Vitamin D Could Impact On Hepatitis Cure Rates

Feb 27 2014 05:07 AM

A team of researchers from Dundee University, key Scottish Hepatitis services and Hepatitis Scotland is to test speculation as to whether Vitamin D can enhance Hepatitis C cure rates when used in combination with currently available treatment therapies.

New Hepatitis C treatments will soon be available but are likely to be very expensive. With approximately 150 million people chronically infected with Hepatitis C worldwide, and 38,000 in Scotland alone, cost factors are likely to play a significant part in future treatment decisions. The research team will use evidence from previous small trials as a basis for a new investigation which will provide firm evidence to confirm the impact that Vitamin D might have on cure rates.

Hepatitis Scotland’s Lead Officer, Leon Wylie said, “This study could have significant impact on the future of Hepatitis C treatment, both here and internationally. If this study replicates other findings then a very cheap and safe method of increasing treatment success rates could be available, at a cost of pennies a day. When we first saw the early research it seemed very exciting and I am extremely pleased that our partnership working has helped achieve the start of this research. “

Dr John Dillon, Dundee University Clinical Reader, NHS Tayside Consultant Hepatologist and co-Chair of the National Hepatitis C Clinicians group, said, “This trial shows Scotland working together to discover new ways of helping cure patients affected by hepatitis C, here in Scotland and across the world. It further establishes Scotland’s reputation as a world-leading centre for research into Hepatitis C.”

The trial has been funded as a pilot through the Chief Scientist’s Office and depending on its success may be expanded to cover a much larger number of patients. Merck Serono KgAA have supplied the high concentration Vitamin D supplements at no charge.

Source

Vitamin D Levels Vary during Antiviral Treatment but Are Unable to Predict Treatment Outcome in HCV Genotype 1 Infected Patients

PLOS ONE

RESEARCH ARTICLE

Georgios Grammatikos, Christian Lange, Simone Susser, Susanne Schwendy, Nektarios Dikopoulos, Peter Buggisch, Jens Encke, Gerlinde Teuber, Tobias Goeser, Robert Thimme, Hartwig Klinker, Wulf O. Boecher, Ewert Schulte-Frohlinde,  Marissa Penna-Martinez, Klaus Badenhoop, Stefan Zeuzem, Thomas Berg, Christoph Sarrazin

Published: February 07, 2014 DOI: 10.1371/journal.pone.0087974

Abstract

Background

Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed.

Methods

In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome.

Results

Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response.

Conclusions

While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients.

Citation: Grammatikos G, Lange C, Susser S, Schwendy S, Dikopoulos N, et al. (2014) Vitamin D Levels Vary during Antiviral Treatment but Are Unable to Predict Treatment Outcome in HCV Genotype 1 Infected Patients. PLoS ONE 9(2): e87974. doi:10.1371/journal.pone.0087974

Editor: Kostas Pantopoulos, Lady Davis Institute for Medical Research/McGill University, Canada

Received: October 14, 2013; Accepted: December 31, 2013; Published: February 7, 2014

Copyright: © 2014 Grammatikos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: KB is supported by the European Union FP7 program NAIMIT, grant agreement 241447. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Almost 3% of the world population is chronically infected with hepatitis c virus (HCV) and thus potentially confronted with life-threatening complications such as liver cirrhosis and liver cancer[1]. During permanent attempts to improve therapeutic strategies, beside the recent approval of two novel direct acting antiviral compounds [2], several predictors of treatment response have been identified [3] with recent studies including gamma-glutamyl-transferase (gGT) [4], cholesterol [5], early viral kinetics [6], interferon-γ-inducible-protein-10 (IP10) [7], ferritin [8] and the interleukin-28B (IL28B) polymorphism [9] as further important predictors of sustained viral response (SVR) as well. However, the pursuit of further surrogate factors able to optimize therapeutic regimes remains challenging.

Beside the above mentioned parameters many studies suggested vitamin D (VitD) as an additional predictor of SVR, whereas low pretreatment levels of 25-OH-Vitamin D₃ (25(OH)D₃) (<20 ng/ml) associated significantly with low responsiveness to antiviral therapy[10]–[14]. However, recent findings also indicate that the pretreatment concentration of VitD is not always capable of predicting treatment outcome in chronic HCV infection [15] as well as in HCV/HIV-coinfected patients [16], [17]. Moreover, serum concentrations of 25(OH)D₃ are getting affected by various factors such as nutrition, comorbidities and seasonal sunlight exposure [18] and since an additional hydroxylation step is needed, 25(OH)D₃-levels just offer an indirect association to the active form of VitD, 1,25(OH)₂D_3. The latter has a half-life of only 4 hours and is detectable in much lower serum concentrations than 25(OH)D₃. 1,25(OH)₂D₃ is additionally strongly affected by the serum levels of calcium, phosphate and parathyroid hormone with clinical guidelines still recommending the routine assessment of 25(OH)D₃ as the appropriate parameter in order to monitor the VitD status of patients [19]. In this context genetic polymorphisms within key enzymes regulating the pathophysiology of VitD have been shown to affect substantially VitD signaling in clinical diseases [20], [21]. In chronic HCV infection genetic polymorphisms within VitD binding proteins [12], the CYP27B1-hydroxylase [22] and the VitD-receptor [23] have been shown to correlate significantly with the outcome of antiviral therapy.

