Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A-induced tissue injury in vivo, which was strongly associated with reduced liver cell apoptosis. In vitro, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo. Conclusion: The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis. (HEPATOLOGY 2013;57:797-805)

Fibrosis recurrence after liver transplantation (LT) for hepatitis C virus (HCV) is a universal event and strongly determines a patient's prognosis. The recipient risk factors for fibrosis recurrence are still poorly defined. Here we assess a genetic risk score as a predictor of fibrosis after LT. The cirrhosis risk score (CRS), which comprises allele variants in 7 genes (adaptorrelated protein complex 3 S2, aquaporin 2, antizyme inhibitor 1, degenerative spermatocyte homolog 1 lipid desaturase, syntaxin binding protein 5-like, toll-like receptor 4, and transient receptor potential cation channel M5), was calculated for 137 patients who underwent LT for HCV infection and experienced HCV reinfection of the graft. The patients were stratified into 3 CRS categories: <0.5, 0.5 to 0.7, and >0.7. All patients underwent protocol biopsy after LT (median follow-up ¼ 5 years), and liver fibrosis was assessed according to the Desmet and Scheuer score. The data were analyzed with univariate and multivariate analyses. The results showed that the highest CRS category was strongly associated with the presence of F2 or F3 fibrosis in protocol biopsy samples 1, 3, and 5 years after LT (P ¼ 0.006, P ¼ 0.001, and P ¼ 0.02, respectively). Overall, 75.0% of the patients with a CRS > 0.7 developed at least F2 fibrosis, whereas 51.5% developed F3 fibrosis during follow-up. The predictive value of the CRS for fibrosis progression was independent of known clinical risk factors, including the age of the donor, the sex of the recipient, and the occurrence of acute rejection. A Kaplan-Meier analysis confirmed the prognostic value of the CRS with respect to the recurrence of severe liver fibrosis in HCV-infected patients after LT (log rank ¼ 6.23, P ¼ 0.03). In conclusion, the genetic signature of the recipient predicts the likelihood of severe liver fibrosis in the graft after HCV recurrence. The CRS might help with early clinical decision making (eg, the selection of patients for antiviral therapy after LT).

In this report from France, undetectable serum hepatitis C virus (HCV) RNA at 12 weeks (Wþ12) (409 patients) post-treatment follow-up was as relevant as undetectable serum HCV RNA at 24 weeks (Wþ24) (sustained virological response [SVR]; 408 patients) after the end of treatment.Current standard therapy is based on a combination of pegylated interferon (PEG-IFN) and ribavirin, but it leads to only $50% SVR in patients with HCV genotype 1 and high viral loads.2 IFN reduced the risk for HCC, especially among patients with SVR.3,4 Then, we need to accurately judge whether the patient is SVR or non-SVR, applying the present standard for the judgment of SVR with the undetectability of serum HCV RNA at post-treatment Wþ24.We investigated 102 patients with chronic hepatitis C genotype 1 treated with PEG-IFN-alfa 2a plus ribavirin for 48 weeks. Some of these patients had already been included in previous reports. 5,6 Serum HCV RNA was measured using the COBAS TaqMan HCV test with a detection limit of 1.2 logIU/mL. At the Wþ24 posttreatment follow-up, 40 (39.2%) patients had SVR, and 31 (48.4%) and 9 (23.6%) were treatment naïve and previously treated patients, respectively. At Wþ12, serum HCV RNA was undetectable in 42 patients, and 40 patients were SVR (PPV, 95.2%). We found two relapsers at Wþ24 (undetectable at Wþ12).In the case of using direct-acting antivirals, earlier knowledge of treatment outcome would be useful for retreatment for the same patient. Taken together, our findings show that Wþ12 undetectable serum HCV RNA is not suitable for predicting persistent virological response. Further understanding of the mechanism of relapse could be useful in reducing the posttreatment follow-up period from the current standard of 24 weeks. Reply:We read, with interest, the letter by Kanda et al. regarding our article. As you know, the primary end-point of antiviral therapy for chronic hepatitis C virus (HCV) is achieving sustained virological response (SVR), defined as undetectable HCV-RNA in serum 24 weeks after stopping antiviral therapy. SVR is equivalent to viral eradication and is associated with a reduction in the risk of cirrhosis and hepatocellular carcinoma.1 Recently, it has been proposed that a 12-week post-treatment follow-up might be as relevant as 24 weeks to determine the SVR in patients with HCV receiving pegylated-interferon (PEG-IFN) and ribavirin.2 In our study, 573 patients who received combination PEG-IFN and ribavirin and had a virological response at the end of treatment were evaluated. Serum HCV-RNA was measured, using a new assay based on transcription-mediated amplification (TMA), with a lowest detection limit of 5-10 IU/mL, at week (W)þ12 and Wþ24 after the end of treatment. At the Wþ24 post-treatment follow-up, 408 (71%) patients had an SVR, 181 (71.2%) were treated with PEG-IFN alpha-2a and ribavirin, and 227 (71.1%) were treated with PEG-IFN alpha-2b and ribavirin. At Wþ12, serum HCV-RNA was undetectable in 409 patients, and 408 patients were SVR (positive predictive value [PPV]: 99.7%; 9...