The C allele at rs12979860 also third is associated with higher baseline viral load [8], [11], which otherwise is an established negative predictor of response to peg-IFN/ribavirin therapy [3], [4], [5]. Similarly counterintuitive is the report that a C allele at rs12979860 is more common in Caucasians with HCV genotype 2 and 3 infection than in genotype 1 infected or in HCV uninfected individuals [11], [12]. In addition, two studies reported that homozygous carriage of GG at rs8099917 was associated with slightly lower PBMC mRNA expression of IL28 in 49 and 20 individuals, respectively [9], [10], although another study reported no difference in IL28B mRNA expression when stratified regarding rs12979860 genotype in PBMC from 80 individuals [8].

In line with this latter finding, G allele carriage at rs8099917 has been reported to be associated with elevated intrahepatic mRNA expression of a panel of 37 interferon-stimulated genes (ISGs) but not IL28B in 91 HCV infected patients [13]. Interferon-gamma inducible protein 10 kDa (IP-10 or CXCL10) is a chemotactic CXC chemokine of 77 amino acids in its mature form [14], [15]. IP-10 targets the CXCR3 receptor but, unlike other CXC chemokines, lacks chemotactic activity for neutrophils and instead attracts T lymphocytes, NK cells, and monocytes to sites of infection [15], [16], [17]. IP-10 is produced by a variety of cells, including hepatocytes, and levels of IP-10 at onset of therapy are reportedly elevated in patients infected with HCV of genotypes 1 or 4 who do not achieve SVR [18].

In difficult-to-treat genotype 1 infected HCV patients, cut-off levels of IP-10 in plasma of 150 pg/mL (approximately equal to 2 standard deviations above the mean IP-10 level of HCV seronegative blood donors) and 600 pg/mL have yielded positive and negative predictive values for SVR of 71% and 100%, respectively [19]. IP-10 in plasma is mirrored by intrahepatic IP-10 mRNA, and strongly predicts the HCV RNA decline during the first days (��first phase decline��) during interferon/ribavirin therapy for all HCV genotypes [20]. The impact of IP-10 on the elimination of HCV RNA during therapy in the setting of IL28B genetic variants is not known. We therefore assessed plasma IP-10 in relation to genetic variants at three major IL28B SNPs (rs12979860, rs12980275, and rs8099917) in patients chronically infected with HCV genotypes 1-4. Our results demonstrate a significant association between IL28B genetic variants and IP-10 in plasma and imply that combined Drug_discovery assessment of these predictive factors may improve prognostication of the rate of first phase elimination of HCV RNA, as well as achieving a rapid virological response (RVR) and SVR.