoing infection persists, it sure is a mysterious (albeit largely benign) bird indeed.
The studies that and Mike present are within the past few years and both indicate that viral RNA was found in less than 2-3% of the patients after five years.
Forgive my ignorance here but do we know that in that 2 to 3 percent its the same virus and not a new infection? I mean, in those studies have they taken steps to ensure that its the same infection reasserting itself?
Every little speck is now gone and somehow magically flushed out to the nth degree so that not one single viral particle (viable or not) remains?? Considering the *astronomical* scenario described above, that just seems fantastically unlikely doesn’t it?
I wonder if some of these things depend on how long you've had the virus and if SVR is a progressive thing that continues after SVR is declared. If one SVR is not like the other. That would explain why sometimes they find complete eradication and then there are a certain small percentage of times when they don't.
What I'm trying to say is that perhaps if you've had the virus for a very long time, such that as you say, you are utterly swimming in it, you might be successful in reaching SVR via some drug therapy but there remains some low level virus that your body is able to suppress and it continues to fight it over the years and maybe your complete and total eradication doesn't occur until years after your SVR is declared, if at all, whereas someone who treated five years after they were infected, or someone who treats acutely, reaches a total eradication of the virus much more easily, such that when they reach SVR their virus really is eradicated completely and you don't find any low level virus reservoir hanging out in their system.
Is there a correlation between the amount of fibrosis / cirrhosis and SVR / eradication of the virus?
I've read that the virus hides in the scar tissue. I have also read that in the abscense of virus or damaging behavior such as alcohol abuse, your liver begins to reabsorb fibrosis and eventually works on the scar tissue.
Could it be that as your body heals...maybe taking years to get to the scar tissue, depending on the amount of damage...that your virus rears it's ugly head from out of the scar tissue?
The study link below uses a different method to capture the PBMC . The PBMC are not exposed to artificial stimulation and specialized chemical compounds which may affect the outcomes in unknown ways. The reference footnotes are well-detailed and lead to more reading on the topic. The problem I have with a low level replication scenario is the 'predicament' it would put HCV in. I expound just a little more on the topic below.
I think your logic falls into line with many researcher's thoughts. When you study all of the mechanisms used by the virus to maintain its existence, low level replication beyond detection by the most sensitive RT-PCR for the purpose of viral reemergence at a later time (up to years according to some) does not seem to follow what is known about HCV.
factual ramblings--As with all viruses, to continue to exist is the end goal of HCV. Among the known primary defense mechanisms used by HCV to achieve this are extremely fast replication rates. This trait is made even more effective because it uses rna in the production of its viral copies. Rna is an inherently unstable molecule and very prone to errors (mutations). HCV uses this to its advantage to overwhelm and confuse the host's immune system by producing virions that all 'look' a little different.One virion can produce from thousands to millions of quasi-species (mutants or errors) per day in the attempt to evade the body's immune defenses. At the same time it is producing up to a trillion copies per day of viable, infective virus PER virion. All in all, our immune system does an incredible job of keeping the virus as low as it does, and for long as it does. Finding incomplete viral particles does not mean there is an ongoing infection. Dna and rna genomic strands can last for thousands of years---in dead cells, no less. Now, if the rna found has a lipid layer with two coats of glycoproteins, icosahedral, and about 50nm in diameter I would be much more inclined to worry. ;)
opinion-I've said this before, but when a disease has one main method of transmisson, in this case direct blood-to-blood contact, it must maintain a constant presence in the sera to have any reasonable chance of continued existence ( the aforementioned goal). The opportunity to infect may not come for years, if ever, or perhaps that event will occur within 5 minutes. When it does come, the virus cannot be laying so low it cannot be found in the sera or it will miss perhaps the only opportunity it will have to infect. In view of the known defenses of HCV, receding into a dormant or near-dormant stage would appear to be antithetical .
Many cases of spontaneous clearance of HCV may involve the initial infective incoculum size. In other words, infection can be dose-dependent. This is why more spontaneous clearance cases are seen among IVDU than those who were infected via transfusion or other blood products. The size of the infective dose plays a major role in this observational finding. To take this a step further, HCV would put itself into great peril of being eradicated if it were to reside in a cell, slowly replicating while being eliminated just as fast as it was being released into the sera, so that it managed to remain under the radar of the most sensitive tests. This is no formula for success and I highly doubt HCV would put forth the energy to evolve a system that would by its very nature put the virus into jeopardy of being eradicated. Thats not the HCV I've come to know, anyway.
ok guys. this is an important question because some of the newer biologics for arthitis, which I will be faced with trying soon, render the immune system less... he11, I can't think of the word because my brain is mush, but less. oh yeah, there it is, effective. ok. So, if that is the case and hepc sits at some subliminal level down in the dark places with gollum somewhere in the body, what happens when you take these biologics and your immune system no longer works as well, hmmm? Am I then at risk for losing my SVR?
Thanks for posting in the way you did, both this thread, and also your thesis. It matches my view. I have no medical expertise at all, but it is logical to me, that the virus is eradicated. I suspect that the "trace" signs of "ocult" Hep C are not Hep C, they are merely the reamins of the diesase we had, the dead left overs if you will. The tests are no doubt so sensitive, that the methodology being used is what is resulting in that dead left over being misinterpreted as an active virus, rather than the reality itself. In saying that, time will tell, although I personally don't see the point in this research "war", when I think instead, researchers could be working on finding a less damaging treatment.
when the underlying truth is far from evident, DATA is all the more important.
- tn has done a great job of collecting peer-reviewed articles on the topic; pro and con. Omissions should be added, but as it stands, it seems there is far more data discounting eradication than supporting it (using techniques that are simply finely-tuned variants of what's available at the local quest lab).
- the Halfon'08 article referenced by mr.l above is the same one I had referenced in an earlier post in this thread. It is also included on tn's page, and along with bernandin'08 and Maylin'08 is one of 3 recent papers refuting occult vl in PBMCs. Unfortunately none of these 3 have applied a step identified by Pham/Michalak as crucial to reliable detection; furthermore there is no discussion in any of the three of any rationale for this omission (eg we did not apply mitogen because..)
- the "trapped in protoplasmic amber" suggestion by mre above is undermined by the presence of catabolic pathways that would quickly degrade any given instance of viral RNA within a cell. Life happens, somewhat improbably, as an equilibrium betwen countless chemical reactions moving in opposing directions. For every metabolic pathway synthesizing something, there is a catabolic path tearing it apart into piles of spare parts. Lifetime of mRNAs transcribed from our own genes is on the order of 2-3 minutes and there's no reason to believe the viral RNA would endure longer; thus if it continues to be detectable it must be because new copies are being generated.