Purpose of the present study is therefore to evaluate the predictive potential of serum VitD levels both prior to as well as during antiviral therapy in a large (n = 398), well characterized cohort of genotype 1 HCV infected patients treated prospectively with pegylated interferon-α (PEG-IFNα) and ribavirin (RBV) for 24–72 weeks (INDIV-2 study) [24]. Since liver histology and genetic data were available in the majority of patients, we additionally evaluated genetic polymorphisms within major enzymes regulating 25(OH)D₃- and 1,25(OH)₂D₃-concentrations,CYP2R1, CYP27B1, DHCR7, CYP24A1 and within VitD binding proteins (DBP). Findings concerning the prediction of treatment outcome were further analyzed in association with several prognostic parameters being available prior to initiation, during and after completion of antiviral therapy in our patient cohort.

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Bone Mineral Density Measurements, Bone Markers and Serum Vitamin D Concentrations in Men with Chronic Non-Cirrhotic Untreated Hepatitis C

PLOS One

OPEN ACCESS PEER-REVIEWED

RESEARCH ARTICLE

Luciana G. S. Orsini, Marcelo M. Pinheiro, Charlles H. M. Castro mail, Antônio E. B. Silva, Vera L. Szejnfeld

Published: November 28, 2013 DOI: 10.1371/journal.pone.008165

Abstract

Introduction

The high prevalence of chronic hepatitis C (CHC) and its consequent cirrhosis has been associated with bone fragility. Whether CHC may cause bone and mineral abnormalities in the absence of hepatocellular dysfunction is still unknown. In this study we aimed to determine the prevalence of osteoporotic vertebral fractures and low BMD measurements in men with non-cirrhotic CHC. Risk factors for low BMD and fractures were also investigated.

Methods

Morphometric vertebral fractures and BMD measurements were performed in 60 non-cirrhotic untreated men with CHC and 59 healthy controls, matched for age and gender, weight and current smoking. Serum CTx, calcium, phosphate, intact PTH, alkaline phosphatase and vitamin D (25OHD) concentrations were measured in all participants. Clinical risk factors for low BMD and fractures were evaluated by a structured questionnaire as well as details regarding HCV infection.

Results

Trochanter and total femur BMD were significantly lower in CHC patients as compared to healthy men (p = 0.04). In men 50 years and older, the prevalence of osteoporosis was significantly higher among CHC patients (p = 0.01). Lower levels of physical activities and more often report of prolonged immobilization were observed among CHC patients (p<0.05). Liver inflammation and fibrosis, viral load and genotype did not correlate with BMD measurements. Bone markers and 25OHD concentrations were similar in both groups. Only a few vertebral fractures were observed.

Conclusions

Our results demonstrate that non-cirrhotic untreated CHC patients have lower BMD at the femur as compared to healthy men in spite of the absence of significant bone and mineral abnormalities.

---

itation: Orsini LGS, Pinheiro MM, Castro CHM, Silva AEB, Szejnfeld VL (2013) Bone Mineral Density Measurements, Bone Markers and Serum Vitamin D Concentrations in Men with Chronic Non-Cirrhotic Untreated Hepatitis C. PLoS ONE 8(11): e81652. doi:10.1371/journal.pone.0081652

Editor: Luc Malaval, INSERM U1059/LBTO, Université Jean Monnet, France

Received: June 10, 2013; Accepted: October 15, 2013; Published: November 28, 2013

Copyright: © 2013 Orsini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was funded by a grant from the Rheumatology Division at the Universidade Federal de São Paulo/Escola Paulista de Medicina (Unifesp/EPM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

The World Health Organization (WHO) has estimated that about 3% of the world population has positive serology for hepatitis C virus (HCV) (approximately 170 million of people) [1]. Bone diseases are common complications of chronic hepatitis C (CHC), mainly related to the associated cirrhosis. Among the bone abnormalities reported, hepatitis C-associated osteosclerosis (HCAO) is a rare acquired condition characterized by generalized increase in bone mineral density (BMD), bone pain, elevated serum alkaline phosphatase, generalized cortical thickening and increased uptake on bone scan [2]–[4].

Bone loss has been described as a complication of viral cirrhosis [5]–[9] and its prevalence increases in more severe cases [5]–[7]. Higher levels of serum soluble tumor necrosis factor (TNF) receptor 55 [8] and lower levels of 25-hydroxy vitamin D (25OHD) [5], [7], [8], testosterone [5], [7] and IGF-I in more advanced Child-Pugh stages [7], [8] may all contribute to the lower BMD measurements observed among patients with more severe disease.

Bone disorders have been clearly associated with the presence of cirrhosis per se, regardless of its cause. In patients with CHC and other viral hepatitis, their treatment may also be considered as a confounder when evaluating bone complications. It has been reported that the combination therapy for patients with CHC consisting of interferon-α (INF-α) plus ribavirin resulted in bone loss after 12 months [10]. Increased BMD as well as no change have also been reported after treatment with INF-α in patients with CHC [11], [12].

