Will Vitamin D Supplementation Have a Role in the Treatment of Patients with Chronic Hepatitis C

1 Matsumura T*,y, Kato Ty, Sugiyama Ny, Tasaka-Fujita My, Asako Murayama Ay, Masaki Ty, Wakita Ty, Imawari M*. 25-Hydroxyvitamin D3 suppresses hepatitis C virus production. Hepatology. 2012;56:1231–1239. *Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan; yDepartment of Virology II, National Institute of Infectious Diseases, Tokyo, Japan. Because the current interferon (IFN)-based treatment for hepatitis C virus (HCV) infection has a therapeutic limitation and side effects, a more efficient therapeutic strategy is desired. Recent studies show that supplementation of vitamin D significantly improves sustained viral response via IFNbased therapy. However, mechanisms and an active molecular form of vitamin D for its anti-HCV effects have not been fully clarified. To address these questions, we infected HuH7 cells with cell culture-generated HCV in the presence or absence of vitamin D3 or its metabolites. To our surprise, 25-hydroxyvitamin D3 [25(OH)D3], but not vitamin D3 or 1,25-dihydroxyvitamin D3, reduced the extraand intracellular levels of HCV core antigen in a concentration-dependent manner. Single-cycle virus production assay with a CD81negative cell line reveals that the inhibitory effect of 25(OH)D3 is at the level of infectious virus assembly but not entry or replication. Long-term 25(OH)D3 treatment generates a HCV mutant with acquired resistance to 25(OH)D3, and this mutation resulting in a N1279Y substitution in the nonstructural region 3 helicase domain is responsible for the resistance. Conclusion: 25(OH)D3 is a novel anti-HCV agent that targets an infectious viral particle assembly step. This finding provides insight into the improved efficacy of anti-HCV treatment via the combination of vitamin D3 and IFN. Our results also suggest that 25(OH)D3, not vitamin D3, is a better therapeutic option in patients with hepatic dyshttp://dx.doi.org/10.1016/j.jceh.2012.10.008 2012, INASL Journal of Clinical and function and reduced enzymatic activity for generation of 25(OH)D3. Abstract 2 Falleti E*, Bitetto D*, Fabris C*, Fattovich Gy, Cussigh A*, Cmet S*, Ceriani Ez, Fornasiere E*, Pasino My, Ieluzzi Dy, Pirisi Mz,x, Toniutto P*. Vitamin D binding protein gene2 Falleti E*, Bitetto D*, Fabris C*, Fattovich Gy, Cussigh A*, Cmet S*, Ceriani Ez, Fornasiere E*, Pasino My, Ieluzzi Dy, Pirisi Mz,x, Toniutto P*. Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C. Hepatology. 2012; May 18. http://dx.doi.org/10.1002/ hep.25848. [Epub ahead of print]. *Department of Medical Sciences, Clinical and Experimental, Medical Liver Transplantation Unit, Internal Medicine, University of Udine, Italy; yGastroenterology Clinic, Department of Medicine, Azienda Ospedaliero-Universitaria, University of Verona, Italy; zDepartment of Clinical and Experimental Medicine, Universit a del Piemonte Orientale ‘‘A. Avogadro’’, Novara, Italy; xInterdepartmental Research Centre for Autoimmune Diseases (IRCAD), Novara, Italy. Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after antiviral treatment in hepatitis C virus (HCV) difficult-to-treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of antiviral responses in patients affected by chronic hepatitis C. In all, 206 HCV patients treated with a combination therapy of pegylated (PEG)-interferon plus ribavirin were retrospectively evaluated. GC rs7041 G > T, GC rs4588 C > A, and IL-28B rs12979860 C > T polymorphisms were genotyped. Frequencies of GC rs7041 G > T and rs4588 C > A polymorphisms were: G/G = 64 (31.1%), G/T = 100 (48.5%), T/T = 42 (20.4%) and C/C = 108 (52.4%), C/A = 84 (40.8%), A/A = 14 (6.8%). Patients were divided into those carrying $3 major alleles (wildtype [WT]+: G-C/G-C, G-C/T-C, G-C/G-A, N = 100) and the remaining (WT : G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N = 106). Four groups were identified: vitamin D #20 ng/mL and WT , vitamin D #20 and WT+, vitamin D >20 and WT , vitamin D >20 and WT+. In difficult-to-treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (P = 0.003). At multivariate analysis, having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (odds ratio 4.52, Experimental Hepatology | December 2012 | Vol. 2 | No. 4 | 396–398 JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY P = 0.015). Conclusion: In difficult-to-treat HCV genotypes, simultaneous pretreatment normal serum vitamin D levels and the carriage of GC-globulin WT isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy. H ep a to lo g y E ls e w h e re Abstract 3 Nimer A*, Mouch Ay. Vitamin D improves viral response in hepatitis C genotype 2–3 naive patients. World J Gastroenterol. 2012;18(8):800–805. *Department of Liver, Ziv Medical Center, Safed 13100, Israel; yDepartment of Liver, Hillel Yaffe Medical Center, Hadera 38100, Israel. Aims: To examine whether vitaminD improved viral response and predicted treatment outcome in patients with hepatitis C virus (HCV) genotype 2–3. Methods: Fifty patients with chronic HCV genotype 2–3 were randomized consecutively into two groups: Treatment group [20 subjects, age 48 ± 14 years, body mass index (BMI) 30 ± 6, 65%male], who received 180 mg pegylated a-interferon-2a plus oral ribavirin 800 mg/ d (Peg/RBV), together with oral vitamin D3 (Vitamidyne D drops; 2000 IU/d, 10 drops/d, normal serum level > 32 ng/ mL) for 24 week; and control group (30 subjects, age 45 ± 10 years, BMI 26 ± 3, 60% male), who received identical therapywithout vitaminD.HCVRNAwas assessed by reverse transcription polymerase chain reaction. Undetectable HCV RNA at 4,12 and 24 week after treatment was considered as rapid virological response, complete early virological response, and sustained virological response (SVR), respectively. Biomarkers of inflammation were measured. Results: The treatment group with vitamin D had higher BMI (30 ± 6 vs. 26 ± 3, P 400 000 IU/mL, 65% vs. 40%, P 15 ng/mL, OR 2.2, P 30, OR 2.6, P < 0.01) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV.Conclusion: Low vitaminD levels predicts negative treatment outcome, and adding vitamin D to conventional Peg/RBV therapy for patients with HCV genotype 2–3 significantly improves viral response.