- the benefits of SVR (reduced fibrosis, etc.) are equally credible with and without eradication. After all, the stellate cell activation in our livers that leads to fibrosis is not triggered by the virus but by the inflammatory response to it. If residual virus triggers so little inflammation that post-SVR AST/ALT levels nearly always return to normal range regardless of whether occult virus is detected, one would also expect other side-effects of inflammation, like fibrosis progression, to abate.
“When the underlying truth is far from evident, DATA is all the more important.”
I disagree with your categorization that the “underlying truth” is far from evident. Firstly because you’re implying that the real truth here can only be “underlying” and not patently obvious. I think it’s quite obvious that one very plausible, and even likely explanation of what’s going on with SVR’s is true eradication (i.e. the obvious explanation, not the underlying/hidden one). I agree it’s not proven conclusively yet, and Castillo/Pham et al’s results do cast doubt on this. But again, it’s quite possible that the low level persistence camp may very well eventually be proven either outright wrong due to experimental error, or “effectively” wrong due to them detecting non-viable/inert viral remnants that are not capable or re-infection (and are not the product of an ongoing low level infection). That is a distinct possibility that you do not seem to acknowledge in your statements regarding “the DATA.”
Secondly, you refer to “DATA” as “all the more important.” Sure, data is very important – but data must be measured and recorded accurately. And it must be interpreted properly too. The point of my post above, was to suggest that the DATA may not be accurate, there may be experimental error. They *are* exploring extremely prototypal/hyper-sensitive experimental test techniques that have not gained wide acceptance nor use after all – there’s room for error, room for mistakes when you’re dabbling in this realm. And science is full of historical examples of this very phenom. (remember Pons and Fleischmann ala cold fusion?) That’s why there’s so much debate, controversy and inquiry by well informed scientists in the field of hepatology as to what Castillo/pham have really “found”.
And all of this leads us directly into the equally important realm of properly interpreting the data. Maybe their test methodologies are sound, perhaps they really have detected the presence of the virus? That’s possible too. But then to instantaneously interpret that data as “proof” of a low level viable/ongoing infection with the capacity to initiate relapse, possibly cause further damage to the host or to provoke infection in others is yet another matter. Like I alluded to above, I think there’s a distinct possibility that if they are detecting HCV RNA, it may turn out to be harmless, dead vestigial remnants, or some unexpected, currently misunderstood variation on that theme.
Lastly, you take issue with my speculative layman’s hypothesis about harmless viral residue being trapped in situ on a cellular level:
“…the "trapped in protoplasmic amber" suggestion by mre above is undermined by the presence of catabolic pathways that would quickly degrade any given instance of viral RNA within a cell.”
You sound like you know for a fact this is not happening and discuss the matter with authority as if you are educated in the realm of viral microbiology (which you may well be). If you don’t mind my asking, what are your credentials and how do you know this with such certainty? Can you expound on your response in layman’s terms so we can all understand what you mean in regard to this specific point? How do you know for an absolute fact that ALL dead/deactivated viral remnants are wholly cleansed in every single way, from every single cell, from every single nook, cranny and interstitial cavity within the body after eradication? And I recall HR referring to a way that the cells “take out the trash” that probably pertains to this, but again the taking out of the trash mechanism would have to be applied with 100.00000000% perfection with all cells functioning with zero error in every single infected cell throughout the entire body - which again to me seems unlikely (especially considering the cell’s internal defenses and machinery had been successfully thwarted/hijacked by the virus in the first place). Assuming a trillion virus in your body, even eliminating 99.99999999% of it still leaves ten-thousand copies behind!
And once again let’s remember all of this within the context of the colossally astronomical viral footprint that’s left behind in all of us after many years of infection. Speaking for myself, I know literally down to the hour when I was infected. I also know when I became UND during my tx. So I can actually estimate how many virions have swarmed through my body throughout its active acute/chronic cycle. I was infected for very close to exactly 23 years (assuming the virus went dead about 6 weeks into my tx (or 4 weeks after first becoming UND)). That’s 8,377 days, and assuming a rough average daily viral production of about 1 trillion virions, that comes out to a total of 8,377,000,000,000,000 virions that have come and gone through my body during my infection. Again, that’s EIGHT QUADRILLION, THREE-HUNDRED SEVENTY-SEVEN TRILLION virions that have passed through my body within that timeframe. And your assertion is that nary the tiniest speck should remain afterwards in your entire body if eradication takes place after SVR? Again, please explain in great detail in layman’s terms how you are so certain this is the case, because I’d sure like to understand that concept considering the orders of magnitude we’re dealing with here. Our bodies are literally a viral universe. They are also a viral graveyard of truly astronomical proportions. So please explain how you know that the bones of more viral soldiers than there are stars within this galaxy must be utterly expunged from my body if there is eradication?
Lastly, getting back to the data you referred to previously. What about the huge body of circumstantial evidence/data that supports eradication? Please apply your apparent microbial acumen and explain just a few of the factual observations discussed previously, including:
1. SVR relapse rates – Why don’t we see relapse in the vast, vast, vast majority of truly confirmed SVR’s, even in the face of very significant immunosuppression? I myself took handfuls of prednisone (up to 80mg a day) for several weeks coupled with bolus IV solumedrol followed up with even more prednisone - all while I was a mere 7-12 weeks INTO treatment (not after treatment!). And that’s without taking telaprevir (stopped at week 7) and with significant ribavirin reductions too. I was tested with a sensitive PCR before, during and after the whole thing – nada, zip, no viral re-emergence. Went on to officially SVR later. How did that happen? How do so many other confirmed SVR’s also “get away” with serious drug and/or disease related immunosuppression without relapse? Please explain…
2. Post SVR HCV Antibody Taper – Why does this happen? If there’s ongoing viral presence/reproduction, why do AB’s typically fall off after SVR-ing? This is a significant phenomena, typically it takes very little viral presence to stimulate a significant AB+ response. So why do they fall off and given enough time often become UND? Please explain…
3. SVR patients CAN be reinfected with HCV – SVR does NOT impart immunity from reinfection. Considering this is a fact (which it is), if there is viable/reproducing virus already within the body (as Castillo/Pham assert), quite simply – WHY don’t SVR’s relapse?? And even, how do we ever achieve SVR status in the first place? Please explain…
I don't look at these reports anymore as a good news guys vs. the bad news guys.