On the other hand, BMD and bone metabolism abnormalities in non-cirrhotic hepatitis C patients have not been well investigated. Whether chronic HCV infection in the absence of cirrhosis or viral treatment is a risk factor for the development of bone disease has long been controversial.

Only a few studies have evaluated bone status in CHC patients [13]–[15]. Some methodological questions associated to current treatment in some of the patients and the absence of a healthy control group for comparison has limited the results of those studies. Considering the lack of solid evidence for an effect of chronic HCV infection on bone status, in the present study we evaluated BMD measurements, bone and mineral metabolism and the prevalence of vertebral osteoporotic fractures in non-cirrhotic men with untreated CHC infection as compared to healthy age-matched controls.

Materials and Methods

Ethics Statement

Ethical approval was obtained from the Universidade Federal de São Paulo's ethics committee and all participants gave written informed consent prior to their inclusion in this study.

Patients

Sixty men (mean age 41.5±10.9 years old) with CHC infection consecutively seen at the UNIFESP's outpatients clinics and fifty-nine healthy men (mean age 41.7±10.8 years) were invited to participate in the present study. Anti-HCV/HCV RNA-positive patients (N = 60) had been followed for at least 6 months with persistently positive serology for HCV and negative serological markers for hepatitis B and human immunodeficiency virus (HIV). Healthy men (N = 59) were selected from blood donators registered at our center.

CHC patients with any clinical, laboratorial or histological cirrhosis were excluded, as well as those previously or currently treated with interferon/ribavirin therapy. Other exclusion criteria for both CHC patients and healthy controls included alcoholism (defined as more than 2 drinks per day) [17], diseases or use of drugs that interfere with bone metabolism (corticosteroids, levothyroxine, calcium and vitamin D supplements, diuretics, bisphosphonates, anabolic agents), diabetes mellitus, lung diseases and autoimmune hepatitis.

Body weight was measured (after removal of shoes and heavy outer clothing) using a balance beam scale. Height was measured (after removal of shoes) using a Filizola stadiometer. Height and weight were used to calculate the body mass index (BMI; kg/m²). Data about smoking and drinking habits, physical activity, prolonged immobilization, familial history of osteoporosis and hip fracture were obtained using a structured questionnaire based on the European Vertebral Osteoporosis Study (EVOS) [18], [19] and validated for our language and culture [20]–[22]. Patients and controls were matched for age, gender, weight, current smoking and alcohol use.

Bone density measurements

BMD measurements were performed in all subjects at the lumbar spine (L1-L4) and proximal femur (neck, trochanter and total hip) using dual X-ray absorptiometry (DXA) (DPX MD+, GE-Lunar, Madison, WI, USA). The coefficient of variation for BMD measurements was 1.5% and 2% at lumbar spine and total hip, respectively. Long-term quality control of the instrument was assured by daily scan using a standard spine phantom as instructed by the manufacturer. All scans were performed in the same machine by the same operator and were analyzed by a physician blinded to the group the participant belonged. Consistent with the recommendations from WHO [23] and from the International Society of Clinical Densitometry [16], men 50 years and older were classified according to T-score as normal bone density (T-score above – 1.0 SD), osteopenia (−1.0< T-score <−2.5) or osteoporosis (T-score below – 2.5 SD). Z-score was used to classify younger men (less than 50 years old) as within the expected range for age (Z-score above – 2.0) or below the expected range for age and sex (Z-score below – 2.0). For comparison purposes, BMD measurements in both groups were adjusted for age and body weight.

Laboratory tests

Blood was drawn in the morning after an overnight fasting. Routine tests included total serum calcium, phosphate, and creatinine and total alkaline phosphatase using standard methods. Intact parathyroid hormone (iPTH) (Nichols Advantage® Chemiluminescence Intact Immunoassay; interassay coefficient of variation of 7%; normal range 10–65 pg/mL), 25-hydroxy vitamin D (25OHD) (radioimmunoassay technique, DiaSorin, Stillwater, MN, USA; intra- and inter-assay coefficients of variation were 9.5% and 15.2%, respectively) and type I collagen C-telopeptide (CTx) serum concentrations (Elecsys 2010 automated analyzer, Roche; interassay coefficient of variation of 6%; normal range 0.081–0.850 ng/mL) were also determined.

HCV viral load and genotype, liver biopsy classification and serum albumin were obtained from an extensive review of the patients' charts.

Vertebral fracture assessment

Radiographic lateral and posterior-anterior images of thoracic and lumbar spine were taken according to standard protocols aiming to evaluate asymptomatic vertebral fractures. Thoracic films were centered at T8 and lumbar films at L3. Focus film distance was 1.5 m. A semi-quantitative method [24] was used to determine the prevalence of vertebral deformities. Only grades II and III were considered as vertebral fractures. Intra and inter-observer coefficients of variation and kappa indexes for the method in our unit are 4.8% (concordance 95.2%) and 6.3% (concordance 93.7%) and 0.84 (95%CI 0.78–0.92) and 0.82 (95%CI 0.75–0.9), respectively[21].

