Vitamin D serum levels seem to influence antiviral response in chronic hepatitis C. Polymorphic loci rs7041 G>T and rs4588 C>A of the vitamin D transporter GC-globulin rs10741657 G>A of the vitamin D 25 hydroxylase CYP2R1 and rs10877012 G>T of vitamin D 1-hydroxylase CYP27B1 were genotyped. A genetic model named VDPFA Trichostatin-A (vitamin D Pathway Functional Alleles) was constructed considering for each patient the sum (from 0 to 8) derived from every functional allele carried associated with the achievement of SVR. Three groups were identified: those carrying ≤4 VDPFA (N=108) those carrying 5-6 VDPFA (N=78) and those carrying ≥7 VDPFA (N=20). Significant associations were found between the rates of SVR and the VDPFA value both in all (61/108 53 17 p=0.009) and in 1/4-5 HCV genotypes (17/56 23 6 p=0.003). Moreover in patients who don’t achieve rapid viral response (RVR) SVR and VDPFA were found to be in stronger associations in all (12/55 17 7 p<0.001) and in 1/4-5 HCV genotypes (4/41 Trichostatin-A 12 5 p=0.001). VDPFA value ≥7 could aid to select among RVR negative difficult to treat 1/4-5 HCV genotypes those achieving SVR. These observations could permit to extend the indication to adopt dual antiviral therapy beyond RVR positivity rule without reducing the chances of SVR. Introduction With the introduction of hepatitis C virus (HCV) protease inhibitors antiviral therapy of chronic hepatitis C has been dramatically evolved. Waiting for the incoming third generation pan-genotypic HCV protease and polymerase inhibitors which will be used without interferon and ribavirin [1] COL1A1 the current adopted triple therapy regimens using boceprevir or telaprevir with pegylated interferon-α and ribavirin greatly Trichostatin-A increased the rate of sustained viral response (SVR) in HCV genotype 1 infected patients. Despite the enhance of SVR rate triple therapy schedules are complex and are engraved by new and more serious adverse events compared to standard dual therapy. While triple therapy appears to be the only suitable choice in the treatment of patients who previously failed to achieve SVR with standard dual treatment more questionable is the cost-effectiveness ratio of triple therapy in treating all HCV genotype 1 na?ve patients [2]. Thus despite the progress of triple therapy there is still room for optimizing the efficacy of the less toxic and less costly standard dual antiviral therapy in na?ve patients. This aim could be obtained by further refining the identification of the pre and on treatment factors associated with maximal benefit from dual therapy. Several predictors of successful treatment of chronic hepatitis C have been identified [3]. Factors related to the virus appear to be carefully characterized: infection by HCV genotypes 2 and 3 and a low basal HCV viral load confer a much greater possibility of a successful Trichostatin-A treatment. Host predictors are Trichostatin-A classifiable into genetic and non-genetic. Among the latter higher degree of liver inflammation and fibrosis lower serum cholesterol and higher serum IP-10 and γ-glutamyl-transpeptidase (γ-GT) appear to have a major role [4 5 Among the former the major genetic determinant of HCV clearance has been identified in interleukin 28B (IL-28B) polymorphisms. Possessing the IL-28B rs12979860 C/C genotype confers a great advantage for HCV clearance with standard therapy than the carriage of one or two T alleles [6]. Beside the classical action on calcium metabolism vitamin D appears to possess an important immune-modulator effect [7]. In fact pre-therapy serum 25(OH) vitamin D levels were found to be an independent predictor of SVR in na?ve HCV genotype 1 infected patients treated with standard dual therapy [8]. Basal serum 25(OH) vitamin D levels >20 ng/mL were associated to an increase of about 20% in the probability to achieve SVR in patients carrying the IL-28B C/C genotype [9]. Moreover vitamin D supplementation was associated with an enhancement of SVR rate in patients with chronic hepatitis C irrespectively of the viral genotype [10 11 Vitamin D undergoes two activation processes before its interaction as active 1 25 vitamin D with vitamin D receptor [12]. The first activation is performed in the liver by CYP2R1 and produces the 25-hydroxylated form of vitamin D [13]. This step produces the main circulating though biologically inactive 25 vitamin D form which circulates bound to GC-globulin also named vitamin D binding protein. GC-globulin is a serum α2-globulin synthesized only by the liver in three genetically determined isoforms [14]. By means of CYP27B1.