We can all hope that in the ned the good news proves truest, and I'm sure we all do.
That said, you still have those little hangers on in titers, or 1.7%, or only 60 of 67, depending on what study you read.
the glass is half full Harry....because we can all hope to be in the numbers that stay clear.
the glass is only half empty in the sense that
A. I think it would be irressponsible to list oneself as an organ donar even in SVR because the verdict is still out, and
B. until research can advance to the point of proving why certains ones do continue with some occult remnants (which may prove to be their own reexposure but is not known at this point), but until more is known it would seem prudent to tell any potential mate that you had it, and explain the current medical thoughts. (in order to have a truly loving relationship it must be an honest one).
Since HCV is the first virus to get the coveted "cure" label, minus vaccines, and since the other retrovirus, HIV is still far from a cure, I think it behoves those of us treating and "curing" to be careful how we represent the cure, and careful how our organs are distributed in our absense.
Example: Let's say I was awaiting a liver transplant. There were no healthy livers available and I was near death. Suddenly I was presented with the opportunity to get a liver, of a former HCV patient who had SVR for 3 years. Now as a patient, you might choose to take that liver, and the day may come when they'll offer them, but it will need to happen with some real information to the patient, and some real expectation that that liver is not still harboring that 1.7%...which in an immunosuppressed new Transplant patient could spell disaster. I think that is one reason why such an effort is still being made to get to the bottom of all this....for just such eventualities.
MB: think it would be irressponsible to list oneself as an organ donar even in SVR because the verdict is still out, and
It's a misconception that you can't donate organs if your SVR, or even if you're Hep C positive and not SVR. So, if you want to donate your organs, Hep C or not, please do as they are badly needed.
“I wonder if some of these things depend on how long you've had the virus and if SVR is a progressive thing that continues after SVR is declared.”
Yes, I suspect that after we SVR the inert remnants of the disease are slowly flushed from our cells and system over time. To me it only makes sense. As previously mentioned, I find it almost inconceivable that a ~25 year old viral presence on the order of many thousands of trillions of virions could be *completely* evaporated and erased in just a few months to a year of treatment. I do believe it can be permanently deactivated/killed or "eradicated" in that sense within that same timeframe (especially considering its short lifespan), but not completely and comprehensibly physically removed immediately after deactivation. That’s just awfully hard to swallow for very obvious reasons. So it stands to reason that what’s left of the virus (after SVR-ing) would slowly shake out over time (IMO). I think this might explain how HCV RNA is possibly being picked up using these ultra sensitive test methods (assuming they are accurate). Otherwise you’re left with a bunch of square pegs in the form of the “macroscopic SVR features” described above to fit into the round holes of the theory of ongoing viable viral persistence. And the macroscopic features of SVR are remarkable and statistically overwhelming in their repeatability and coherence - they ain't going away and they're not easily explained nor fit into this viral persistence theory *at all.*
"Example: Let's say I was awaiting a liver transplant. There were no healthy livers available and I was near death. Suddenly I was presented with the opportunity to get a liver, of a former HCV patient who had SVR for 3 years. Now as a patient, you might choose to take that liver, and the day may come when they'll offer them, but it will need to "
Many infected livers and some SVR cadaveric livers have been transplanted to date. If you are near death and and an infected liver at stage 1,2, or even 3 becomes available, trust me, you'd take it.
This type of tp is considered a temporary solution in most cases. in cases where the liver comes from someone who is SVR it would most likely will be a final permanent solution.
none of the various alternative interpretations of SVR discussed : (1) every functional virion has been eliminated (2) an ever-decreasing population of marginally functional virions lurches towards extinction or (3) a low-level viral population persists but is kept in check by a more competent immune response , has unequivocal experimental support. So yes, the underlying truth is far from evident and DATA is a more valuable guide than conjecture (which can simultaneously seem quite reasonable and be dead wrong).
-the studies collected on tn's health page make (1) seem quite unlikely but don't distinguish (2) and (3). You seem to favor (2), which I agree is quite plausible, but I think it's still too early to make the call.
- re degradation of HCV virions see for example,
an approximate half-life of 2.7h is consistent with other estimates of hcv kinetics (if hcv's phenomenal production rate was one sided you never would have survived the production of that much virus..)
- re degradation of mRNAs within a cell see for example
True, viral RNA is not one of our own mRNAs, but it's close Additional searching might turn up specific estimates of decay of viral RNAs, though I suspect this would be hard to quantify.
- re reliability of studies detecting residual virus. This has been discussed at length before: one the papers is out of the Mayo clinic; the results have been replicated in many labs; HR, who certainly qualifies as a world-class expert on use of PCRs to detect viral RNA, commented he found no fault with Castillo's methods. The methods being used are simply sensitive PCRs, one of the most fundamental tools of mol bio. Probably the most significant difference with routine clinical tests are that they are often based on lysed cells whereas the standard VL test only looks for free virions in serum.
Re your questions
(1) durability of SVR is more likely due to a fundamentally improved immune response than to absence of virus else fluctuating viral rebound (as documented in the two studies I posted above) and as experienced by Mike on this board simply wouldn't happen
2) post HCV AB taper would support alternative (2) but how much evidence is there of this? I've read that ABs have been observed to disappear but if you've seen studies supporting a consistent decline please post
3) I'm also not sure what level of re-infection SVR does or does not protect against. If you save a vial of your pre-tx blood can this re-infect you? or can you only be re-infected by virus with a sufficiently different sequence. It's worth remembering that one of the virus' strategies is to overwhelm. The post-SVR response may be capable of keeping in check a small population of virus with known epitopes but may collapse in the face of an onslaught of unrecognized virus, much as it did in the initial infection.
I also agree with mrL that the mechanics of chronic, very low-level, infection are puzzling, but note that this basically already happens in cells in which HCV is known to replicate but to do so poorly - eg central nervous system cells.
I’d like to thank all of you who bring up these discussions of the many facets surrounding hepatitis c and how it is all interconnected with the disease. I don’t know how so few can pull together so much information and have the time to do so, I’m envious in that I do not have the time or focus to embark on such endeavors’ but do greatly appreciate all for the information provided in the different topics of discussion which at times can make your head spin trying to piece it together, but then again, that’s what great reading is all about.
