**5. Are lipid/lipoprotein profiles independent predictors of therapeutic outcome in chronic HCV- G1b infection?**

Chronic HCV infection has been treated with PEG-IFN and RBV combination therapy. HCV-G2 and HCV-G3 responded fairly well to this combination therapy. However, the response was weaker in HCV-G1 patients with only half of the patients achieving a

sustained virological response. Before the discovery of the IL28B genotype, a decrease in TC, LDL-cholesterol or apoB-100-related cholesterol had been considered as an independent predictor of the outcome of PEG-IFN plus RBV therapy in HCV-G1. However, after the discovery that the genotype near the IL28B gene was a potent predictor, serum lipid levels have since been considered to be a confounding factor of the IL28B genotype. Actually, as we described earlier in this chapter and also in an earlier manuscript [36], the IL28B genotype may profoundly affect serum lipid levels in HCV-G1b infection.

Our latest knowledge, based on a prospective study examining predictive factors for the outcome of PEG-IFN plus RBV therapy, indicates that an increase in serum apoB-100 levels is an independent factor predicting rapid virological response (decline of serum HCV RNA at 4 weeks) to PEG-IFN plus RBV therapy. However, it does not appear to be an independent predictor of the final outcome of virological response in chronic HCV-G1b infection (data currently under consideration for contribution). These findings may partly indicate that disturbance of the lipid profile may reflect the efficiency of HCV replication due to efficient entry of HCV into hepatic cells and efficient production/secretion of HCV along with VLDL.

Although the evidence described in this chapter is not based on in vitro studies using HCVsecreting cells, our observations based on clinical samples may contribute to furthering the understanding of HCV-lipid metabolism interaction. From this viewpoint, it is noteworthy that lipoprotein lipase may act not only in the conversion of VLDL to LDL, but also in inhibiting HCV entry into liver cells [23]. Interestingly, in in vitro studies using naturally HCV-secreting cells, the enzymatic activity of lipoprotein lipase may be reduced in HCVinfected cells and may act to promote cell entry of HCV. This may contribute to an increase in the number of large-size (suitable for VLDL particle size) LVP having a chemical nature of LDL as suggested in our HPLC-based study.

Finally, hepatic steatosis may be associated with dyslipoproteinemia in chronic HCV infection and has been extensively studied with special attention to its relation to the IL28B genotype [40] and substitution at aa 70 [17] in HCV-G1b. However, in our experience, the relationship between hepatic steatosis and these host and/or viral factors was equivocal, perhaps because there are other environmental and host factors strongly affecting hepatic steatosis other than the factors discussed in this manuscript.

#### **6. Summary**

The features of dyslipoproteinemia in chronic HCV infection have been described. Serum lipid/lipoprotein profiles were in part HCV-genotype specific. The HCV core protein of HCV-G1b is closely associated with lipoprotein metabolism, and substitution of amino acid (aa 70) in the core protein may precipitate dyslipoproteinemia, in addition to substitution of aa 2356 in NS5A. In addition, dyslipoproteinemia in chronic HCV-G1b infection is largely affected by the genotype near the human IL28B gene. Therefore, dyslipoproteinemia in chronic HCV infection may involve complicated interplay between viral and host factors that could affect human lipid metabolism. Further study of lipids/lipoproteins in chronic HCV infection will be valuable to clarify the interaction of HCV and host lipid metabolism in detail. Dyslipoproteinemia in chronic HCV-G1b infection may play a role in the rapid decline of HCV during PEG-IFN plus RBV therapy. However, the clinical utility of dyslipoproteinemia as a predictor of final response to PEG-IFN plus RBV treatment remains controversial.
