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
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/
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.
AHOOOOOOOOOOOOOOOOOOOOOOOO...
and many congratulations on your SVR - may it be as durable as Gibraltar!
If anyone believes the virus, though VL UND, was ever really gone, please explain.
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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
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.