“So yes, the underlying truth is far from evident and DATA is a more valuable guide than conjecture (which can simultaneously seem quite reasonable and be dead wrong). “
No argument there, although as stated previously (and repeatedly) the validity of the data and the proper interpretation of what the data means are of paramount concern (and what remain in question here). Both of those issues have not been conclusively resolved as pertaining to the persistent infection theory. Also, you keep saying the data is a “more valuable guide” than conjecture. You’re right, but you can’t pick and choose your data. You can’t pick and choose your facts. You must present a unified field theory that accommodates ALL the facts and ALL the observable data. By that I mean you have to marry up the aforementioned macroscopic observable (and statistically overwhelming) facts concerning SVR (i.e. SVR durability, antibody taper etc etc). You can’t just take *in isolation* the controversial data from Castillo/Pham et al which appears to support persistent infection and then simply ignore, or gloss over, or apply some awkward and obviously kluged together *conjectural* theory to “make it all work.” You also have to fully explain and accommodate the much larger picture of solid, repeatable observations (which don’t require controversial test methods) that very strongly suggest eradication. All of it must be integrated into a whole and make sense – all of it must concur and marry up in order for the low level persistence theory to move from hypothesis into fact. And let me tell you, that sure hasn’t happened yet. And right now, I have a hard to seeing how it is going to happen anytime soon.
“…an approximate half-life of 2.7h is consistent with other estimates of hcv kinetics (if hcv's phenomenal production rate was one sided you never would have survived the production of that much virus)”
Apparently you’re under the impression I was suggesting that *all* of the virus produced in our bodies during our active infection cumulatively remains (and our bodies are filled with dead virus). Of course that’s not what I meant at all (and if you re-read what I said above, you’ll see that’s true). What I mean, in a simple albeit imperfect analogy, is that during our infection our bodies are like houses that have a river of mud flowing through them for many years. The vast, vast majority of the mud comes and goes passing through after its short stay. But after the river is finally turned off and a thorough and meticulous cleanup ensues afterwards, it is not reasonable to assume that even if all of the walls and ceilings and floors look perfectly clean, that a few grains of dirt won’t remain somewhere hidden within the house.
“- re reliability of studies detecting residual virus. This has been discussed at length before: one the papers is out of the Mayo clinic; the results have been replicated in many labs; HR, who certainly qualifies as a world-class expert on use of PCRs to detect viral RNA, commented he found no fault with Castillo's methods. The methods being used are simply sensitive PCRs, one of the most fundamental tools of mol bio. Probably the most significant difference with routine clinical tests are that they are often based on lysed cells whereas the standard VL test only looks for free virions in serum.”
Yes I recall HR commenting on this, but he definitely stopped short of endorsing this theory. He never said anything much pro or con concerning this theory (that I ever saw) and was generally short on words on this topic. Nor did he assert that he was privy to all of the intricate details of methodology or how it was actually carried out (i.e. he didn’t participate in this research). I’ve also seen him comment in terms that definitely suggest he thinks in terms of eradication (as many other reputable doctors do). Paraphrased from memory something to the extent of “every last virion must be removed” etc. Also, you assert these methods are “simply sensitive PCRs”...really? That’s interesting because I’ve never heard them described that way. No doubt they are built upon existing technology/methods (as all new methods/technology are), but how do you know this? Again, can you share your credentials with us so we can know where you’re coming from? Also, the space shuttle is based on simple bottle rocket technology. Does that mean that the space shuttle is “simply” a fancified bottle rocket? There’s a lot more to it than that, isn’t there? I suspect the same applies to this test methodology, and it’s also probably why several other follow up tests (performed by equally reputable scientists) attempting to replicate Castillo/Pham et al have not found what they found – as referenced in the links on this thread (apparently because they’ve left out some additional step that is not used in the existing test as you’ve stated previously).
“Re your questions (1) durability of SVR is more likely due to a fundamentally improved immune response than to absence of virus else fluctuating viral rebound”
A “fundamentally improved immune response” is what’s responsible for SVR durability? Really? That’s interesting. So what you’re suggesting (or outright stating) is that IFN/riba treatment leading to SVR permanently “improves” the immune system. It’s not that it permanently eradicates the virus, it’s that the immune system has been permanently “improved” in a manner that enables it to permanently contain the virus. The virus is still there, still viable, still reproducing and would launch a full blown reinfection if it could - it’s just that the immune system has been permanently “improved” and thereby contains (or quarantines) the virus thereafter. Hmmm. Well, a few issues with this new theory (to me at least): (cont...)
1. Where is your evidence and your “data” that the immune system is improved after SVR? Politely to you, this sounds like the wildest conjecture. I’ve never heard any such thing. I’ve certainly heard that sometimes people have autoimmune issues (i.e. a form of misguided immune amplification) after drug induced or natural clearance leading to SVR, but not that there is this generalized “improved” immune system. And improved to the extent that it can now so thoroughly and reliably contain an active infection many, many years after SVR-ing in the way you are asserting it is? Please present your data that directly supports this radical theory of yours.
2. And apparently this improved immune system that is improved through drug treatment is some sort of strange cumulative process leading to a binary yes or no outcome (strangely, looking just like an eradicative process!). If you take SOC for 48 weeks and achieve UND status by, say week 8, your immune system is sufficiently improved by week 8 to bring the virus to UND levels. But if that person relapses after tx and experiences full viral rebound even over what baseline VL is (which is what commonly occurs), his immune system hadn’t been sufficiently “improved” yet? Is that how it works? And if that same patient then goes on to treat again, and performs similarly during treatment, except this time achieves SVR – the improvement has “taken” on the second attempt? Is that it?? I’ll ask again, if eradication was what was actually happening during successful HCV treatment – what would it look like? How does what we see in successful (stubborn) viral treatment meaningfully differ from what we see in the successful treatment of a stubborn bacterial infection? Aren’t their profiles extremely similar? Why do you suppose that is?
3. And as already clearly and repeatedly stated, what about during significant IMMUNOSUPPRESSIVE events as occurring in large numbers of SVR’s where the virus does NOT come back? You’ve conspicuously not answered that question (which was posed directly to you) – why is that? Is the immune response permanently “improved” during those times too? By definition the immune response is suppressed during immunosuppression - that’s why it’s called “immunosuppression.” It’s far from “improved!”
So, y’see how you have to hammer round pegs into square holes to make all of this work? Y’see how these facts are a real obstacle to viral persistence? They’re not fitting together.