Statistical analysis

Results were expressed as mean ± standard deviation. Chi-squared tests were used to evaluate the prevalence of osteoporosis, osteopenia, and low BMD as well as the vitamin D status between CHC men and their healthy controls. We compared the BMD, anthropometric variables, frequency of risk factors for osteoporosis and laboratorial tests between CHC patients and healthy controls using Student's t-tests. Two-way ANOVA analyzes were used to adjust vitamin D concentrations according to the season of the year. Pearson's and Spearman's coefficient of correlation were used to estimate association between clinical variables and BMD measurements with the prevalence of low bone mass and osteoporosis in CHC patients. Potential risk factors for low bone mass and osteoporosis were analyzed by backward stepwise regression analysis using variables identified in correlation analyzes. SPSS statistical package for Windows (version 15.0) was used to analyze the data. Significance level was set as p<0.05.

Results

Relevant demographic and clinical characteristics for both CHC patients and healthy men are shown in Table 1. CHC patients had lower physical activity and reported prolonged immobilization more often than healthy men (p<0.05). In spite of their similar weight and height, CHC patients had significantly higher BMI values as compared to the healthy controls (p = 0.04).

Table 1. Demographic data and clinical characteristics of chronic hepatitis C (CHC) men and healthy controls.

Spine and femoral neck BMD did not differ significantly between HCV patients and healthy men, as demonstrated in Table 2. On the other hand, total femur and trochanter BMD values were significantly lower in CHC men as compared to healthy controls, even after adjustments for body weight (p<0.05).

Table 2. Bone mass measurements in CHC patients and healthy controls.

For subjects younger than 50 years old, BMD measurements below the expected range for age and sex (Z-score below – 2.0) were found in 1 (at the femur) out of 41 CHC patients (3%) and 2 (one at the femur, one at the lumbar spine) out of 40 controls (5%). Again, no statistically significant difference was observed between groups. For men 50 years old or more, osteoporosis was detected in 36% of the CHC patients (two patients at both femur and lumbar spine, three patients at the femur and two other patients at the lumbar spine) and in only 4% of the healthy men (2 at the femur and two others at the lumbar spine). Osteopenia was observed in 32% of both groups (three patients at the femur and three others at the lumbar spine; five healthy controls had osteopenia at the lumbar spine and one of them had osteopenia at the femur). BMD classified as normal was found in 32% of the CHC patients and in 64% of the controls (p = 0.01).

Serum concentrations of biochemical bone markers were in the normal range for both CHC patients and controls as shown in Table 3. Total calcium, phosphate, alkaline phosphatase, iPTH, CTx and vitamin D did not differ significantly between HCV patients and controls. The mean serum albumin was also within the normal limits in CHC patients (4.25±0.4 mg/dL).

Table 3. Biochemical bone markers and laboratory tests of bone and mineral metabolism in CHC men and healthy controls.

Using previously published criteria [25], 25OHD status was classified in patients and controls as follows: sufficiency (above 30 ng/mL), insufficiency (11–29 ng/mL) and deficiency (below 10 ng/mL). After adjustments for the season of the year, no statistically significant difference was observed between the groups in terms of 25OHD status (Table 4).

Table 4. Classification of vitamin D status in CHC men and healthy controls.

Chi-squared test and linear backward stepwise regression analyses were performed to investigate potential determinants for low BMD in our sample. BMD measurements at all skeletal sites did not correlate with lifetime tobacco exposure (pack-years of smoking), alcohol consumption (drinks/week), physical activity [26], prolonged immobilization, time since diagnosis and contamination, viral load and genotype, degree of liver inflammation and fibrosis at the biopsy in CHC patients. Although CTx serum concentrations correlated negatively with lumbar spine BMD (r = −0.21; p = 0.04), no other significant correlation was found between BMD measurements and other biochemical markers. Multivariate analyzes performed did not allow to identify any parameter significantly associated with low BMD measurements in CHC patients.

Morphometric vertebral fractures were observed in three healthy men and one CHC patient. The CHC patient was a 57 years-old man with history of current smoking (40 pack-years) and alcohol use (10 drinks/week). BMD measurements, bone markers and vitamin D status were in the normal range for this patient. Due to the few number of vertebral fractures in the sample, correlation and regression analyzes were not feasible and so the study was not able to evaluate whether vertebral fractures are associated with HCV infection.

Discussion

Our results demonstrated that non-cirrhotic untreated CHC men have lower total hip and trochanter BMD when compared to healthy men. Only a few studies had evaluated BMD measurements in non-cirrhotic CHC patients and their results are conflicting due to methodological questions [13]–[15]. In our present sample we were able to demonstrate that HCV infection affects BMD at the proximal femur independently of liver function, current cirrhosis or anti-viral medication.

In spite of the lower BMD values in CHC patients when compared to healthy men, mean BMD at all skeletal sites were within normal range. It is interesting to note that both CHC patients and healthy controls exhibited high prevalence of overweight and that is well recognized as having a protective effect on bone density [27]–[30].

