Prednisone and HCV

[VXman]

I am most fortunate to have an SVR for 1.5-years. I was a successful statistic in a Prove 3 telaprevir clinical trial. Recently I developed a sinus infection (no relation) and was prescribed an anitibiotic and prednisone. I just started the antibiotic, but am delaying the use of the prednisone until I have an opportunity to speak with my past hepatologist. My father-in-law is a retired MD and told me that there was a remote, but none-the-less possible relapse of HCV due to the use of prednisone. I am inclined to disbelieve this, but do not want to gamble. I'm certain that I'll clear the sinus infection with antibiotics and nasal rinsing, without the use of the prednisone: however, I wanted to see whether their was any information regarding this issue. I performed a Google search and was unsuccessful in narrowing it down to my specific concern. Any information would be most appreciated. Lastly, for each of you living with HCV, keep your spirits high. Telaprevir and other medicines will radically change the SOC in the very near future. Vertex has indicated that it expects to file for a NDA (new drug application) in early 2011. The SVR rate for HCV is significant for treatment naive and experienced patients. I was a non-responder to Peg/Ribavirn. The clinical trial MD claims that I was undetectable within the 1st 2-weeks of my 24-week trial!

[Mr Liver]

Willing--

I would like to read the study you posted if it's available.I looked around for a bit and couldn't find it::
"Late Virologic Relapse Rates Defined by Detection of HCV RNA in Serum in Immunocompromised Patients with Former Chronic Hepatitis C and Sustained Virologic Response After (PEG-)Interferon-Alfa-Based Antiviral Therapy"

Is there a website or link that you could refer me to ? I am interested in the topic of post tp relapse and therapy.

Willing---"but the discrepancy between 'has been shown' and 'has been reported'  is hardly grounds for charging unethical behavior.."

If that was all there was to it I wouldn't have said anything about it.
I believe it to be a bit more than that.
Lee laid out several reasons that could have been the cause of the apparent 'relapse". If you read his conclusion he doesn't have any science to support any of the various reasons he listed as the possible cause(s) of relapse. He mentions, almost in a 'thinking out loud' moment that other studies have suggested that immunotherapy may have implications in this patients relapse so that is the most plausible reason to him in this case.. Again, no science, nor citations just a guess ( can't even rise to the level of scientific postulation ).

Lee: "“The very-delayed relapse of infection after >8 years MAY have resulted from transient immunosuppression due to repeated corticosteroid use. HOWEVER, OTHER factors, including abnormal immunity and cytokine signaling associated with hypogammaglobulinemia, COULD also have effected this relapse pattern [14]

So what began as Lee's listing of SEVERAL possible reasons for relapse , all with no supporting science to reach a definitive conclusion ,ended up becoming  this in Pham et al, paper:

“In this regard, corticosteroid-induced immunosuppression has been shown to affect HCV reactivation years after spontaneous resolution of acute hepatitis C[37].” (citing Lee’s paper)

There can be no mistake here as he specifically cited Lee's paper as suppporting evidence for his research paper. And we know that Lee reached no such conclusion based on his study at all.

I suppose one could characterize this in another way that I haven't thought of. But I personally believe it to be a serious matter of dishonest research. And this type of misconduct does nothing to help Pham et al with their credibility factor.

Thanks for your reply and if you have an addy for that study I would certainly appreciate it.
ML

[willing]

tough audience here, seems there's a bit of shooting the messenger - I know the results of the Pham/Michalak lab are not popular but to accuse them of unethical conduct is extreme.

It's quite true that to write "corticosteroid-induced immunosuppression has been shown to affect HCV reactivation " is overstating the evidence. For example the Welker Zeuzem review phrased this somewhat more accurately, as "Reactivation of HCV in patients with compromised immunity has been reported within case reports and small studies.  Late relapse, however, in immunocompromised patients achieving SVR after (PEG-)IFN-based antiviral therapy is rare (Table 3)." , citing Lee'05 along with:

102 Thomson EC, Fleming VM, Main J, McClure M, Karayiannis P. Reactivation of hepatitis C in a patient with advanced human immunodeficiency virus infection [Abstract]. J Hepatol 2008; 48(S2): S250.

103 Kim AY, Schulze zur Wiesch J, Kuntzen T, Timm J, Kaufmann DE, Duncan JE, et al. Impaired hepatitis C virus-specific T cell responses and recurrent hepatitis C virus in HIV coinfection. PLoS Med 2006; 3: e492.