“…but how much evidence is there of this? I've read that ABs have been observed to disappear but if you've seen studies supporting a consistent decline please post”
Didn’t you read the studies referenced in this very thread? Here’s a few excerpts:
“The most significant decrease was observed with anti-NS5 antibodies (p = 0.001)…” and “HCV antibody titers showed a marked decrease.” And I’m sure you recall the study (that I don’t have offhand) that measured antibodies in the large cohort of Irish nurses that were infected in the ‘70’s, and again were found to decline to even UND levels over the years. You remember that one right? Why didn’t you include it in all the other links you posted? Also, anecdotally I’ve observed one person I know who cleared naturally that exhibited a remarkable and dramatic reduction in AB’s just a few months after clearing the virus. Bottom line: AB’s decline in the vast majority of those that SVR. So once again, if viral persistence is a fact (or probable fact) please explain and accommodate AB taper and explain it in terms a simple layman like me can understand. Once again, round peg – square hole.
“I'm also not sure what level of re-infection SVR does or does not protect against. If you save a vial of your pre-tx blood can this re-infect you? or can you only be re-infected by virus with a sufficiently different sequence. It's worth remembering that one of the virus' strategies is to overwhelm. The post-SVR response may be capable of keeping in check a small population of virus with known epitopes but may collapse in the face of an onslaught of unrecognized virus, much as it did in the initial infection.”
Well now *that* sounds like conjecture! One last time: round peg – square hole.
>You must present a unified field theory that accommodates ALL the
> facts and ALL the observable data.
not very interested in doing that, sorry. My point is much more specific: the majority of direct data currently available makes it very hard to believe in total eradication at SVR (ie complete absence of viable virions). By data I mean direct PCR amplification of HCV RNA sequence, both + and - strand.
Whether SVR durability, AB decline, fibrosis regression, etc., etc. do or don't "prove" complete absence of virus seems a pointless argument; as you point out one can spin endless conjectures on both sides. For example, loss of ABs, while interesting, does not prove absence of virus - see for example
and references cited there. However the PCR evidence is unequivocal , either it's contamination or HCV RNA is present.
>it is not reasonable to assume that even if all of the walls and
> ceilings and floors look perfectly clean, that a few grains of
> dirt won’t remain somewhere hidden within the house.
sorry - RNA degrades; if you don't believe the above review on mRNA degradation read further (and note the PCRs in question are amplifying a fairly long stretch)
>Also, you assert these methods are “simply sensitive
> PCRs”...really? That’s interesting because I’ve never
> heard them described that way.
look at the Pham/Michalak medscape article cited above. It gives detailed PCR protocols for detection in plasma as well as for tissue and pbmc cells
>this sounds like the wildest conjecture. I’ve never heard
> any such thing.
how do you think people get to SVR via SOC? unlike PIs, IFN/RBV have no toxic effect on the virus (one can quibble about the RBV) they simply stimulate anti-viral pathways. Improvement of the immune response, via stronger HCV-specific CD4/CD8 cells etc. etc. is the whole point of SOC..
>Didn’t you read the studies referenced in this very thread?
you're right - I missed the reference to ABs in that abstract. I'm still skeptical that there's widespread support for "AB’s decline in the vast majority of those that SVR" but will read a bit further when I get the chance.
I agree with your comments and reference support cited above. Its hard to discuss or debate an issue like this, especially when the scientific research that one offers to support a point of view is either dismissed as inaccurate or ignored by other parties...but at the same time any research studies offered up on their end are expected to be taken as the 'last word', and accepted as absolutely valid, without that same chance of error, or oversight that are applied to your reference studies. I have pretty much given up debating many of the issues that are sometimes considered controversial because no matter what you might offer up in support of a view it is generally dismissed as invalid, subjective, biased by contamination, or worst of all, based on one's own 'paranoid' point of view regarding the virus. If all else fails in an argument, then the final resort in discounting the person debating the other side is to just label their position as wacky!
There has been little or no scientific explanation for the many research studies using more extreme amplification of the virus which have shown low level REPLICATION years down the road after SVR. I am interested in what this might mean, rather than trying to just explain it away with my own conjecture. I also get a bit irritated whan people refer to the 'toxins' washing out of our bodies after tx, and that the interferon slowly stops 'poisoning' our cells over a long period of time, which supposedly explains post-tx problems. The fact is that interferon just up-regulates our entire immune response, thus causing our systems to go into a sort of hyper-immune-overdrive mode during tx. Some of this immune re-regulation does not just 'go away' after tx, even though the interferon itself is gone pretty quickly from our bodies. Rather than having 'toxins' hanging around in our cells over long periods of time, we are really seeing a system that has been jolted and stimulated, and that does not easily go back to its former configuration quickly or easily. For some people these abberant, often disruptive and painful reactions remain for years, for others their immune systems rebound to more or less normal in a few months.
I really appreciate your calm perseverance, and point by point dispassionate response to the debated issues above. I find it harder and harder to exercise that same degree of patience these days, and hence involve myself far less in controversial debate. I have felt the frustration of presenting research, logical points, and supporting data only to see it either ignored, or just discredited as 'faulty' with no scientific support from the other parties, or proof of just why its not accurate. At the same time we are asked to take any studies supporting the opposing point of view, no matter how unsophisticated or isolated, as proof of point, end of discussion, etc.
I prefer open minded discussion, and am more than willing to modify my beliefs and positions if someone can scientifically show my why I should, and explain why the studies I might cite are as absolutely 'invalid' as their studies are 'valid'!
I hope you are well, and enjoying life. I am very much, and have been doing a good bit of world travel with my family, interspersed with running my business. In spite of the downside of post-tx life, I find that overcoming obstacles, and enjoying the positive stuff is still my forte. Thanks for your always extremely lucid discussions, and the absolute calm rational approach that you bring to the forum.
You didn't respond to the vast majority of what I said above, so I think it's pretty obvious at this point that you are unable to accommodate the factual observations carefully described above (that tend to cast significant doubt on viable/reproductively active viral persistence). It's also obvious at this point that your mind is made up and you believe in viral persistence (which is certainly your prerogative). I also notice a pattern of behavior of only referencing studies that support your point of view and omitting studies that would tend to contradict or cast doubt on this view. Nothing wrong with that either, I just had previously thought of you as being more dispassionate and non-biased about the whole "creepy crawly" thing (as opposed to DD, for instance). I won't bother discussing it further, other than an obvious response to one of your last comments:
">this sounds like the wildest conjecture. I’ve never heard any such thing.>> how do you think people get to SVR via SOC? unlike PIs, IFN/RBV have no toxic effect on the virus (one can quibble about the RBV) they simply stimulate anti-viral pathways. Improvement of the immune response, via stronger HCV-specific CD4/CD8 cells etc. etc. is the whole point of SOC.."