Total hip BMD is highly influenced by trochanteric BMD since the trochanter occupies the largest area of the proximal femur. The lower values for total hip BMD observed among CHC patients may be explained by the significantly lower BMD measurements at the trochanter in these subjects. In agreement with this finding, other authors have also observed a significant decrease in trochanter BMD in CHC patients, regardless of the liver function [14].

Reduced current physical activity associated with higher prevalence of prior prolonged immobilization were also observed among CHC patients as compared to healthy controls and that may also have influenced our results. Lower mechanical load could be related to the lower values for trochanteric BMD observed among CHC patients. Studies with hemiplegic patients[31] and cosmonauts [32] have demonstrated the association between reduced weight-bearing activities and lower femur BMD. The effect is probably due to an increase of the number of osteoclasts and a decrease in the osteoblast population [33].

Hepatic dysfunction with the intervenient vitamin D deficiency has been associated with low bone density. A direct correlation has been reported between the severity of liver fibrosis and low bone density in non-cirrhotic CHC patients [15]. The issue is however controversial and in CHC patients without cirrhosis the association with low BMD has not been confirmed in all studies. Hofmann et al [34] reported no correlation between non-cirrhotic hepatic disease and BMD measurements. They have also found no association between BMD measurements and disease duration, viral load and lifetime tobacco exposure. Our data have demonstrated no significant correlation between BMD measurements and the severity of liver inflammation and fibrosis at the biopsy, viral load, transmission model, estimated disease duration or alcohol intake. It is important to note that patients with alcoholism were excluded from our study.

Our results have also shown that non-cirrhotic CHC patients present no clinically relevant abnormalities in bone markers and calciotropic hormones, as previously observed [13]–[15],[34]. Mean serum 25OHD concentrations were considered sufficient in CHC patients, corroborating previous findings [14], [34]. To our knowledge this is the first study to classify non-cirrhotic CHC patients according to vitamin D status. No significant difference was observed in 25OHD status between CHC patients and healthy controls. That also suggests that liver injury in our patients was not important, at least in terms of vitamin D synthesis and hydroxylation.

The number of morphometric vertebral fracture was rather small in both groups precluding further analyzes. The absence of vertebral fractures may also result from the normal lumbar BMD values observed in both CHC patients and healthy controls.

Some limitations of the present study need to be pointed out. Our cross-sectional design prevented us of establishing a cause-effect relationship in our results as well as evaluating the long-term effect of HCV infection on bone metabolism and fracture risk. As observed earlier, the high prevalence of overweight in our population might also have influenced our results and could have positively impacted on BMD measurements in both groups. Results in women chronically infected with HCV might be somewhat different from those reported here for men.

This study is the first to evaluate BMD, bone metabolism and the prevalence of morphometric vertebral fracture in a significant number of men with CHC, without the classic confounding factors for low bone density (menopause, cirrhosis and antiviral therapy). Our results demonstrate that non-cirrhotic untreated CHC patients are at low risk for osteoporosis and fractures. We have also observed no significant abnormalities in bone and mineral metabolism and a vitamin D status similar to that seen for healthy men.

Author Contributions

Conceived and designed the experiments: CHMC VLS. Performed the experiments: LGSO MMP. Analyzed the data: LGSO CHMC AEBS VLS. Contributed reagents/materials/analysis tools: CHMC VLS. Wrote the paper: LGSO MMP CHMC VLS.

References

Source

Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis

Eur J Clin Invest. 2013 Nov 15. doi: 10.1111/eci.12205. [Epub ahead of print]

Stokes CS, Krawczyk M, Reichel C, Lammert F, Grünhage F.

Department of Medicine II, Saarland University Medical Center, Homburg, Germany.

Abstract

BACKGROUND: Chronic liver disease is the fifth most common cause of mortality in Europe. Recently, vitamin D deficiency has been associated with an increased risk of mortality in the general population. Since patients with advanced liver disease frequently exhibit vitamin D deficiency, we assessed for a possible association of vitamin D deficiency with survival in a cohort of patients with advanced liver disease.

METHODS:  Sixty-five patients with liver cirrhosis (median age, 58 years; range, 19-76 years; 66% male; Child-Pugh stage C, 46%) were included in our prospective single-center survival study. Serum 25-hydroxyvitamin D concentrations were measured by chemiluminescence immunoassay. The optimal cut-off was determined using area under the curve (AUC) and Kaplan-Meier analysis. Chi-square statistics and multivariate binary logistic regression analysis were also conducted.

RESULTS: Median serum vitamin D levels were 8.2 ng/ml (range < 4.0-95.8 ng/ml). Overall, 48% of patients (31/65) died during a 24-month follow-up period. AUC analysis determined a vitamin D level of 6.0 ng/ml as optimal cut-off for discriminating survivors from non-survivors. Kaplan-Meier analysis of survival confirmed low vitamin D levels as significant predictor of death (P = 0.012). Finally, multivariate analysis identified low vitamin D levels (OR = 6.3; 95% CI, 1.2-31.2; P = 0.012) and MELD scores (OR = 1.4; 95% CI, 1.2-1.7; P < 0.001) as independent predictors of survival.

