Hepatic Toll-Like Receptor 3 expression in chronic hepatitis C genotype 1 correlates with treatment response to peginterferon plus ribavirin.

ABSTRACT

Recent studies have shown that enhanced hepatic expression of several innate immune genes predicts non-response to 48 weeks of peginterferon plus ribavirin in chronic hepatitis C genotype 1. This study aimed to further address how gene expression of TLR3/RIG-I signalling correlates with the outcome of the 72-week extended treatment regimen. Relative hepatic mRNA expression and copy numbers of positive- and negative-strand hepatitis C virus (HCV) RNA were determined by real-time PCR in 49 patients. Then, a 48-week peginterferon-alpha2b plus ribavirin treatment was commenced and extended to 72 weeks in cases of HCV RNA clearance after week 12. High rate of sustained virologic response was seen both in patients with early HCV clearance (85% [11/13]) and slow virologic responders (85% [11/13]) (per protocol analysis). The response was associated with low TLR3 expression (median, 0.9; range, 0-4.2 vs median, 1.9; range, 0.4-4.9; P = 0.004) but had no relation to the expression of TRIF (P = 0.315), RIG-I (P = 0.953), IPS-1 (P = 0.425), IRF3 (P = 0.329) and interferon-beta (P = 0.584). ROC curve analysis identified TLR3 expression of <1.5 as the best cut-off for predicting response (positive and negative predictive values, 89% [16/18] and 70% [14/20], respectively). The expression was not affected by HCV replication but was higher in female patients (P = 0.043). Multivariate analysis showed TLR3 to be a single baseline predictor (odds ratio 18.5 [95% CI 3.2-111], P = 0.001). Low hepatic TLR3 expression is a novel predictor of response to peginterferon plus ribavirin in genotype 1 patients.