Of course I think people get to SVR via SOC via the immunostimulative and possibly directly antiviral effects of SOC. But, clearly and very obviously, those effects are temporary, and only work as long as you keep taking the drugs (that's why many people achieve and maintain UND status during tx, only later to relapse once the drugs stop). But, again obviously, the point here isn't what happens during tx, the point is what happens after tx when SVR is achieved. That's why the title of this thread is "SVR eradicates HCV", and that's what we we've been talking about all along. Your conjecture above was our old friend the "quarantine" theory (an old favorite of DD's). Except you didn't call it that, you called it "improvement". You inferred that the immune system is "improved" *after* SOC treatment and so improved that it contains or quarantines the virus permanently afterwards due to its "improvement." Even in the face of all kinds of conditions and challenges to the immune system. You fail to provide any information or evidence or data to substantiate this improvement, nor do you explain how this improvement process takes place in tx failures and SVR's, nor (once again for the 4th time) did you address (in any way) the *very* obvious and devastatingly pertinent facts concerning SVR durability in the face of disease and drug induced IMMUNOSUPPRESSION. I think at this point it's fairly obvious you're not taking that one on because it doesn't fit into the "big picture" as you see it (as explained above). But like it or not, it *is* a part of the big picture, and all the blinders in the world will not make it go away.
And DD - please, accept that the creepy crawlies are a part of your world. Accept that they're in your eyelashes right now. Accept that they're coursing through your veins and running through your gut. Accept that they're in your bed and in your brain. They're *there* dude. They will always be there and there's nothing you can do about it. We are a part of a much larger ecosystem; we ourselves *are* an ecosystem in and of itself. Zillions upon zillions of hitchhikers are around us, on us, and *inside* us. Many for our own good, many we owe our very survival to! Some not there for our own good. But just as we live parasitically off of plants and animals, and take what we need from the ecosystem to survive and prosper, we have creepy crawlies that do the same to us. And they'll feast on us, buffet style, when we die too. But you know what? It's all good, it's all good dude. It's all a part of god's plan, pilgrim. So be well and accept your place in the universe. Because you're gonna drive yourself nuts fighting the creepy crawlies dude...and I mean flat out bonkers man. Please, turn back before it's too late. If nothing else, do it for the children! ;-) And always remember: COOTIES REIGN SUPREME!
Am I the only one who sees one side drifting more and more into the "argumentum ad hominem"? It's really becoming more and more predictable and more humorous too - arms flailing wildly in the air.
I'm not certain about this SVR issue by any means and I wonder how someone can appear to be so sure about this. But I do have an opinion about see who is winning the argument here - it's willing with his hands down, sitting calmly amidst the tempestuous sea of desperate insult and innuendo swirling around him .
I must admit that I'm enjoying a bit of the ad hominem directed at both Willing and DD, as both have directed some at me in the past on this same topic, and same with you my friend, on other topics -- so I guess you all were losing your arguments with me? LOL. Ad hominem aside, I think good non-ad hominem points have been made on both sides. Job well done, fellows. One of the better discussions on the issue to date, so thank you to the participants.
BTW my take (and my liver specialists), as expressed before, is when the virus is gone, it's gone -- at least in a *meaningful* way. And until whatever it is that some researchers repor they see under a microscope/centrifuge are given some clinical signficance, I'm not going to lose much sleep over it. Yes, in the words of "Mre", the "cooties" are all around us, so as long as they leave me alone...
I think we all - or the vast majority anyway - agree that SVR means it's gone in a "meaningful" way. I cannot speak for DD on this point but when I see normalized liver enzymes, undetectable viral load and improved histology that sure looks meaningful to me. And durability is a big plus too. But, that really wasn't what I thought this thread was about.
If it is gone in a meaningful way, why is this research important? Why are some researchers saying it is completely eradicated, and other researches stating otherwise? It is either gone, or it isn't. Some think it is, some think it isn't. I'm inclined to "think" it is gone, and the arguments above I think, on balance, support that view, particularly as it matches peoples experiences. IMO the odds are that this is a research / testing issue rather than a medical misunderstanding about some mysterious property of Hep C that may or may not exist, whereby Hep C can change such that it is not Hep C, or whereby our bodies are magically stronger at containing after treatment. In saying that, I might be wrong, but for me, I'm happy with the eradication research which is a highly plausible and compelling hypothesis, and find the thread an interesting read - not disturbing at all.
Don't worry jim, I can handle the viral persistence club as it adjoins the back patting DD/willing/mikesimon clique. And although there may be some saucy words exchanged here, make no mistake - bringing up these incredibly obvious, plain as the nose on your face issues is absolutely salient, pertinent, applicable, within scope, exactly on target and exactly on topic. Nothing ad hom about it mikesimon. And for you of all people to be the ad hom policeman around here is a joke anyway. If you don't like what I have to say, feel extremely free to SKIP IT, bub.
I just find it amusing how there are a couple of self appointed experts around here on viral persistence who have begun to carry themselves as if "the argument's over", or as in DD's case constantly coloring himself as the noble, besieged, objective and scientific inquirer who just "wants to get to the truth" but is constantly unfairly attacked and dismissed by a moblike horde of doubting idiots. I usually skip over these persistence threads because I really don't care that much about it. I don't obsess over it like DD and a few others do. I don't have a file catalog with every study done on it that just happens to agree with my preconceived notion that it's already true (leaving out reports like the one on this thread's heading). And I don't sit around just waiting for another thread that even remotely pertains to the subject to come around so I can weigh in with my "expertise" on the matter (often scaring newbies with the concept that you're "never really cured").
So just this once I thought I'd probe into this issue using some common sense inquiry and very basic observations with "the experts" and see if they could teach me something I didn't already know. Well, big surprise - isn't it funny how they really don't know much about it at all? They don't have any answers to these perfectly reasonable questions, but yet they're still "the experts", with the implied swagger that the argument's over when it comes to viral persistence. Unless there's someone else out there reading this that knows a lot more than you guys do about this subject, sure sounds like the argument's FAR from over to me.