104 Melisko ME, Fox R, Venook A. Reactivation of hepatitis C virus after chemotherapy for colon cancer. Clin Oncol (R Coll Radiol) 2004; 16: 204-205.

105 Zekri AR, Mohamed WS, Samra MA, Sherif GM, El Shehaby AM, El Sayed MH. Risk factors for cytomegalovirus, hepatitis B and C virus reactivation after bone marrow transplantation. Transpl Immunol 2004; 13: 305-311.

but the discrepancy between 'has been shown' and 'has been reported'  is hardly grounds for charging unethical behavior...

[apache1]

quote from Co:
It certainly seems like two different versions.  Thank you for pointing it out
========================================================

Co, you seem surprised ?
Medical politics. Pham is an expert at twisting results. I am surprised he hasn't been named as our new 'Research Czar'.

Its all in the money. Good Researchers get grants. Some researchers take this way to far. Research has to produce results that are 'favorable'... or grants... end.  

Imo, the least biased studies and interpretations of studies come from state run Universities. But even then, still lots of politics in play.  Makes it hard for a layman like me to understand what is really going on.
  Sometimes the eloquently written article is not what it seems...

jmo
apache

[CoWriter]

It certainly seems like two different versions.  Thank you for pointing it out.

Co

[alagirl]

pt 3 References

1. Rossi G, Tucci A, Cariani E, Ravaggi A, Rossini A, Radaeli E. Outbreak of hepatitis C virus infection in patients with hematologic disorders treated with intravenous immunoglobulins: different prognosis according to the immune status. Blood 1997; 90:1309-14. First citation in article | PubMed

2. Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med 1994; 331:1607-11. First citation in article | PubMed | CrossRef

3. Booth JC, Kumar U, Webster D, Monjardino J, Thomas HC. Comparison of the rate of sequence variation in the hypervariable region of E2/NS1 region of hepatitis C virus in normal and hypogammaglobulinemic patients. Hepatology 1998; 27:223-7. First citation in article | PubMed | CrossRef

4. Gale M Jr, Blakely CM, Kwieciszewski B, et al. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 1998; 18:5208-18. First citation in article | PubMed

5. Gretch DR, Polyak SJ, Wilson JJ, Carithers RL Jr, Perkins JD, Corey L. Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients. J Virol 1996; 70:7622-31. First citation in article | PubMed

6. Kolykhalov AA, Agapov EV, Blight KJ, Mihalik K, Feinstone SM, Rice CM. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA. Science 1997; 277:570-4. First citation in article | PubMed | CrossRef

7. Enomoto N, Sakuma I, Asahina Y, et al. Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996; 334:77-81. First citation in article | PubMed | CrossRef

8. Chang KM. Immunopathogenesis of hepatitis C virus infection. Clin Liver Dis 2003; 7:89-105. First citation in article | PubMed | CrossRef

9. Pavio N, Lai MM. The hepatitis C virus persistence: how to evade the immune system? J Biosci 2003; 28:287-304. First citation in article | PubMed

10. De Francesco R. Molecular virology of the hepatitis C virus. J Hepatol 1999; 31(Suppl 1):47-53. First citation in article | PubMed | CrossRef

11. Li Y, Zhang T, Ho C, Orange JS, Douglas SD, Ho WZ. Natural killer cells inhibit hepatitis C virus expression. J Leukoc Biol 2004; 76:1171-9. First citation in article | PubMed | CrossRef

12. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001; 194:1395-406. First citation in article | PubMed | CrossRef

13. Kumar U, Monjardino J, Thomas HC. Hypervariable region of hepatitis C virus envelope glycoprotein (E2/NS1) in an agammaglobulinemic patient. Gastroenterology 1994; 106:1072-5. First citation in article | PubMed

14. Ma CS, Hare NJ, Nichols KE, et al. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J Clin Invest 2005; 115:1049-59. First citation in article | PubMed | CrossRef

15. Radkowski M, Gallegos-Orozco JF, Jablonska J, et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2005; 41:106-14. First citation in article | PubMed | CrossRef    

-------------------------------------------------
I have many thoughts about this particular study.  I am a bit too tired to address them at the moment and will come back later after some rest.

[alagirl]

pt 2 - "Case patient, materials, and methods.

