| World J Gastroenterol. 2011 December 21; 17(47): 5184–5190. Published online 2011 December 21. doi: 10.3748/wjg.v17.i47.5184 | PMCID: PMC3243885 |
Saif Abu-Mouch, Liver Unit, Department of Internal Medicine B, Hillel Yaffe Medical Center, Hadera 38100, Israel
Zvi Fireman, Jacob Jarchovsky, Department of Gastroenterology, Hillel Yaffe Medical Center, Hadera 38100, Israel
Abdel-Rauf Zeina, Liver Unit, Hillel Yaffe Medical Center, Hadera 38100, Israel
Nimer Assy, Liver Unit, Ziv Medical Center, Technion Institute, Safed 13100, Israel
Author contributions: Abu-Mouch S and Assy N wrote the paper and contributed equally to this work; Fireman Z and Jarchovsky J participated in study design; Zeina AR participated in the discussion.
Correspondence to: Saif Abu-Mouch, MD, Liver Unit, Department of Internal Medicine B, Hillel Yaffe Medical Center, POB 169, Hadera 38100, Israel. saif@hy.health.gov.il
Telephone: +972-4-3044110 Fax: +972-4-6304408
Received February 14, 2011; Revised March 27, 2011; Accepted April 3, 2011.
Abstract
AIM: To determine whether adding vitamin D, a potent immunomodulator, improves the hepatitis C virus (HCV) response to antiviral therapy.
METHODS: Seventy-two consecutive patients with chronic HCV genotype 1 were randomized into two groups: the treatment group (n = 36, 50% male, mean age 47 ± 11 years) received Peg-α-2b interferon (1.5 μg/kg per week) plus ribavirin (1000-1200 mg/d) together with vitamin D3 (2000 IU/d, target serum level > 32 ng/mL), and the control group (n = 36, 60% male, mean age 49 ± 7 years) received identical therapy without vitamin D. HCV-RNA was assessed by real-time polymerase chain reaction (sensitivity, 10 IU/mL). The sustained virologic response (SVR) was defined as undetectable HCV-RNA at 24 wk post-treatment.
RESULTS: Clinical characteristics were similar in both groups. The treatment group had a higher mean body mass index (27 ± 4 kg/m2 vs 24 ± 3 kg/m2; P < 0.01), viral load (50% vs 42%, P < 0.01), and fibrosis score (> F2: 42% vs 19%, P < 0.001) than the controls. At week 4, 16 (44%) treated patients and 6 (17%) controls were HCV-RNA negative (P < 0.001). At week 12, 34 (94%) treated patients and 17 (48%) controls were HCV-RNA negative (P < 0.001). At 24 wk post-treatment (SVR), 31 (86%) treated patients and 15 (42%) controls were HCV-RNA negative (P < 0.001). Viral load, advanced fibrosis and vitamin D supplementation were strongly and independently associated with SVR (multivariate analysis). Adverse events were mild and typical of Peg-α-2b/ribavirin.
CONCLUSION: Adding vitamin D to conventional Peg-α-2b/ribavirin therapy for treatment-naïve patients with chronic HCV genotype 1 infection significantly improves the viral response.
Keywords: Hepatitis C, Vitamin D, Sustained viral response, Genotype 1, Fibrosis
The results of this study suggest that the addition of a vitamin D supplement to current standard therapy can significantly improve the rate of RVR, EVR and SVR in treatment-naïve patients with HCV genotype 1 compared the rates with standard therapy alone. The observed SVR in the control group (42%) was consistent with previous reports[2,3]. Overall there was a marked increase in the virologic response at week 4 (44% vs 17%), week 12 (94% vs 48%), and week 24 after the cessation of therapy (86% vs 42%), and a low rate of relapse (8% vs 36%) with vitamin D supplementation compared with no supplementation. The rate of relapse in the control group was within the reported 18%-40% range for current standard HCV antiviral therapy[2,22].
There are only two reports examining the association between vitamin D status and outcome of antiviral therapy in patients with chronic HCV viral infection. Petta and co-workers retrospectively analyzed a cohort of 167 patients treated with Peg/RBV for hepatitis C, and detected an association between lower vitamin D serum levels and failure to achieve SVR[23]. Our results provide further support for that data. The second study by Bitetto and co-workers showed that vitamin D supplementation improved the response to antiviral treatment for recurrent HCV in liver transplant recipients[24]. Several differences between those two studies should be noted. Bitetto and co-workers’ HCV patients were immunocompromised, and they were supplemented with low-dose vitamin D (800 IU/d) after liver transplantation. In addition, most of their HCV patients (75%) had low vitamin D levels despite treatment. Finally, that study was retrospective and focused on the prevention of osteoporosis, not on the treatment of hepatitis C.
The exact mechanism of action leading to improved RVR, EVR, and SVR in patients receiving vitamin D is unknown. Vitamin D is metabolized by the liver and converted to 1,25-dihydroxy-vitamin D3, which is the active form of the vitamin[6,7]. Individuals with chronic liver disease may have poor conversion from vitamin D3 or any of its other biologically active metabolites[11]. 1,25 vitamin D3 appears to modulate immunity principally via regulation of T-cell function[25]. The vitamin D receptor (VDR) is expressed on virtually every type of cell involved in immunity[26]. The immunomodulatory actions of vitamin D are elicited through its direct action on T-cell antigen-presenting cell function[27]. T helper cell type 1 (TH1) actions are intensified when vitamin D is insufficient, as in the majority of our patient population, or when signals through VDR are weak. Regulatory T cell and TH2 cells are diminished, thus favoring an autoimmune TH1 response[28]. This is a pro-inflammatory response which may impair IFN and insulin signaling, thus decreasing the viral response[29,30]. A recent study on 120 patients with chronic HCV genotype 1 infections reported that a TH1 to TH2 ratio of < 15.5 was significantly associated with SVR (odds ratio 9.6)[31]. TH1 and TH2 measurements were not performed in the present study. Persistent HCV infection modulates the balance between immune stimulatory and inhibitory cytokines which can prolong inflammation and lead to fibrosis and chronic liver diseases[32]. More recently, Gutierrez and co-workers showed that vitamin D3 increased VDR protein expression and inhibited viral replication in cell culture[33].
