SVR Eradicates HCV

[mremeet]

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

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

"SVR Eradicates HCV

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

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

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

ABSTRACT

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

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

Results:

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

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

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

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

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

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

Regression of cirrhosis was observed in 7 of 10 patients.

Conclusion:

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

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

[mikesimon]

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.

[nygirl7]

Wow - wow - wow.   Wow - wow - wow.

Those results are simply STAGGERING!!!!!  

Eradication, what a LOVELY LOVELY word! :)

[mremeet]

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!  ;-)

http://www.natap.org/2007/DDW/DDW_09.htm

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."

[mikesimon]

http://tiny.cc/Bkucp

[mremeet]

Thanks. May 2008 from Gastroenterology: recent and authoritative.

[mikesimon]

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.
Mike

[willing]

not at all  sure there's anything new here.

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

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.

[Mr Liver]

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.
Mr Liver

[mikesimon]

I don't understand. Would you explain it further?
Mike

[jmjm530]

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.

-- Jim

[mikesimon]

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.
Mike

[DoubleDose]

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.  

DD

[HARRYBEADS]

to the negative ones

I am liking this report, we're getting close. eh!
  
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!

Harry

[mikesimon]

Thanks Harry. That was insightful and very illuminating. Mike

[CockSparrow]

Perhaps this from Hepatology might open your mind. Its not negative just facts, and there is nothing wrong with facts.

Histological changes in HCV antibody positive, HCV RNA negative subjects suggest persistent virus infection.

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.

Abstract
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.

CS

[Mr Liver]

Hi Jim, Mike

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.

Mr Liver

[mikesimon]

Thanks. Mike

[willing]

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)
http://www.medscape.com/viewarticle/563337_5

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.

[mikesimon]

My thinking ran essentially the same way though I couldn't have expressed nearly as concisely. Thank you Willing. Mike

[Mr Liver]

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.
Mr Liver

http://www.wjgnet.com/1007-9327/7/228.asp

[snippets69]

I'm slightly confused by the doubter(s).

Hep C replicates, yes???  If there was some trace left, it would replicate and then be detected in the RNA tests after some time had passed, which is not the case.

[mikesimon]

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.
Mike

[willing]

> 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:
http://www.ncbi.nlm.nih.gov/pubmed/18053213
and  the ever-popular
http://www.ncbi.nlm.nih.gov/pubmed/16107964
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.

[Andromedae]

"172 HCV-antibody positive, serum HCV-RNA negative patients underwent diagnostic liver biopsy between 1992 and 2000 "

That study was before the current Riba and peg protocols (almost 16 years ago) so it is not surprising that the results are more negative.

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.

I'm calling that a cure (personally ) and hope that it works for me!  :)