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Alimentary Pharmacology & Therapeutics March 2015
M. Hedenstierna*,, O. Weiland*,, A. Brass, D. Bankwitz, P. Behrendt, I. Uhnoo, S. Aleman**, K. Cardell,
A. Fryden, G. Norkrans, A. Eilard, H. Glaumann, T. Pietschmann, M. Sallberg & E. D. Brenndorfer
*Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Department of Infectious Diseases, Akademiska University Hospital, Uppsala, Sweden.
**Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna and Huddinge, Stockholm, Sweden.
Department of Infectious Diseases, University Hospital, Linkoping, Sweden. Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden.
Clinical Pathology and Cytology, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Summary
Background
A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses.
Aim
To determine clinical, histological, virological and immunological markers 5-20 years after SVR.
Methods
In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation.
Results
Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies.
Conclusions
Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.
Alimentary Pharmacology & Therapeutics March 2015
M. Hedenstierna*,, O. Weiland*,, A. Brass, D. Bankwitz, P. Behrendt, I. Uhnoo, S. Aleman**, K. Cardell,
A. Fryden, G. Norkrans, A. Eilard, H. Glaumann, T. Pietschmann, M. Sallberg & E. D. Brenndorfer
*Department of Infectious Diseases, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Experimental Virology, Twincore Centre for Experimental and Clinical Infection Research, Hannover, Germany.
Department of Infectious Diseases, Akademiska University Hospital, Uppsala, Sweden.
**Department of Gastroenterology and Hepatology, Karolinska University Hospital Solna and Huddinge, Stockholm, Sweden.
Department of Infectious Diseases, University Hospital, Linkoping, Sweden. Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden.
Clinical Pathology and Cytology, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Summary
Background
A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses.
Aim
To determine clinical, histological, virological and immunological markers 5-20 years after SVR.
Methods
In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation.
Results
Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies.
Conclusions
Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.
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