It is well known that people of African and Hispanic descent are less likely to respond to standard therapy[34]. This may be due to a polymorphism of the interleukin (IL)-28B gene, polymorphism of VDR or vitamin D deficiency[13,35]. The vast majority of the Russian/Jewish/Arab patients in the present study had vitamin D insufficiency, possibly related to paradoxically low exposure to the sun in this predominantly sunny country and/or to a low supply of vitamin D from their diet.
The impact of diet on liver fibrosis and on response to IFN therapy in patients with HCV chronic hepatitis has been reported before[36]. HCV patients also lack vitamins E and B12[37,38]. A recent study showed that higher levels of vitamin B12 were associated with SVR, but there was no difference in serum levels of those vitamins between the group treated with vitamin D and the controls[39].
The impact of diet on liver fibrosis and on response to IFN therapy in patients with HCV chronic hepatitis has been reported before[36]. HCV patients also lack vitamins E and B12[37,38]. A recent study showed that higher levels of vitamin B12 were associated with SVR, but there was no difference in serum levels of those vitamins between the group treated with vitamin D and the controls[39].
Insulin resistance emerged as one of the most important host factors in the prediction of the response in non-diabetic HCV patients treated with Peg/RBV, and is a common factor in the features associated with difficult-to-treat patients[40]. Vitamin D is also known to help prevent type 2 diabetes, and it is possible that low levels of vitamin D lead to insulin resistance[9]. The direct effect of vitamin D may be mediated by binding of its circulating active form to the pancreatic B cell vitamin D receptor[41]. Vitamin D deficiency or insufficiency may alter the balance between the extracellular and intracellular cell calcium pools, which may interfere with normal insulin release[42]. Thus, a lack of either calcium or vitamin D can result in peripheral insulin resistance[41]. Moreover, oxidative stress leeches calcium, and vitamin D helps absorb calcium[43]. Our current results confirm these findings: the HOMA-IR was higher at baseline in the vitamin D treatment group and improved after 4 wk of therapy compared to the control group. Moreover, the changes in HOMA-IR were strongly associated with SVR (multivariate analysis).
The definition of normal vitamin D serum levels is a subject of debate. In the current study, increasing the vitamin level D to > 32 ng/mL increased the response to antiviral therapy to the same extent in patients with vitamin D deficiency as well as those with vitamin D insufficiency. Multivariate analysis revealed that viral load, advanced fibrosis and vitamin D supplementation remained as independent predictors. Thus, it can be concluded that vitamin D supplementation is responsible for a higher SVR, rather than the baseline vitamin D level. It remains to be determined whether the addition of vitamin D acts by a mechanism other than improvement of insulin resistance or immune function such as the upregulation of toll-like receptors involved in the immune response in HCV-infected patients
Limitations of the present study include the small number of patients, lack of vitamin D level assessment during therapy for the treatment and control groups, and that this prospective and randomized study was not placebo-controlled, thus the patients knew whether or not they received a vitamin D supplement. Another limitation is the lack of data on the TH1 and TH2 immune response. The identification of determinants of the response, such as polymorphisms of the IL28B gene, polymorphism of the VDR and immune function[13,35], may help explain the difference in response rates between patients with different ethnic backgrounds. This was not done in our study since data on IL-28B and on VDR polymorphism were not available at the time the study was designed.
In conclusion, the addition of vitamin D to Peg/RBV combination therapy in treatment-naïve patients who were infected with HCV genotype 1 significantly increased the rates of rapid, early, and sustained viral responses.
COMMENTS
Background
Treating chronic hepatitis C virus (HCV) (genotype1) patients with pegylated interferon and ribavirin, which is considered to be the standard of care, has achieved viral clearance in less than 50% of the patients. Vitamin D is a potent immunomodulator with a beneficial effect against viral and bacterial infections. The vast majority of patients with chronic hepatitis C have low levels of vitamin D. Different new drugs such as protease or polymerase inhibitors are still under investigation and are expensive and have many side effects like rash.
Research frontiers
Vitamin D deficiency is well documented in patients with chronic liver disease. However, treating patients with chronic HCV infection by adding a vitamin D supplement to the standard of care has not been addressed. There are only two reports dealing with the association between vitamin D status and outcome of antiviral therapy for chronic HCV infection.
Innovations and breakthroughs
The current study shows that adding a vitamin D supplement to pegylated interferon and ribavirin significantly increases the rapid, early and late clearance of the virus, in chronic hepatitis C genotype 1 treatment-naïve patients.
Applications
This study emphasizes the importance of vitamin D supplementation when added to standard treatment in all patients with chronic hepatitis C. Further studies are needed to explain the mechanism of vitamin D supplementation for these patients.
Terminology
Hepatitis C is a chronic liver infection that can be complicated by liver failure and liver cancer. Clearance of the virus from the blood is achievable by a combination of pegylated interferon and ribavirin in less than 50% of the patients. Vitamin D has an important role in the treatment of different bacterial and viral infections; this vitamin is synthesized in the skin by absorption of ultraviolet from the sun light. The mechanism of action of this vitamin is unknown, but it may improve the activities of immune cells that are important in the eradication of HCV.
Peer review
This is a well conducted study with a relevant finding, and it is well written.
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