A 23-year-old white woman with recurrent sinusitis and bronchitis/asthma received a diagnosis of subclass 3 IgG immunodeficiency in late 1991 and began receiving treatment with intravenous immunoglobulin (IVIG) at 2-week intervals (20-25 g each dose). The results of her liver-function tests were entirely normal. In early March 1994, she began to develop nonspecific symptoms of fatigue and anorexia around the time her physician was notified of the contamination of units of Gammagard (Baxter Healthcare) by HCV, and screening for infection was suggested. Her aminotransferase levels were 217/347 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]) IU/L, increasing to peak values of 1850/2020 IU/L 1 month later (figure 1A). A polymerase chain reaction (PCR) assay for HCV RNA was initially positive, but then a quantitative PCR assay was negative (Roche Amplicor RT PCR Assay [limit of detection, <1000 copies/mL]). After 5 weeks, her aminotransferase levels had decreased to 54/281 IU/L. Her total bilirubin level remained normal.

Because of a concern that her infection would persist and be aggressive in this setting, treatment with IFN-a2b (Intron A; 3 million units 3 times/week; Schering-Plough) was initiated on 25 April 1994. Her aminotransferase levels remained normal or near normal throughout treatment, HCV RNA was undetectable on 1 occasion during therapy, and the medication was discontinued at her request on 13 September 1994. Two days later, she developed fatigue, myalgias, anorexia, nausea, and vomiting, and she was hospitalized 5 days after discontinuation with aminotransferase levels of 8078/8531 IU/L (figure 1A). She was repeatedly positive for HCV RNA by PCR assays during this period, with the titers decreasing in parallel with her aminotransferase levels. Other causes of her high aminotransferase levels, such as acetaminophen ingestion, were excluded. Her total bilirubin level peaked at 4.2 mg/dL 3 days later, and her symptoms resolved rapidly, with her aminotransferase levels returning to normal within 3 weeks without further treatment. She continued IVIG treatment over the next decade with no evidence of ongoing HCV infection, having consistently normal aminotransferase levels and negative results of PCR assays documented in 1994, 1995, 1996, and 2000. However, in early March 2003, she complained of symptoms that were "like my previous hepatitis." During the previous 6 months, she had been receiving intravenous methylprednisolone (125 mg) with each dose of IVIG as well as intermittent prednisone therapy for asthmatic episodes. On physical examination, there were no abnormalities. Her aminotransferase levels were elevated (1200/1085 IU/L), and she was again positive for HCV RNA (figure 1B); quantitative PCR indicated an HCV RNA titer of 267,000 IU/L. The genotype of the infecting virus was 1a. One week later, her HCV RNA titer had decreased to 15,200 IU/L. All corticosteroid therapy was discontinued, and, over the next 2 months, her HCV RNA titer again became undetectable without further treatment. Her aminotransferase levels returned to normal, and she has remained negative for HCV RNA during repeated testing (6 occasions) for 18 months. Liver biopsy was not performed.

Serum samples stored at -80C were available from the 1994 treatment period and all later time points. HCV RNA was quantified in serum samples from 1994 by use of the Roche Amplicor RT PCR Assay (limit of detection, <1000 copies/mL). Negative assays were confirmed by use of more-sensitive assays (limit of detection, <200 copies/mL) after 1996 and, most recently, by a Roche Amplicor assay (limit of detection, M mutation at HCV polyprotein amino acid position 370, which is outside the HVR1. In contrast, we identified 5 NS5A quasispecies variants, each harboring mutations within the PKR-BD and the ISDR, as well as 1 sequence with an additional mutation in a previously described variable region, termed "V4," that flanks the PKR-BD [7]. Sequence analysis was also performed for the virus associated with the patient's relapse in 2003, and these sequences were compared with those associated with her previous infection. With the exception of a P->Q reversion at position 2235 in the NS5A coding region, the sequences of the HVR1 and the NS5A coding region of 10 independent clones at this time point were identical to the dominant sequences of the previous isolates.

[alagirl]

It will surprise no one when I say that I of course have some questions about this 2005 case study of the woman with hypogammaglobulinemia.  

natap.org

Reemergence of Hepatitis C Virus after 8.5 Years in a Patient with Hypogammaglobulinemia: Evidence for an Occult Viral Reservoir

The Journal of Infectious Diseases
Sept 15, 2005;192:1088-1092

William M. Lee,1 Julie E. Polson,1 D. Spencer Carney,1 Bogachan Sahin,2 and Michael Gale, Jr.2

1Department of Internal Medicine, Division of Digestive and Liver Diseases, and 2Department of Microbiology, University of Texas Southwestern Medical Center, Dallas

