However, in our study, 25(OH)D3 serum levels were not associated with treatment outcome in a subgroup of 269 patients with available baseline serum samples before antiviral treatment. In fact, 25(OH)D3 serum levels were even somewhat lower in patients who subsequently always find useful information achieved SVR as compared to those who failed to respond to treatment. In two previous studies, including 167 and 211 patients treated with IFN-��-based therapy, a weak but significant correlation between 25(OH)D3 serum levels and SVR was observed [16], [34]. In our previous analysis we did not observe any significant association between 25(OH)D3 serum levels and SVR to IFN-��-based therapy in a cohort of 317 HCV genotype 1-infected patients, but a significant association in a cohort of 156 patients infected with genotype 2 or 3 [18].

Two studies in HCV-HIV-coinfected patients found no correlation between 25(OH)D3 serum levels and treatment outcome as well [35], [36]. The reasons for these discrepancies remain unclear at the moment, but apparently 25(OH)D3 serum levels cannot be considered as an established predictor of treatment outcome at the moment. Importantly, it is well-known that 25(OH)D3 serum levels correlate poorly with calcitriol serum concentrations, and 25(OH)D3 serum levels are therefore not a suitable marker for bioactive vitamin D or vitamin D receptor signaling, especially not for local calcitriol levels during inflammatory conditions [24]. Thus, the lacking lack of an association between 25(OH)D3 serum levels and SVR may simply reflect the limited biological relevance of 25(OH)D3 serum levels.

Unfortunately, there are no reliable methods to quantify serum levels of the bioactive vitamin D metabolite calcitriol, and the majority of clinical trials assessing the vitamin D status of patients focus on the calcitriol precursor 25(OH)D3 [24]. Therefore, despite the lack of an association between 25(OH)D3 Anacetrapib serum levels and SVR, the replicated association between SVR and a functionally relevant genetic polymorphism in the vitamin D cascade, CYP27B1-1260 rs10877012, suggests a role of vitamin D in the response to treatment of chronic hepatitis C. In line with this notion, we have recently identified an interaction between the vitamin D receptor and IFN-��-induced signaling through the Jak-STAT pathway, which results in a synergistic effect of calcitriol and INF-�� on interferon-stimulated gene expression as well as on HCV replication in vitro (CML, MHH and DM, unpublished data). Therefore, the question as to whether optimization of the patients�� vitamin D status may be beneficial before or during antiviral therapy remains open.