Novel Biomarkers Associated With the Outcome of Interferon-Based Hepatitis C Virus Therapy

he past 25 years since the discovery of hepatitis TC virus (HCV) have been marked by significant advances in both understanding the biology of the virus and its interactions with the human host as well as developing treatment strategies that now allow a majority of patients to be cured. Combination therapy consisting of pegylated interferon-a (IFNa) 2a/2b and ribavirin was the standard of care for treating hepatitis C for almost a decade until the approval of first generation NS3/4A protease inhibitors in 2011. A variety of host factors that influence the outcome of IFN-based treatment regimens have been identified and established as predictors for the achievement of a sustained virological response (SVR). The best-characterized host factors are single-nucleotide polymorphisms within the interleukin 28B (IL28B) gene locus that are associated with an approximately twofold change in treatment response. Other patient characteristics that influence treatment outcome, such as insulin resistance, hepatic steatosis, liver fibrosis, and patient age, have been described, but their role as a predictor for SVR is less well characterized. In the search for biochemical markers that can predict the outcome of IFN-based therapies, several studies identified baseline low-density lipoprotein (LDL) levels to positively correlate with SVR rates. The knowledge that the HCV life cycle is closely tied to the hepatic lipid pathway has resulted in the identification of several potential treatment targets, but the link between HCV replication and LDL in particular was not obvious. Based on their previous observation that oxidized LDL (oxLDL) acts as an HCV entry inhibitor by disrupting the interaction between HCV and one of its entry factors, scavenger receptor class B member I (SR-BI), Solbach et al analyzed the oxLDL levels of 379 patients from the INDIV-2 study chronically infected with HCV genotype 1. The authors demonstrated that oxLDL serum baseline levels were an independent predictor of SVR in IFN-based treatment regimens. Area under the receiver operating characteristic curve values of oxLDL and LDL were not statistically significantly different, so both parameters are largely equivalent predictors of SVR, adding to the appeal of these findings in a clinical setting because LDL is a routine parameter unlike oxLDL. As a next step, Solbach et al addressed how the correlation between oxLDL and SVR could be explained. They hypothesized that (1) elevated oxLDL levels may result from an ongoing inflammatory, antiviral immune response, (2) oxLDL might enhance the antiviral effect of exogenous IFN, or (3) oxLDL may reduce the infection of new hepatocytes during IFN treatment, thereby enhancing the clearance of infected cells.