The question of whether viruses persist after apparent clearance of infection remains unanswered. Here, we describe a patient with hypogammaglobulinemia whose acute hepatitis C virus (HCV) infection appeared to resolve after receipt of interferon therapy, relapse immediately, and then clear spontaneously-only to relapse after receipt of corticosteroid therapy, and clear again, 8.5 years later. Sequencing indicated that the viruses detected during each relapse were virtually identical, with the hypervariable region 1 of E2 appearing to be monoclonal, which is typical of patients with hypogammaglobulinemia. Nonstructural 5A sequences exhibited quasispecies diversity initially but, after 8.5 years, had become monoclonal. The prolonged period of negativity for HCV RNA followed by relapse suggests that HCV may persist in apparent sustained viral responders.

Discussion.

Humoral immunity appears to play little role in HCV clearance, possibly because of immune escape by way of rapid mutation of the HVR1. Viral clearance is associated with a broad and vigorous T cell response and is likely influenced by intracellular antiviral defenses [8, 9]. Innate and IFN-induced antiviral pathways may determine viral clearance by interfering with viral replication and translation and by enhancing cell-mediated immunity [10]. Examination of the response to HCV infection in patients with hypogammaglobulinemia provides an opportunity to study these responses.

Following an episode of severe active hepatitis (with remarkably high aminotransferase levels), our patient had complete resolution of infection after discontinuation of IFN therapy. Resolution-as evidenced by long-term normalization of aminotransferase levels and clearance of the virus for 8.5 years-then was followed by relapse with a nearly identical viral species. The initial resolution of infection after a striking disease flare appears to have resulted from strong intracellular and/or cell-mediated immune processes that were independent of the humoral immune response.

As was expected, when we sequenced multiple clones from the time of initial relapse and from the time of the second relapse 8.5 years later, we found virtually no evidence of heterogeneity in the HVR1 of the viral envelope [3, 11]. This finding is consistent with previous evidence indicating that HVR1 diversity results from the selection of escape variants in response to humoral immune pressure but contrasts with the level of quasispecies variation within NS5A at the time of the initial relapse. Higher numbers of amino acid mutations in the ISDR, compared with the previously described HCV genotype 1a viral sequence, correlate with increased sensitivity of HCV to the intracellular antiviral response and to IFN in general [4, 7]. The viral evolution to a single NS5A sequence at the time of the second relapse could have resulted from intracellular immune pressure and selection of a single persistent variant. The documentation of viral mutation in response to this host pressure in the absence of antibody argues that the immune selection of viral quasispecies that are resistant to intracellular defenses and/or T cell immunity may be responsible for viral persistence in this patient.

Acute hepatitis C responds to IFN, and successful viral clearance in patients with hypogammaglobulinemia has been reported [12]; spontaneous viral clearance without treatment is rare [13]. The role of IFN in our patient's disease course is unclear. Our patient experienced an immediate relapse after 5 months of IFN therapy, which was followed by viral clearance for 8.5 years. The very-delayed relapse of infection after >8 years may have resulted from transient immunosuppression due to repeated corticosteroid use. However, other factors, including abnormal immunity and cytokine signaling associated with hypogammaglobulinemia, could also have effected this relapse pattern [14]. That the phenomenon did not represent reinfection was proved by the fact that only a single amino acid difference in the NS5A region was found over the 8.5-year period. We interpret the minimal shift in quasispecies diversity and the repeatedly negative serum HCV RNA PCR assays to represent a low level of viral replication during this long quiescent period. Although considered to be a sustained viral responder, our patient continued to have a reservoir of low-replicating virus that was held in check but not eradicated by her immune system until the corticosteroid-induced immune suppression led to the relapse. Recent studies in immunocompetent patients support the presence of such a reservoir [15]. An HCV reservoir that requires continued innate or T cell immune surveillance to prevent disease activity even years after the infection appeared to have resolved may exist in at least some sustained viral responders.

Patients with hypogammaglobulinemia who become infected with hepatitis C virus (HCV) tend to have severe disease that may progress to cirrhosis and liver failure after only a few years [1, 2]. Responses to interferon (IFN) therapy have varied in these patients.

