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Keywords:

  • adipokines;
  • core;
  • hepatitis C virus;
  • NS3;
  • sustained viral response;
  • TNF-alpha

Abstract

Background & Aims

Immune-mediated processes are thought to influence the efficacy of treatment in chronic hepatitis C virus (HCV) infection. This study evaluated the association of baseline immune responses with the achievement of a sustained viral response (SVR) upon pegylated interferon and ribavirin treatment.

Methods

Baseline serum and peripheral blood mononuclear cells (PBMC) cytokine activity was assessed. Metabolic and liver injury parameters were evaluated as underlying factors.

Results

Baseline demographics and disease parameters did not differ between the SVR− (n = 14) and SVR+ (n = 25) cohorts except for body mass index (BMI) values and liver injury scores. Baseline circulating TNF-α levels were three-fold higher with subsequent treatment failure vs. success (P = 0.124). Baseline peripheral blood mononuclear cells (PBMC, n = 25) were cultured with HCV core and non-structural (NS)3 proteins. Core (P = 0.0003) and NS3 (P = 0.018) induced greater TNF-α production within the SVR−, compared with the SVR+, cohorts. Similar findings were noted for interleukin (IL)-1β and IL-10 synthesis. Furthermore, HCV core-induced TNF-α synthesis correlated with patient BMI values (r = 0.489, P = 0.015). Core (r = 0.432, P = 0.065) and NS3 (r = 0.530, P = 0.020)-induced TNF-α displayed a positive relationship with serum adiponectin concentrations. In addition, lipopolysaccharide stimulated cytokine synthesis associated with BMI and adiponectin levels. Although unable to predict treatment outcomes, NS3-induced IL-6 synthesis and serum leptin concentrations corresponded to liver injury scores.

Conclusion

An enhanced PBMC susceptibility to core and NS3-induced TNF-α synthesis at baseline was associated with treatment failure. This phenomenon appeared to involve the interaction of virally generated TNF-α activity and metabolic disease. In contrast, IL-6 activity and leptin levels may indicate liver damage.