CONCLUSION: Low vitamin D levels are associated with increased mortality in patients with advanced liver disease. Thus, serum levels of vitamin D might represent a critical marker of survival in advanced liver cirrhosis. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

KEYWORDS: 25-hydroxyvitamin D, cholecalciferol, chronic liver disease, survival analysis

PMID: 24236541 [PubMed - as supplied by publisher]

Source

Low Vitamin D Predicts Death in HIV-Positive

Medscape Medical News > Conference News

Daniel M. Keller, PhD
November 19, 2013

BRUSSELS — Among patients infected with HIV, current levels of 25-hydroxyvitamin D are associated with the risk for death but not for other adverse events, a new study suggests.

"Earlier levels of 25-hydroxyvitamin D failed to predict death, suggesting the association diminishes with time," Jean-Paul Viard, MD, from the Hôtel-Dieu, Université Paris Descartes in France reported here at the 14th European AIDS Conference.

The study included patients from a previous study of the EuroSIDA cohort, in which severe vitamin D deficiency at baseline was associated with the risk for progression to death in a 5-year follow-up period.

The aim of the current study was to further assess the short- and long-term prognostic value of vitamin D deficiency for AIDS-defining and non-AIDS-defining events and death and to study the association of vitamin D deficiency with inflammatory markers.

The work used a 1:1 case-control design nested within the EuroSIDA cohort for each of the outcomes of AIDS events (n = 50 pairs), non-AIDS events (n = 63 pairs), and death (n = 42 pairs). Control individuals were matched with cases on the basis of age, sex, region of residence, CD4 count, and HIV RNA level at baseline and on the dates of the final samples.

Vitamin D was lower in cases of death than in controls, but only for the latest sample.Dr. Jean-Paul Viard

Measurements of vitamin D and inflammatory markers were done on stored plasma from the time of study entry, at the time of an event, and at a midpoint of follow-up, if available. The time from the first to last samples averaged 44.6 months (interquartile range, 22.7 - 72.3 months).

Of 50 deaths, 88% were from chronic conditions and 12% were sudden events such as heart attack, stroke, suicide, lung embolism, gastric hemorrhage, or violent death.

Although the odds of death were not associated with the baseline vitamin D level, they "decreased significantly by 46% for a 2-fold higher level of 25-hydroxyvitamin D," Dr. Viard reported. There was no association of the baseline, latest measurement, or annual percentage change in the level of vitamin D on AIDS-related or non-AIDS-related events.

"Vitamin D was lower in cases of death than in controls, but only for the latest sample, while interleukin-6 [IL-6] was higher in cases than in controls for all items," Dr. Viard said.

"Similarly, CRP [C-reactive protein] was higher in cases than in controls at the latest sample for AIDS-events and death, and it was also higher at baseline for people who were going to die. CD14 levels were higher in cases and in controls for AIDS events and death."

The percent change in the level of inflammatory biomarkers and the CD4 cell count reflected the vitamin D status. If patients were severely vitamin D deficient (<10 ng/mL), high-sensitivity IL-6, and high-sensitivity CRP increased by 4.66% per year and by 8.35% per year after adjustment for several variables, including season, sex, age, and region of residency. There was no change in these markers if patients had normal or moderately deficient vitamin D levels.

Soluble CD14 increased regardless of vitamin D status. CD4 counts increased by 7.00% per year for people deficient in vitamin D and by 11.14% per year for people nondeficient in vitamin D (both P < .01), but not at all for patients who were severely deficient.

Asked for perspective on these findings, session cochair Andrea Antinori, MD, from the National Institute for Infectious Disease in Rome, Italy, who was not involved with the study, told Medscape Medical Newsthat he found the results interesting because "probably we don't have much information about the role of vitamin D, and more interestingly, not only its role in bone mineral density and fracture in the long term but even in immune activation inflammatory pathways" that can increase other risks, for example, for cardiovascular disease.

His recommendation is "monitoring vitamin D in all types of patients before treatment in the first phase of induction by drugs for long-term treatment," with eventual supplementation for patients found to be vitamin D deficient.

This study was supported by grants from the European Commission and the Swiss National Science Foundation and unrestricted grants from BMS, Janssen R&D, Merck, Pfizer, and GSK. Dr. Viard reports no relevant financial relationships. Dr. Antinori reports financial ties to BMS, Gilead, ViiV; Abbvie, BMS, Gilead, and Janssen-Cilag.

14th European AIDS Conference: Abstract BPD1/2. Presented October 17, 2013.

Source

Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients

J Infect. 2013 Nov 1. pii: S0163-4453(13)00326-5. doi: 10.1016/j.jinf.2013.10.011. [Epub ahead of print]

Guzmán-Fulgencio M, García-Álvarez M, Berenguer J, Jiménez-Sousa MA, Cosín J, Pineda-Tenor D, Carrero A, Aldámiz T, Alvarez E, López JC, Resino S.

Unit of Viral Infection and Immunity, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.

Abstract

OBJECTIVE: To study the association of plasma 25-hydroxy vitamin D (25(OH)D) levels in HIV/HCV coinfected patients with severity of liver disease and virological response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV).

