PloS ONE- Vitamin D Metabolism in the Response to Interferon-Alfa-Based Therapy of Chronic Hepatitis C

A Genetic Validation Study Reveals a Role of Vitamin D Metabolism in the Response to Interferon-Alfa-Based Therapy of Chronic Hepatitis C

Editor: Stephen J. Polyak, University of Washington, United States of America

Received: April 2, 2012; Accepted: June 1, 2012; Published: July 12, 2012

Christian M. Lange1,2*, Stephanie Bibert3, Zoltan Kutalik4, Philippe Burgisser1, Andreas Cerny5, Jean-Francois Dufour6, Andreas Geier7, Tilman J. Gerlach8, Markus H. Heim9, Raffaele Malinverni10, Francesco Negro11, Stephan Regenass7, Klaus Badenhoop2, Jörg Bojunga2, Christoph Sarrazin2, Stefan Zeuzem2, Tobias Müller12, Thomas Berg13, Pierre-Yves Bochud3, Darius Moradpour1*, the Swiss Hepatitis C Cohort Study Group¶ 1

Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland, 2 Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität Frankfurt a.M., Frankfurt a.M., Germany, 3 Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland, 4 Division of Medical Genetics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland, 5 Liver Unit, Ospedale Moncucco, Lugano, Switzerland, 6 University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland, 7 Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland, 8 Division of Gastroenterology, Kantonsspital St. Gallen, St. Gallen, Switzerland, 9 Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland, 10 Hôpital Neuchâtelois, Neuchâtel, Switzerland, 11 Division of Gastroenterology and Hepatology, University Hospital Geneva, Geneva, Switzerland, 12 Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité Campus Virchow Klinikum, Berlin, Germany, 13 Klinik für Gastroenterologie und Rheumatologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany

Abstract Background
To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.

Methodology/Principal Findings
Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome.

Conclusions/Significance
Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.

Discussion ONLY

View Full Text @ PloSONE

The results of the present genetic validation study suggest, in line with our previously published findings [18], an association between the CYP27B1-1260 promoter SNP rs10877012 and SVR to treatment of chronic hepatitis C with PEG-IFN-α and ribavirin. In the present study, this association was found only in patients with a poor-response IL28B genetic background, whereas CYP27B1-1260 rs10877012 was not significantly associated with SVR in patients with good-response IL28B genotype. CYP27B1-1260 rs10877012 is a functional polymorphism in the promotor of the 1α-hydroxylase, the enzyme required for the bioactivation of 25(OH)D₃ to 1,25(OH)₂D₃ (calcitriol) [20]. It has been shown that the CC genotype of CYP27B1-1260 rs10877012 impairs the expression of the 1α-hydroxylase, which results in reduced concentrations of bioactive vitamin D [18], [27].

Consistently, the CC genotype of CYP27B1 is associated with poor response to interferon-α-based treatment of chronic hepatitis C in the present and in our previous study [18], as well as with the risk of bone disease or autoimmune disorders such as multiple sclerosis or type 1 diabetes [19], [20], [27], [29]. Importantly, 1α-hydroxylase is expressed not only in the kidney but also in inflamed tissue and even in immune cells, were it serves as a local, inducible producer of calcitriol [30]. Bioactive vitamin D is an important immune modulator, as for example T cells and macrophages crucially depend on calcitriol in various conditions [31]–[33]. Thus, one may speculate that the “poor-response” CYP27B1-1260 rs10877012 genotype CC may result in lower local concentrations of calcitriol in the HCV-infected liver, resulting in reduced responsiveness to IFN-α or impaired adaptive immune responses. This may be especially relevant in patients with unfavourable IL28B genotype, who in general poorly respond to IFN-α.

The present study confirms that patients with chronic hepatitis C patients have a high prevalence of vitamin D insufficiency. 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 achieved SVR as compared to those who failed to respond to treatment. In two previous studies, including 167 and 211 patients treated with IFN-α-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-α-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 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-α-induced signaling through the Jak-STAT pathway, which results in a synergistic effect of calcitriol and INF-α 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.

In conclusion, the present study suggests a role of vitamin D metabolism in the response to treatment of chronic hepatitis C, especially in patients with poor-response IL28B genotype, but importantly 25(OH)D₃ serum levels are not a reliable marker of treatment outcome.

Click here to view full text.....