The real novelty and probably the most important finding of this study is the association between serum vitamin A deficiency and the condition of nonresponse to antiviral therapy, suggesting that vitamin A could be an important Rapamycin mw and modifiable factor interfering with IFN sensitivity in patients with chronic hepatitis C. This finding, together with the data suggesting an antiviral activity against HCV of ATRA, suggests that vitamin A supplementation and normalization of its serum levels, before antiviral treatment, could enhance

the responsiveness to INF-based antiviral therapy. These considerations seem to confirm those derived from in vitro experiments that provided evidence of a pivotal role of retinol in enhancing the expression of IFN receptor and IFN signaling, linking vitamin A deficiency Peptide 17 molecular weight to IFN unresponsiveness. The fact that vitamin A and vitamin D serum levels are not reciprocally influenced suggests that they can exert an additive and probably synergistic effect on viral response. Indeed, the analysis showed that a concomitant vitamin A and D deficiency strongly impairs the responsiveness to antiviral therapy and that its impact is not so far from that exerted by IL-28B polymorphisms. The major and obvious

difference is that, instead of IL-28B polymorphisms, vitamins serum levels might be modified. Moreover, it is important to note that a strong additive effect in determining nonresponse was observed in patients with concomitant carriage of the IL-28B T/* genotype and vitamin A serum levels ≤100 ng/mL. A possible

concern in terms of the use of vitamin A supplementation in clinical practice is represented by its possible hepatotoxicity.22 However, the experiences concerning the use of polyprenoic acid, a synthetic vitamin others A derivate, in the prophylaxis of HCC in patients with chronic viral hepatitis23 and the study by Bocher et al.9 did not support this assumption. The main limitations of the present study lie in its retrospective design and in the lack of data concerning the dietary intake of both vitamin A and D. It is conceivable that vitamin D serum levels could be greatly influenced by the season, since sunlight exposure is recognized as a key factor in determining vitamin D synthesis. Nevertheless, it cannot be excluded that season-related dietary variations could influence vitamin A intake and serum levels. Nevertheless, the multicenter design of the study supported the external validation of data that have been confirmed in each center. In conclusion, a high percentage of patients with chronic HCV infection presented serum vitamin A deficiency. This condition is strongly associated with nonresponse to antiviral therapy, suggesting that vitamin A serum levels could modulate the responsiveness to IFN-based antiviral therapy.