In patients with chronic HCV infection, the hypervariable region 1 (HVR1) of the viral E2 envelope glycoprotein exhibits a range of quasispecies variation that is considered to be the result of host humoral immune pressure that leads to viral adaptation and antibody-escape variants. By contrast, the sequence diversity of the nonstructural (NS) 5A protein-coding region has been shown to be associated with antiviral pressure from IFN defenses of the infected cell, such that quasispecies variation in the protein kinase R-binding domain (PKR-BD) and the included IFN sensitivity determining region (ISDR) of NS5A may influence intracellular defenses. These processes likely play a role in viral persistence by facilitating immune evasion and regulation. Studies of patients with hypogammaglobulinemia have demonstrated little quasispecies variation in the HVR1 over periods of up to 8 years of infection [3]. This lack of rapid sequence variation is attributed to a lack of humoral immune selection pressure, but an effect on the NS5A sequence of HCV in such patients has not been addressed.

Here, we describe the course of HCV infection in a patient with subclass 3 IgG deficiency who, in 1994, developed acute HCV infection and was treated with IFN-a2b for 5 months. Immediately after treatment, the patient experienced a brief, self-limited relapse. She then experienced a sustained virologic remission that lasted for 8.5 years, only to experience another brief relapse before the infection remitted again in 2003. We explore the virologic features of this unique infection pattern and report on the level of sequence heterogeneity within the HVR1 of the E2 protein and the PKR-BD of the NS5A protein during the 2 separate relapses.  pt 1



  

[alagirl]

The fact that we are taking apart such a small number of cases shows how durable SVR is.  

PBMC Not A Reservoir for HCV for Patients Who Clear HCV RNA, Study Reports
  
  Clearance of hepatitis C virus RNA from the peripheral blood mononuclear cells of blood donors who spontaneously or therapeutically control their plasma viremia

Hepatology March 2008 Advance Publication

Flavien Bernardin 1 2, Leslie Tobler 1, Irina Walsh 1, Joan Dunn Williams 3, Mike Busch 1 2, Eric Delwart 1 2 * 1Blood Systems Research Institute, San Francisco, CA 2University of California, San Francisco, CA 3Blood Systems, Tempe, AZ

"On the basis of our results, the clearance of HCV from PBMC therefore appears complete in both spontaneously aviremic and successfully treated seropositive blood donors......These results indicate that PBMC-associated HCV is unlikely to be maintained as a viral reservoir with the potential to rekindle plasma viremia in aviremic subjects as determined by plasma TMA assays. This conclusion is supported by a recent analysis that similarly failed to detect PBMC-associated HCV RNA in 9 spontaneous and 2 treatment-induced aviremic patients.[16] A greater than 90% rate of clearance of HCV RNA in the liver of sustained virological response also indicates that a long-lived hepatic reservoir is unlikely to exist"

Abstract

We determined whether hepatitis C virus (HCV) RNA could be detected associated with peripheral blood mononuclear cells (PBMC) of seropositive blood donors who had spontaneously or therapeutically cleared their plasma viremia. Blood donor plasma viremia status was first determined with a highly sensitive transcription-mediated amplification (TMA) test performed in duplicate assays. PBMC from 69 aviremic and 56 viremic blood donors were then analyzed for the presence of HCV RNA with TMA adapted to detect viral RNA in PBMC and with a reverse transcription-nested polymerase chain reaction assay. PBMC-associated HCV RNA was detected in none of the 69 aviremic donors, including all 6 subjects with a sustained viral response following antiviral therapy. PBMC-associated HCV RNA was detected in 43 of the 56 viremic donors. The 13 viremic donors with no detectable PBMC-associated HCV RNA all had very low viral loads (6 positive only in 1 of 2 duplicate plasma TMA assays, 6 with viral loads below 100 HCV RNA copies/mL, and 1 with a viremia of 2700 HCV RNA copies/mL). The absence of detectable PBMC HCV RNA detection in all 69 aviremic donors reported here contrasts with prior studies, possibly as a result of the higher sensitivity of the TMA assay used to test for plasma viremia.

Conclusion: Our results indicate that PBMC are unlikely to serve as a long-lived reservoir of HCV in aviremic subjects.


http://natap.org/

[alagirl]

I've taken prednisone at a pretty high level for a week to ten days at a time two or three times since my SVR about fourteen months ago.  I would not take it while on treatment and for the first few weeks after treatment.  Perhaps I just haven't seen the right studies, but the 2008 study I saw recommended only that prednisone be avoided for the first few weeks after treatment.

I would guess that a percentage of us who have achieved SVR - including me - have ai issues that will necessitate steroids and/or biologics in the future.  I'm not super worried about it.

[willing]

AHOOOOOOOOOOOOOOOOOOOOOOOO...


and many congratulations on your SVR - may it be as durable as Gibraltar!

