CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

Hoare, Matthew; Gelson, William T.H.; Das, Abhi; Fletcher, Jean M.; Davies, Susan E.; Curran, Martin D.; Vowler, Sarah L.; Maini, Mala K.; Akbar, Arne N.; Alexander, Graeme J.M.

doi:10.1016/j.jhep.2010.03.005

« Previous Next »Journal of Hepatology
Volume 53, Issue 2 , Pages 252-260, August 2010

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

Matthew Hoare
- Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
William T.H. Gelson
- Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Abhi Das
- Department of Immunology, University College London, London, UK
Jean M. Fletcher
- Department of Immunology, University College London, London, UK
Susan E. Davies
- Department of Pathology, University of Cambridge, Cambridge, UK
Martin D. Curran
- Clinical Microbiology and Public Health Laboratory, Health Protection Agency, Addenbrooke’s Hospital, Cambridge, UK
Sarah L. Vowler
- Centre for Applied Medical Statistics, Department of Public Health and Primary Care, University of Cambridge, Institute of Public Health, Forvie Site, Robinson Way, Cambridge, UK
Mala K. Maini
- Department of Immunology, University College London, London, UK
Arne N. Akbar
- Department of Immunology, University College London, London, UK
Graeme J.M. Alexander
- Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, UK
- Corresponding author. Address: Department of Medicine, Box 157, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel.: +44 1223 336008; fax: +44 1223 216111.

Received 9 November 2009; received in revised form 4 February 2010; accepted 3 March 2010. published online 22 April 2010.

Background & Aims

Increasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection.

Methods

Circulating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome.

Results

Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p=0.003), independent of male sex (p=0.04), CMV positivity (p=0.003), previous HBV infection (p=0.007), and age (p=ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p<0.001), portal tract inflammatory grade (p=0.035), prothrombin time (p<0.001) and bilirubin (p=0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p=0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p=0.001) independent of other factors.

Conclusions

CD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.

Abbreviations: HCV, hepatitis C virus, HCC, hepatocellular carcinoma, CMV, cytomegalovirus, HBV, hepatitis B virus, EBV, Epstein–Barr virus, HIV, human immunodeficiency virus, IFN-α, interferon-α, PBMCs, peripheral blood mononuclear cells, APCs, antigen presenting cells, HR, hazard ratio