METHODS: A cross-sectional study in 174 HIV/HCV coinfected patients that underwent a liver biopsy previously to start HCV therapy and a retrospective study of 125 of them. Plasma 25(OH)D levels were quantified by enzyme immunoassay. Liver biopsies were evaluated by METAVIR score. A sustained virological response (SVR) was defined as an undetectable serum HCV viral load (<10 IU/mL) up through 24 weeks after the end of HCV treatment.

RESULTS: The median of plasma 25(OH)D level was 48 nmol/L (p25th: 32.5; p75th: 56.1) and 27 (15.5%) had 25(OH)D deficiency (<25 nmol/L). The percentage of 25(OH)D deficiency was higher in patients with significant fibrosis (F ≥ 2) (92.6% vs. 57.1%; p = 0.010) and moderate necroinflammatory activity grade (A ≥ 2) (85.2% vs. 60%; p = 0.043). However, adjusted logistic regression analyses showed that 25(OH)D deficiency was only associated with severity of liver disease [F ≥ 2 (OR = 8.47 (95% of confidence interval (CI) = 1.88; 38.3); p = 0.005) and A ≥ 2 (OR = 3.25 (95%CI = 1.06; 10.1); p = 0.040)]. Moreover, any significant relationship was found between 25(OH)D deficiency and SVR after HCV therapy.

CONCLUSION: Plasma 25(OH)D deficiency was associated with liver disease severity in HIV/HCV coinfected patients, but it was not associated with HCV treatment failure.

Copyright © 2013. Published by Elsevier Ltd.

KEYWORDS: AIDS, Antiviral therapy, Chronic hepatitis C, Hepatic biopsy, Liver fibrosis, Vitamin D

PMID: 24184809  [PubMed - as supplied by publisher]

Source

Association between vitamin D and hepatitis C virus infection: A meta-analysis

World J Gastroenterol. 2013 September 21; 19(35): 5917-5924.

Published online 2013 September 21. doi: 10.3748/wjg.v19.i35.5917.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Livia Melo Villar, Elisabeth Lampe, Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ 210360-040, Brazil

José Antonio Del Campo, Isidora Ranchal, Manuel Romero-Gomez, Unit for the Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, 41014 Sevilla, Spain

Author contributions: Villar LM and Romero-Gomez M contributed to the study concept and design; Villar LM, Del Campo JA and Ranchal I performed data extraction, analysis and interpretation of the data; Lampe E and Romero-Gomez M drafted the review; all authors have read and approved the paper.

Correspondence to: Livia Melo Villar, PhD, Viral Hepatitis Laboratory, Helio and Peggy Pereira Pavillion, Ground Floor, Room B09, FIOCRUZ Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ 210360-040, Brazil. lvillar@ioc.fiocruz.br

Telephone: +55-21-25621918 Fax: +55-21-22706397

Received December 14, 2012; Revised January 31, 2013; Accepted February 9, 2013;

Abstract

AIM: To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and sustained virological response (SVR) in hepatitis C virus (HCV) infected individuals.

METHODS: Relevant studies were identified by systematically searching MEDLINE databases up to March 2012 and abstracts of the European and American Congress of Hepatology conducted in 2011. Studies must provide information on SVR and the levels of 25(OH)D₃ and/or 25(OH)D₂ [henceforth referred to as 25(OH)D] in sera samples from HCV infected individuals. The inclusion criteria were: clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group; provided information on SVR rates; and were reported in the English language as full papers. Due to the heterogeneity of studies in categorizing serum vitamin D levels, a cut-off value of 30 ng/mL of serum 25(OH)D was used. Heterogeneity was assessed using I² statistics. The summary odds ratios with their corresponding 95%CI were calculated based on a random-effects model.

RESULTS: Overall, 11 studies (8 observational and 3 interventional) involving 1575 individuals were included and 1117 HCV infected individuals (71%) showed low vitamin D levels. Most of the studies included mono-infected HCV individuals with the mean age ranging from 38 to 56 years. Four studies were conducted in human immunodeficiency virus/HCV infected individuals. Regarding vitamin D measurement, most of the studies employed radioimmunoassays (n = 5) followed by chemiluminescence (n = 4) and just one study employed high performance/pressure liquid chromatography (HPLC). Basal vitamin D levels varied from 17 to 43 ng/mL in the studies selected, and most of the HCV infected individuals had genotype 1 (1068/1575) with mean viral load varying from log 4.5-5.9 UI/mL. With regard to HCV treatment, most of the studies (n = 8) included HCV individuals without previous treatment, where the pooled SVR rate was 46.4%. High rates of SVR were observed in HCV individuals with vitamin D levels above 30 ng/mL (OR = 1.57; 95%CI: 1.12-2.2) and those supplemented with vitamin D (OR = 4.59; 95%CI: 1.67-12.63) regardless of genotype.

CONCLUSION: Our results demonstrated high prevalence of vitamin D deficiency and high SVR in individuals with higher serum vitamin D levels or receiving vitamin D supplementation.