[apache1]

If anyone believes the virus, though VL UND, was ever really gone, please explain.
==========================================================

Hey willing, how ya doing on this full moon...lol.

No I do not believe the virus was eradicated. Thats the problem. Something very different and unusual is obviously going on here.  Her case does not conform to any usual HCV or SVR statistical study data standards. She is the exception not the norm.

After I read the full articles will maybe have a better idea of whats going on...maybe.

apache

[willing]

aye, vxman, the moon is full and you've started another occult howl; the usual suspects be gathering..

methinks you're doing exactly the right thing. Take the antibiotic and punt on the prednisone. At the small dose involved you'd probably be fine but why risk it? Your father-in-law knows whereof he speaks. In addition to the studies already cited you might want to look at
http://www.ncbi.nlm.nih.gov/pubmed/19105211
a recent comprehensive review of available data on occult hcv. In particular Table 3 titled

"Late Virologic Relapse Rates Defined by Detection of HCV RNA in Serum in Immunocompromised Patients with Former Chronic Hepatitis C and Sustained Virologic Response After (PEG-)Interferon-Alfa-Based Antiviral Therapy"

enumerates documented cases of late relapse, mostly among transplant recipients, from 99-07 . Overall total in tat group is 7/399 (2%).

This is certainly an unsettled area, but IMHO, DD's summary is the conclusion in best agreement with the data. As noted in the recent Lin'08 paper cited by fretboard, the various documented cases of (rare) late relapse and occult detection "suggest that sterilizing immunity with complete elimination
of virus is unlikely." More likely SVR marks durable immune control over any  residual virus, control which becomes progressively more firmly  established

and BTW in Lin'08 a number of the tests were Heptimax TMAs <5iu.

ML: "I've never seen a proven case of relapse beyond 3 yrs "

if the Lee paper doesn't meet your criterion I doubt you ever will see such proof. The  remarkable aspect of this case is that they happened to have frozen HCV RNA going back 8.5 years and thus could rule out re-infection.  

"In other words he believes no relapses or spontaneous cleances really occurred. "
how so ? The patient in Lee'05 requested discontinuation of tx on Sep. 13, 94.
"the initial relapse occurred promptly (within 5 days) after cessation of therapy. Viral clearance followed within 3 weeks, and the patient was well. She then had repeatedly documented normal aminotransferase levels and negative HCV RNA assays until March 2003, when hepatitis symptoms and elevations in aminotransferase levels and HCV RNA titers were once more observed. The infection cleared again without further treatment, and the patient has remained negative for HCV RNA and has had normal aminotransferase levels for an additional 18 months."

The initial relapse occurred after a few days after premature discontinuation of tx and the initial spontaneous clearance 3 weeks later. That spontaneous clearance was durable until '03 and the 2nd relapse coincided with iv dosing of 125 mg of prednisone. The 2nd spontaneous clearance followed cessation of the immuno-suppressant.

If anyone believes the virus, though VL UND, was ever really gone, please explain.

[apache1]

Mr Liver thanks for explaining your figures on the 1000 relapse rate. It is a bit heavy on the 'creative' statistical data extreme, don't ya think ?... but ok, I see how you got there.

I do agree with you, and also am not sold on occult HCV.

apache

[Pharaoh]

I understand that and that is a problem with the test.  Yet it remains a fact that those who are SVR for more than 5 years are considered cured.  I am not aware of ANY case of relapse after 5 years.  Even after one year the relapse rate is minuscule.

I've read some of those research reports that hypothesize what you are saying.  It is certainly a possibility, but it remains a hypothesis.

[Mr Liver]

Apache1-

Thanks for the reply.
If 99.000 people in a year achieve SVR it doesn't change the fact that appx 1000 will be told they relapsed beyond the 6 mo post-tx PCR.  Just find one and ask them. The point being made was that SVR is not ironclad at the 6 mo post tx PCR.

To arrive at the number of 1000 late relapsers some math is required and research into numbers. Find how many treat per year which has been 100,000 the last few years. Source: http://www.hepcproject.typepad.com/

Using the SVR rate across all genos (50%-60%) would mean that appx 40-50,000 ppl who achieved SVR status last year. If you use 2% as the avg for those who have relapsed beyond their 6 mo PCR. (there were a few of these studies not too long ago on this board that support this as an avg)  you end up with 900-1,000 in the US with late relapse. There isn't any research anywhere that states SVR status at 6 mo post tx is a cure.  I can’t find any research that demonstrates the SVR rates are 100% durable simply because one remains undetectable at their 6 mos post tx PCR. And I'm not talking about 'occult' infections here either which is another discussion topic altogether. Personally I am not sold on the ‘occult’ theory.

