HCV protein-induced cytokine predicts treatment outcomes in chronic hepatitis C virus infection

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-alpha 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-alpha production within the SVR-, compared with the SVR+, cohorts. Similar findings were noted for interleukin (IL)-1 beta and IL-10 synthesis. Furthermore, HCV core-induced TNF-alpha 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-alpha 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-alpha synthesis at baseline was associated with treatment failure. This phenomenon appeared to involve the interaction of virally generated TNF-alpha activity and metabolic disease. In contrast, IL-6 activity and leptin levels may indicate liver damage.