This study found significant differences in plasma CXCL9 and CXCL10 concentrations between patients with chronic hepatitis C (genotype 1) who achieved SVR to PEG IFN-α2b and ribavirin compared to non-SVR patients. Higher CXCL10 concentrations were associated with treatment failure. Importantly, CXCL10 concentrations after 4 weeks of treatment (RVR) had a higher predictive value for achieving SVR compared to pretreatment concentrations of this chemokine. To our knowledge, this is the first study showing that CXCL10 concentrations above 250
pg/mL 4 weeks after treatment initiation were independently associated with non-SVR. Although CXCL10 levels after 4 weeks of treatment are associated with a 40-fold greater risk of non-SVR after adjustment for age and stage of fibrosis, these data should be interpreted cautiously because of the small number of patients.
Several studies have shown CXCL10 to be a negative predictive marker of SVR to standard treatment of chronic hepatitis C (PEG IFN-α2 and ribavirin) in patients with genotypes 1 and 4. The majority of the studies so far focused on the predictive value of CXCL10 concentrations before treatment as possible markers of SVR.
Diago and others (2006
) have shown that, in patients with HCV genotype 1 infection, pretreatment CXCL10 concentrations predict SVR to treatment with PEG IFN-α2 and ribavirin.
Romero and others (2006
) analyzed an association between plasma CXCL10 concentrations and liver histological results and the virological response and treatment outcome in patients with HCV genotypes 1–4. Low plasma CXCL10 levels were found to be independent predictors of RVR and SVR. A separate analysis of patients infected with the HCV genotype 1 showed that using cutoff CXCL10 concentrations of 150 and 600
pg/mL for predicting SVR correspond to specificity and sensitivity of 81% and 95%, respectively.
Lagging and others (2006
) also showed that pretreatment CXCL10 concentrations predict RVR and SVR in patients with the HCV genotype 1. A baseline cutoff CXCL10 concentration of 600
pg/mL yielded a negative predictive value of 79% for achieving SVR in that study.
The results of our study have also shown that higher concentrations of CXCL10 in the plasma are associated with failure to achieve SVR. Due to the fact that the above-mentioned studies did not measure CXCL10 concentration at the time of RVR (4 weeks of treatment), a comparison with our findings on the higher predictive value for achieving SVR at week 4 compared with pretreatment values is not possible.
Butera and others (2005
) showed elevated levels of all CXCR3 ligands (CXCL9, CXCL10, and CXCL11) in HCV-infected patients with the genotype 1. However, only CXCL10 concentrations at baseline were significantly higher in patients who subsequently become nonresponders to treatment, whereas CXCL9 and CXCL11 levels failed to show significant association with the treatment outcome. Contrary to these findings, our study has shown significant differences in plasma CXCL9 concentrations between patients achieving SVR and nonresponders. To the best of our knowledge, this is the first study demonstrating the role of CXCL9 in identifying patients with chronic hepatitis C who subsequently fail to respond to treatment.
The value of CXCL10 concentrations in the plasma at baseline for predicting the virological response to treatment of chronic hepatitis C with PEG IFN-α2 and ribavirin has been also shown in patients with HIV/HCV coinfection (HCV genotype 1) (Reiberger and others 2008
; Vargas and others 2010
). Reiberger and others (2008
) have also shown that a CXCL10 cutoff value of 400
pg/mL might serve as a useful predictive marker for treatment of chronic hepatitis C in patients with HIV/HCV coinfection because it predicted SVR.
A biological foundation for a negative prognostic value of CXCL10 in the context of treatment response has been recently explained by a study showing that CXCL10 in the plasma of patients with chronic hepatitis C exists in an antagonist form (Casrouge and others 2011
). The CXCL10 antagonist is formed via in situ
aminoterminal truncation of the protein that is mediated by dipeptidyl peptidase IV (DPP4 or CD26). The antagonist form of CXCL10 successfully binds to the CXCR3 receptor, but is unable to initiate signal transduction, therefore abrogating the biological effect of the chemokine itself. This finding helped to explain an apparent paradox of why a chemokine responsible for recruitment of activated Th1 type lymphocytes in the liver represents a negative marker of treatment response.
The possible value of other soluble biomarkers as predictors of treatment response in chronic hepatitis C has also been investigated. For example, Lee and others (2010
) correlated a number of soluble markers (sCD30, interleukin-13 receptor alpha 2, total and active transforming growth factor beta-1, interleukin-18, and CXCL10) with severity of fibrosis and treatment outcome in patients with chronic hepatitis C. The results of this study showed that higher TGF-β1 and low CXCL10 are associated with failure to treatment. These results suggest that attempts to identify other biomarkers of treatment response in chronic hepatitis C should not be limited to chemokines only.
An association between CXCL10 concentrations not only in plasma, but also in liver biopsies with HCV RNA kinetics during chronic hepatitis C treatment was recently investigated by Askarieh and others (2010
). Low levels of intrahepatic and plasma CXCL10 were found to be predictors of favorable first-phase decline (24
h and 4 days) of HCV RNA during treatment with PEG IFN-α2 and ribavirin. However, pretreatment concentrations of CXCL10 in the liver or plasma did not influence HCV RNA decline during the second phase (days 8 and 29) or at later time points.
Zeremski and others (2011
) recently analyzed plasma levels of CXCL9-11 in patients with acute HCV infection showing that chemokine synthesis in vivo
begins between 38 and 53 days after virus aquisition and peaks between days 73 and 83 of infection. Week-to-week variations in chemokine concentrations as well as HCV RNA and ALT levels were interpreted as repeated cycles of gain and loss of immune control during acute hepatitis C. Further analysis on the kinetics of CXCR3 ligands in acute infection as well as characterization of their molecular forms (antagonists or not) is warranted.
In conclusion, the results of this study have shown that CXCL10 concentrations at the time of RVR (4 weeks) are better predictors of achieving SVR compared to baseline levels. Additionally, these results suggest an important role of CXCL9 as a biomarker of SVR in patients with chronic hepatitis C.