It seems  there are doctors out there that are setting some of their patients up for a crushing blow by telling them they are cured if neg PCR 6 mo post tx. I've seen them in here and I've met a few personally, using the most sensitive tests in use commercially. I really don’t think anyone would lose sleep if their doc told them the truth that there was less than a 5% chance of re-emergence of virus in the next 6 months beyond  their neg 6 mo post tx PCR, and beyond that time point the odds are even considerably lower for a relapse for the year following ( <1% ).
ML

[Mr Liver]

Thanks for the link. I am familiar with both of the studies you cited.

The paper by Pham cited the following on Lee’s findings:

  Pham - “In this regard, corticosteroid-induced immunosuppression HAS BEEN SHOWN to affect HCV reactivation years after spontaneous resolution of acute hepatitis C[37].” (citing Lee’s paper)

Here is what Lee actually said:

“The very-delayed relapse of infection after >8 years MAY have resulted from transient immunosuppression due to repeated corticosteroid use. HOWEVER, other factors, including abnormal immunity and cytokine signaling associated with hypogammaglobulinemia, COULD also have effected this relapse pattern [14]

He went on to conclude:

“We interpret the minimal shift in quasispecies diversity and the repeatedly negative serum HCV RNA PCR assays to represent a low level of viral replication during this long quiescent period.” (8.5 years)”. In other words he believes no relapses or spontaneous cleances really occurred.

I would call this re-characterization of what Lee actually said to be misleading. Actually I find it to be worse than that. To state an unproven assertion from a secondhand source with such authority as Pham did is unethical science in my view. I guess when you really want a certain outcome you’ll bend the norms of scientific investigation to suit your needs. Gotta keep those grants coming. This seems to be the case in the examples I provided from the studies you posted.

Again this from the Lee paper which Pham cited in his paper.

““Serum samples stored at −80°C were available from the 1994 treatment period and all later time points. HCV RNA was quantified in serum samples from 1994 by use of the Roche Amplicor RT PCR Assay (limit of detection, <1000 copies/mL). Negative assays were confirmed by use of more sensitive assays (limit of detection, <200 copies/mL) after 1996 and, most recently, by a Roche Amplicor assay (limit of detection, <50 IU/L).”

He did little to further his hypothesis of ’occult’ virus given the testing standards that were employed in the study.

Furthermore, in the Lee paper the authors themselves do not believe that the patient actually had spontaneous clearance (twice!) nor relapses (three times !) over the 8.5 years of surveillance. And they certainly had no foundation to believe it was the steroid that caused relapse as she relapsed two other times while not on steroids. I call that a big leap on Lee’s part.

Citing papers by those who believe in ‘occult’ infection in order to prove late relapse doesn’t make much sense given the fact that they believe there is no such thing as a late relapse. If you never cleared, you can’t have a relapse, right ?
ML

[DoubleDose]

I think you are missing Mike's point here.  I don't think that WE are saying that the 'immuno-suppressed relapsers' in the past were actually NOT really SVR, but that maybe all or most SVR's may actually be more in a state of 'almost' permanent remission, with an underlying minute trace of 'controlled' but persistent virus hiding somewhere in the body...BUT controlled tightly by the immune system.

This is what many of the 'viral persistence' and 'occult virus' researchers are implying.....that ALL (or most) of us SVR's still carry this sub-detectable trace amount of virus, but that only in very rare cases could it ever 're-ignite' into a full blown chronic infection again.  The immuno- suppression drug cases are suspected cases of true SVR's being pushed back to 'chronic viral' status.  So I guess I am saying that MY interpretation of the 'persistent viral research', is that SVR is a great goal, and when we achieve it we are pretty much 99% home free...BUT...the virus may NEVER be entirely gone, or fully eradicated...but only held tightly in check, by a now dominant and capable immune system.  The exceptions to the SVR rule of durability seem to be a handful of cases where heavy doses of immuno-suppressive drugs were given, over a long period of time...thus provoking a 'relapse' of sorts, from a true SVR state previously.

That is how I interpret these researchers' stance on the issue anyway.  They MAY turn out to be wrong....or right...but currently there is little explanation as to why specifically this small subset of SVR's seem to sometimes relapse after being negative for the virus over many years.  I don't know how you explain the fact that their PCR's have been consistently 'undetected' before the administration of immuno-suppressive drugs, but the above commentary is one, logical explanation held by many researchers in the HCV viral study community.  