So in the meantime guys, stay away from those cooties. Except DD of course, he won't be able to - but at least give it the 'ole college try?? ;-)
I have been undetectable since April 2003 and I stopped treatment in June 2004. I have tested every month since I became undetectable with Heptimax test < 5 IU/ml.
I have a biopsy report from June 3rd 2006 which shows a low VL HCV.
I go to a very well known and respected transplant canter and the chief pathologist is a world renown expert.
How do you explain that? Misread biopsy perhaps? Wrong PRCs every single month for 2 years - one just 2 weeks before and one 10 days after my biopsy and both were undetectable. Maybe we transplant recipient SVRs are unique and just happen to show HCV on biopsy.
I know I was very surprised when I learned of the biopsy results.
But, my surgeon wasn't the least bit surprised - he's seen this stuff before because he sees a lot of biopsies - even SVR biopsies. How many SVRs do you know who've undergone a liver biopsy post clearance?
By the way, my surgeon says that he has had SVR patients who showed no sign of HCV anywhere with any test and you know what he said? He said he sees a higher than average incidence of acute cellular rejection in these patients. Must be immune system related somehow.
It's hard to say what to make of that, or what was picked up, especially because when you were asked a year or so ago some specifics of that test you replied that you had failed to ask the surgeon and btw my "renown expert" believes once the virus is gone it's gone for all practical purposes. In any event, sure glad that whatever that single test showed, you're back to UND. Of course, one explanation is that with all the sensitive testing you get that one every blue moon is bound to be a false positive, and frankly that's why I don't test any more :)
As to your surgeon seeing "a higher than average incidence of acute cellular rejection in (SVR) patients -- yes, it could be the immune system still over-primed by the interferon from SOC per this paper here:
Don't worry, our flailing, and foaming brigade will find a way to dismiss your case and your highly experienced surgeon's opinion as not relevant. Or they will just plain ignore the implications. Far from obsessing over 'persistent' virus, as our colorful friend would claim, I am not on the forum day after day ranting and raving over everyone elses opinions and research comments. I am pretty much living and enjoying life.
I continue to be interested in the significance of 'persistent' virus as demonstrated by now numerous studies, and even acknowledged by many researchers and growing numbers of hepatologists. Not because I am obsessed, because in reality I think about it very infrequently, but sometimes when I come back to the forum and see long-winded, insult ridden, conjecture laden diatribes, I just can't resist throwing in my own two cents! Whether I am right or wrong in my opinions on HCV, I can tell you one thing I am dead sure of, and right about: some people make a complete farce of the concept 'intelligent discussion' regularly and repeatedly. It doesn't do much to further the aims of the forum. In my opinion it just promotes more antipathy and displeasure with reading the threads.
This is why I don't like to spend much time or energy on these threads anymore. If you have to wade through constant reams of personal insult, emotional venting, and ridiculous accusations....why bother?
I really do appreciate that there are a few cooler and calmer heads here that can digest and wade through the garbage, and manage to maintain a very mature, respectful, and objective demeanor. (I am not including myself in this comment)
One final thought regarding 'viral persistence', I will say again that I agree with the 'durability of SVR' consensus opinion, and the 'repair of damage' potential for SVR, and even the concept of 'virtual, or effective' viral disappearance'......my concerns with the possibility of, and growing evidence of persistent replicating virus have more to do with the possible effects of keeping a virus in 'remission' by our immune systems (if that indeed is what is taking place), and the long term possibilities of 'reservoir virus' slowly causing changes in the functing of our CNS, or brains. Much of the study on those who 'spontaneously recover' from acute HCV infection shows that the great majority of these people continue to demonstrate typical HCV extrahepatic symptoms, decades after the 'spontaneous resolution' of their initial infection. The scientist in me really needs to fully understand why this happens, and whether it has to do with 'viral persistence', and related issues.
We do know that 'occult HCV' (different than persistent virus) is becoming found more frequently in a number of people, and this alone also indicates viral behavior contrary to current explanation. The doctors and researchers don't really understand how any of this happens...but apparently they should call Mremeet and get some solid answers to their concerns. They will be very gratified to know that we have such a prescient specialist in our midst!
Have a great week guys (and gals), and remember to ENJOY!
thanks for the update; very glad to hear you're doing well. If you can handle long-distance flying and still feel well I'd say your health is way ahead of the median..
>If it is gone in a meaningful way, why is this research important?
(1) in-depth understanding of how hcv interacts with the immune system, even beyond SVR, is of value in vaccine development and in tx design for non-responders/relapsers (2) you learn a lot about how something is put together when it breaks; HCV breaks our immune response in fundamental ways, it has a lot to teach us.
>You fail to provide any information or evidence or data to >substantiate this improvement, nor do you explain how this >improvement process takes place in tx failures and SVR's,
if I'm understanding you correctly, you're questioning whether control of the virus could be due to an improvement in the immune response? But that's precisely what adaptive immunity is all about!
See the wikipedia article for an introduction:
Development of strong HCV-specific, antigen presentation and CDC4+ CD8+ Tcells is the crux of immune control. From a recent review out of Harvard (yeah, I know, more ad-hominem name dropping)
"CD4+ T cells have multiple effector functions in antiviral responses,
both via secreting antiviral cytokines and via activating
viral specific B cells and CD8+ Tcells. A strong preponderence of
evidence demonstrates that in the acute phase of HCV infection,
vigorous, broadly directed and sustained HCV-specific
CD4+ and CD8+ Tcell are closely associated with a self-limited
course of infection [26,84–88]. HCV-specific T cell responses
and the induction of IFNγ in peripheral blood and liver coincide
with a decrease in HCV RNA titers [26,30,89], although there is
a notable lag between the onset of viremia and the onset of T
cell responses [26,89,90]"
A free-access overview is:
The 'strong preponderance' mentioned above is primarily in the context of acute; there's not yet as much data distinguishing successful vs failed tx on the basis of CD4/CD8 profiles but it seems a likely extension.
> nor (once again for the 4th time) did you address (in any way)
I did, it was buried in the 'etc.etc.' fine print regarding conjectures. Maybe the impregnability of SVR even in the face of immune-suppressive medication supports absence of viable virus; equally plausible is the conjecture that the suppression is nowhere near strong enough to cause resurgence (did you develop any major bacterial or viral infections while taking that 80mg of prednisone?). And again note that there *is* some, though scant, documented evidence of resurgence as posted above. However, there's not much point arguing about this - it simply isn't direct evidence, pro or con.
