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

Abstract 1

Matsumura T*^,†, Kato T^†, Sugiyama N^†, Tasaka-Fujita M^†, Asako Murayama A^†, Masaki T^†, Wakita T^†, 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; ^†Department 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 IFN-based 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 HuH-7 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 extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. Single-cycle virus production assay with a CD81-negative 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 dysfunction and reduced enzymatic activity for generation of 25(OH)D₃.

Abstract 2

Falleti E*, Bitetto D*, Fabris C*, Fattovich G^†, Cussigh A*, Cmet S*, Ceriani E^‡, Fornasiere E*, Pasino M^†, Ieluzzi D^†, Pirisi M^‡,§, 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; ^†Gastroenterology Clinic, Department of Medicine, Azienda Ospedaliero-Universitaria, University of Verona, Italy; ^‡Department of Clinical and Experimental Medicine, Università del Piemonte Orientale ‘‘A. Avogadro’’, Novara, Italy; ^§Interdepartmental 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, 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.

Abstract 3

Nimer A*, Mouch A^†. 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; ^†Department of Liver, Hillel Yaffe Medical Center, Hadera 38100, Israel.

Aims: To examine whether vitamin D 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 μg pegylated α-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 therapy without vitamin D. HCV RNA was 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 < 0.02), and high viral load (>400 000 IU/mL, 65% vs. 40%, P < 0.01) than controls. Ninety-five percent of treated patients were HCV RNA negative at week 4 and 12. At 24 week after treatment (SVR), 19/20 (95%) treated patients and 23/30 (77%) controls were HCV RNA negative (P < 0.001). Baseline serum vitamin D levels were lower at baseline (20 ± 8 ng/mL) and increased after 12 week vitamin D treatment, to a mean level of (34 ± 11 ng/mL). Logistic regression analysis identified vitamin D supplement [odds ratio (OR) 3.0, 95% CI 2.0–4.9, P < 0.001], serum vitamin D levels (<15 or >15 ng/mL, OR 2.2, P < 0.01), and BMI (<30 or >30, OR 2.6, P < 0.01) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV. Conclusion: Low vitamin D 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.

Comments

While scientific advances in management of chronic hepatitis C (CHC) have led to optimism in the care of these patients, therapy of patients with CHC in developing countries is far from satisfactory. A large number of patients with CHC in developing countries are not even able to afford investigations for CHC, leave alone therapy. The arrival of directly acting agents (DAA) at the doorstep has further pushed up the anticipated costs of therapy for CHC. The additional costs have dampened the enthusiasm of research in DAA and may make such therapy out of reach for many more. It is therefore important to have an economic evaluation of DAA in guiding policy decisions about the use of newly approved drugs as well as future therapies for hepatitis C.¹ The rate-limiting factor in achieving better outcomes may turn out to be access to diagnostic and treatment modalities.² With this background, the emerging data on efficacy of a cheap drug like Vitamin D in the treatment of CHC is like a breath of fresh air. The above three recent articles reiterate the beneficial effects of vitamin D in management of CHC.

Matsumura et al³ using a culture model, identified 25-hydroxyvitamin D [25(OH)D] as the metabolite of vitamin D with the ability to suppress viral replication of Hepatitis C virus (HCV) by selectively inhibiting the viral assembly step.

Falleti et al⁴ have shown that in difficult-to-treat HCV genotypes, normal vitamin D levels and vitamin D binding protein (GC) gene polymorphisms strongly predicted the achievement of sustained virological response (SVR) after PEG-interferon plus ribavirin (PEG-IFN/Riba) antiviral therapy. The GC-globulin possesses a number of other functions implicated in the modulation of the inflammatory process and may have a vitamin-D-independent role in influencing the response to interferon in the treatment of HCV. Besides GC-globulin polymorphisms, vitamin D receptor polymorphisms have also been recently shown to affect response to antiviral therapy.⁵

Nimer and Mouch,⁶ in a prospective randomized study, have shown that in genotype 2/3 patients, adding vitamin D to PEG-IFN/Riba therapy significantly improves viral response. While there have been similar studies earlier showing the beneficial effect of vitamin D supplementation on response to antiviral therapy in HCV, these studies were either retrospective or used lower doses of vitamin D.^7,8 The authors of this current study have recently also shown the beneficial effect of vitamin D supplementation on genotype 1 patients.⁹

Vitamin D is synthesized in the skin as a result of exposure to sunlight besides absorption from dietary sources. The vitamin D is initially hydroxylated by the liver to form 25(OH)D, a stable metabolite with a long half-life, which can be used as an indicator of the vitamin D status. This undergoes a second hydroxylation in the kidney and some extra-renal tissues to form 1, 25-hydroxyvitamin D [1,25(OH)₂D].

Vitamin D has many effects beyond bone and calcium metabolism. The emerging data on the relationship between vitamin D and CHC has evoked much interest.^10–13 Vitamin D deficiency is more common in patients with CHC as compared to controls. Vitamin D may inhibit HCV replication and vitamin D deficiency is associated with severe fibrosis and poorer response to therapy with PEG-IFN/Riba. Vitamin D levels and IL28B polymorphisms are independently associated with likelihood of achieving rapid virological response (RVR) and SVR.¹⁴ Vitamin D deficiency can be used in a complementary role to IL28B polymorphisms in predicting attainment of SVR. Vitamin D supplementation improves the SVR rates in therapy of CHC with antiviral therapy.

The exact mechanisms of role of vitamin D in improving response to antiviral therapy are unclear. Vitamin D appears to modulate immunity by regulating T-cell function.¹⁵ Besides a direct effect of suppression of viral replication, vitamin D also has immunomodulatory actions, which are mediated through its direct action on T-cell antigen-presenting cell function.¹⁶ In vitamin D deficiency, T helper cell type 1 (Th1) cell actions are intensified and regulatory T cells and Th2 cells are diminished, resulting in a proinflammatory Th1 response which may impair interferon and insulin signaling, thus decreasing viral response.^17–19

Despite the common misconception, even in a tropical country like India, vitamin D deficiency (VDD) is common. According to a study conducted in elderly Indian population of more than 50 years of age, VDD was noted in more than 90% population.²⁰ Patients with chronic hepatitis C with vitamin D levels lower than 20–30 ng/mL should be considered for vitamin D supplementation with a daily dose of 1000–4000 IU/day.

Vitamin D presents as a cheap alternative to DAA in improving outcomes of therapy in difficult-to-treat HCV patients. Large prospective trials are required to confirm the role of vitamin D in the management of HCV. However, unlike the enthusiasm relating to DAA, the research of the role in vitamin D in CHC is likely to be affected by funding. Vitamin D is a cheap drug, so it appears unlikely that pharmaceutical companies will fund and drive such a research. If definitive studies confirm the role of vitamin D in the management of CHC, it may prove a boon for developing countries where cost considerations may not allow widespread use of DAA for difficult-to-treat HCV patients.