DoubleDose

[Pharaoh]

Hello, Mike

Two years sounds about right.  I'm six years SVR now.  I hope things are well with you.

No one had it worse than you did, my friend.  When I was going through tx you were a beacon for me -- how could I complain when I saw what you were going through?  Then, throw in a motor cycle wreck on top of it. :) :)

My only point to VXman is that if we relapse after several years, then we were never really SVR.  That's more a criticism of the tests than anything.  But, given the success rate of SVR -- 99%+ -- we have much to be confident in.

One curious side effect of tx for me:  Before tx my cholesterol was always about 220.  Now it's below 180 with no change in diet.  My doctor can't explain it.

[mikesimon]

Hello my old Friend.
What's it been - 2 years?
Anyway I always like seeing your name and hearing what you have to say.
I hope you're right that SVR = complete and total eradication of the virus but, at this point, I am not absolutely convinced of it. So few SVRs have liver biopsies and a PCR of their tissue samples that I don't see much convincing evidence either way.
I had a biopsy in June 2006 but unfortunately and unjustifiably there was no PCR of my tissue sample. I was shocked that there was no PCR so, in my case, I really don't know for sure.
Regardless of all that I am still pleased to see you Pharaoh.
Be well,
Mike

[apache1]

quote by Mr Liver:
To all: Some may choose to characterize relapse after 6 mo post tx as "rare" but over a 1000 people last year in the US alone received the news that they hadn't been 'cured' as their doctors had told them.
=============================================================

Well if we go by the available statistics, for those 1000 SVR relapses there were approximately 99,000 durable SVR cases...

Would like to see your study or article of "1000 people last year in the US alone " relapse after SVR. Can you post a link or cut and paste a article.

apache

[Pharaoh]

BS.  Suck it up.  A sinus infection is going to do its thing no matter what drugs you take.  

[CoWriter]

"I would recommend that you not take the prednisone OR the antibiotic."
------------------

No antibiotic?  I bet you've never had a sinus infection.  They can be miserable.  Plus they can become chronic if untreated.    

Co

[CoWriter]

"Along with the variables ML listed I think we might consider adding the amount of the dose of steroid administered."
-----------------

I agree.  Dose as well as duration.  The patient from the study I posted had been receiving intravenous methylprednisolone (125 mg) every two weeks for 6 months as well as intermittent prednisone for asthmatic episodes.

Co

[CoWriter]

"I've never seen a proven case of relapse beyond 3 yrs and even then most of the ones in reports and studies I've read who had late relapse beyond a couple of years are questionable."
-----------------

Sequencing indicated that the viruses (from the initial infection and after relapse) were virtually identical.


Reemergence of hepatitis C virus after 8.5 years in a patient with hypogammaglobulinemia: evidence for an occult viral reservoir.

Lee WM, Polson JE, Carney DS, Sahin B, Gale M Jr. Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Tx.

The question of whether viruses persist after apparent clearance of infection remains unanswered. Here, we describe a patient with hypogammaglobulinemia whose acute hepatitis C virus (HCV) infection appeared to resolve after receipt of interferon therapy, relapse immediately, and then clear spontaneously--only to relapse after receipt of corticosteroid therapy, and clear again, 8.5 years later. Sequencing indicated that the viruses detected during each relapse were virtually identical, with the hypervariable region 1 of E2 appearing to be monoclonal, which is typical of patients with hypogammaglobulinemia. Nonstructural 5A sequences exhibited quasispecies diversity initially but, after 8.5 years, had become monoclonal. The prolonged period of negativity for HCV RNA followed by relapse suggests that HCV may persist in apparent sustained viral responders.

For the full study:
http://natap.org/


And this study says that steroid immunosuppression can affect HCV reactivation.

Co
  

Occult persistence and lymphotropism of hepatitis C virus infection (May 2008)

"In certain scenarios, including immunosuppression, immunomodulatory therapy or co-infection, instead of eliciting desirable T cell responses in the host, persistent replicating HCV could represent a potential source for virus reactivation, as it has been shown in other viruses, including hepatitis B virus and human herpesvirus. In this regard, corticosteroid-induced immunosuppression has been shown to affect HCV reactivation years after spontaneous resolution of acute hepatitis C"

http://www.wjgnet.com/1007-9327/14/2789.asp