>your mind is made up and you believe in viral persistence
>only referencing studies that support your point of view
not so - as noted above, in addition to Maylin'08 there are two other recent studies that report no finding of post-SVR HCV RNA in PBMCs (and all three failed to apply mitogen stimulation of cells prior to PCR). The list of research TN has compiled on the 'occult' health page speaks for itself. If you believe it's one-sided you should extend it; I'll be surprised if TN has missed much.
And BTW, his most recent addition (Hoare'08, he now seems to be adding pre-prints even before publication! you'd think keeping that hair-do in shape wouldn't leave him much time) concludes with
"Non-viremic HCV-antibody positive patients have a liver biopsy that is usually abnormal. Fibrosis was present in most with similar inflammatory infiltrate to viremic cases. The presence of a CD8+T rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV-RNA negative cases"
None of these patients had undergone tx, their HCV-RNA und status is due to their unaided immune respose. However, as I recall, you were arguing a while back that all SVRs are created equal..
I think we can just examine the phrase that is used for successful HCV therapy to understand where the medical community is leaning on this issue: Sustained Viral Response.
It means the virus is at undetectable levels on standard PCR testing, and remains so over long periods of time, possibly even permanently. The response (to undetectable levels) has been sustained (ongoing). What the term does not state is: Viral Eradication.
This all gets back to the meaning of "IS" as Bill Clinton would have said...or in this case the meaning of 'cured'. We have all had this discussion many times, with tons of supporting argument and research on all sides, so I won't rehash any of that. I will just say that 'cured' is what SVR now implies, but the meaning of that 'cured' ranges from the concept of 'pushed to undetectable levels on a permanent basis, to at the other extreme, 'totally eradicated from the entire body, and gone forever with no low level replication or compartmentalization'.
I do note that most of the Liver Association, and Medical Advertising literature still hedges the bet considerably by stating in small print that successful therapy causes the virus to 'remain at undetectable levels'. I always get the feeling that none of them really feel comfortable using the word 'eradication' for fear of down road research findings, or possible litigation, etc.
So, in summary, we do have a cure, but lots of disagreement over the finer aspects of what it consists of. Many of us continue to be concerned about these issues chiefly (I believe) because so many of us still experience a host of post-tx, post-SVR issues that seem strikingly similar to the pre-tx HCV symptoms. We want to know if the possibility of having 'persistent viral infection' after SVR could be a reality as much research testing has discovered, and/or could be one of the causes of post-tx problems.
I hope these comments spark no controversy, because that is pretty much how things are in the HCV world today. I don't think that ANYONE has concrete, final, immutable proof or answere, one way or the other. Now the fact that Dr. BigReputation says that SVR is in his opinion equivalent to Total Eradication, means no more than another professional opinion, in a sea of conflicting research and other opinions. I respect the opinions of both sides, but consider them only 'opinions' until finally proven and agreed upon by all leading HCV medical experts and reputable HCV researchers.
I thought I was going to have to bump this thread back to the top with my admission that I was mistaken. It's really not any easier but perhaps it is providential that there has been recent activity in this thread.
I have been operating under the assumption that molecular testing of my tissue sample detected active HCV. My biopsy was a little over two years ago and I thought that I understood the methodology - at least from a layman's limited understanding.
I have been in touch with the chief pathologist at the lab which processed my biopsy and he told me that no additional testing was done on the tissue sample to detect HCV. He said that the author of the report assumed that I had active HCV because that was my underlying disease which necessitated transplantation and he saw some inflammation and fibrosis in the tissue sample which is characteristic of HCV. Basically the report said:
"Well you had HCV pre-transplant and we see inflammation and minor to moderate fibrosis in the tissue sample so we're calling it active HCV".
That certainly doesn't rise to the level I have come to expect from my center and it is somewhat disappointing. But, the bright side is that I suppose that I can once again seriously entertain the idea that I am HCV negative - and that is somewhat comforting. I have never been invested in believing one way or the other. My opinions are driven by information and even when the information isn't favorable I try and keep an open mind about it.
MY BIOPSY OF JUNE 2006 DID NOT SHOW ACTIVE HCV AND ANYTHING I HAVE SAID UNDER THE ASSUMPTION THAT IT DID SHOW ACTIVE HCV SHOULD BE DISREGARDED.
I apologize for not knowing what I was talking about here. Of course my situation doesn't explain the Tram, Pham and Casitllo arguments but neither does it support them.
Thanks for taking the time to double-check on what your liver molecular testing actually showed. In all fairness, you did state back then that you weren't sure of the exact methodology used for those tests, and it was others that seemed to run/extrapolate your anecdotal report more than yourself. Of course, the really good news for you -- and hopefully for all of us - is that they did not find HCV in your liver tissue.
If memory serves me, weren't you put on a short course of interferon after that report read? If so, and if it was based on a false read of that report, I'd be a bit ticked off, but maybe I have things a little off, it's been quite awhile since you posted the incident.
I did follow up on my biopsy and after reading closely the disclaimer which mentioned molecular testing I assumed that was what was used. I also discussed it with my transplant coordinator and she seemed certain that some type of staining was done which detected HCV.
After my biopsy I was put on half dose Pegasys, low dose Ribavirin and increased Prograf (anti-rejection) dose. At the time it seemed like the shotgun approach where you shoot at everything and hope to hit the target. I will say that the chief pathologist acknowledged that there is a possibility that there is active HCV in my tissue sample and that my stimulated immune system anti-HCV attack was responsible for the enzyme elevation. This acknowledgment was not in response to a question from me or any prompting by me. He just listed it as one of two possibilities and, in doing so, stated that some patients with undetectable serum show active HCV per tissue PCR on biopsy. He suggested that if I have another biopsy I should request a tissue PCR which "will help determine whether the treatment has resulted in viral clearance or viral control". He also stated that this is a very complex situation. I think I already knew that.
The other possibility he mentioned was that I "had a minor component of rejection" and that caused my enzyme elevation.
His one statement which is most relevant to this discussion was:
"Negative serum HCV RNA testing does not mean that the liver tissue is negative for HCV".
I trust this man on this issue so I believe that negative serum testing is not necessarily the final word on this "eradication" issue.
As to what happened to me in 2006? I would have to bet I had some degree of organ rejection. It could have been HCV and my immune system but, without evidence of active HCV, I think rejection is the more likely culprit.
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.
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.
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).
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 :)
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
>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!
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.
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
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.
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.
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.
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.
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.
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
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....???
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.
"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).
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.
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.
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.
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.
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?
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