Keywords: Vitamin D, Hepatitis C, Therapy, Meta-analysis, Sustained virological response

Core tip: High vitamin D levels (above 30 ng/mL) or supplementation are associated with sustained virological response in hepatitis C virus infected individuals.

INTRODUCTION

Viral hepatitis C is a serious public health problem worldwide infecting more than 130 million individuals[¹]. Treatment of hepatitis C virus (HCV) infection is usually carried out using pegylated interferon (PEG-IFN) and ribavirin (RBV) for 24 wk for HCV genotypes 2 or 3, or 48 wk for HCV genotype 1 and the main objective of HCV therapy is a sustained virologic response (SVR), defined as an undetectable serum HCV-RNA level at 24 wk after the end of therapy. Rates of SVR range from 60%-70% in chronic hepatitis C (CHC) patients with genotypes 2 and 3, but is less than 50% in patients with genotype 1 using conventional therapy[²].

Recently, studies were conducted to analyze the influence of genetic and metabolic factors in antiviral response[^3-5], and a recent review showed that vitamin D levels can influence HCV treatment[⁶]. Vitamin D itself is considered biologically inactive and is hydroxylated to 25-hydroxyvitamin D [25(OH)D] in the liver. 25(OH)D is the main circulating vitamin D metabolite and is used for classification of the vitamin D status[^7,8]. In the kidney, 25(OH)D is converted to 1,25-dihydroxyvitamin D [1,25(OH)D] by 1-alpha-hydroxylase, however, it has been demonstrated that this conversion can occur in many extra-renal tissues including the liver[^7,9]. Finally, 25(OH)D or 1,25(OH)₂D bind to the ubiquitously expressed vitamin D receptor (VDR), which regulates approximately 3% of the human genome[¹⁰]. In this context, vitamin D deficiency has been associated with an increased risk of cancer[^7,11], cardiovascular[^12,13], autoimmune[^14,15] and infectious diseases[^6,16].

Due to these facts, there is great research interest in the role of vitamin D status in various infectious diseases. Some studies have shown that high levels of serum vitamin D level are an independent predictor of SVR following anti-viral therapy, and higher SVR is achieved with vitamin D supplementation in CHC individuals[^17-22]. However, Lange et al[¹⁸] found that vitamin D deficiency was associated with a lower SVR rate only in CHC genotype 2/3 patients (treated with PEG-IFN and RBV for 24 wk), but not in CHC genotype 1 patients. Moreover, Jazwinski et al[²³] found no association between vitamin D levels and SVR in 82 African American genotype 1 CHC-naïve patients, treated with PEG-IFN and RBV.

As vitamin D has an uncertain clinical value in HCV infected individuals and taking into consideration the limitations of previous reviews, we conducted an updated systematic review and meta-analysis to comprehensively assess vitamin D deficiency regarding antiviral therapy and the influence of vitamin D supplementation on SVR.

MATERIALS AND METHODS

Identification of studies

A broad search string was used in MEDLINE in order to identify relevant studies (all languages, all available years, search last completed 31.03.12) using the following search terms: [(“vitamin D” [MeSH Terms] or “vitamin D” [All Fields] or “ergocalciferols” [MeSH Terms] or “ergocalciferols” [All Fields]) or (“calcifediol” [MeSH Terms] or “calcifediol” [All Fields] or “calcidiol” [All Fields]) or (“25(OH)D” [All Fields] or “25(OH)D₂” [All Fields] or “25(OH)D₃” [All Fields]) and [(“HCV” [MeSH Terms]) or (“HCV” [All Fields] or “Hepacivirus” [All Fields]) or “Hepacivirus” [MeSH Terms])]. Abstracts from the European and American Association Congress of Hepatology (EASL 2011 and AASLD 2011) were also included in order to give more data on this theme.

Potentially relevant papers were accessed in order to review the abstract and/or full text. Only fully published articles were considered. Duplicate publications were deleted. Two researchers independently performed the literature search and data abstraction with regard to the inclusion and exclusion criteria by reading titles and abstracts. When reading titles and abstracts did not allow identification of eligible studies, articles were read in full. Only original studies conducted in humans were considered for the review. Thus, reviews and letters to the editor were excluded in the analysis, but read in full to identify potential relevant original studies. Disagreements between the two observers were resolved by discussion.

The following data were extracted: year of publication, number of patients, age, vitamin D levels, SVR percentage, method of measurement of vitamin D, HCV genotype, HCV viral load, percentage of naive patients. When such data were not explicitly reported, they were derived from data provided in the articles or requested from the authors through personal contacts, wherever possible.

Eligibility criteria

The study must provide information on SVR against HCV and the levels of 25(OH)D₃ and/or 25(OH)D₂ [henceforth referred to as 25(OH)D] in sera samples from HCV infected individuals. The inclusion criteria were: clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group; provided information on SVR rates; and were reported in the English language as full papers. Studies were excluded if they met the following criteria: they did not provide information on 25(OH)D level, HCV status and/or SVR; basic studies; letters ⁄ case reports, or articles not reporting outcomes of interest or primary data (editorials, reviews).

Statistical analysis

Data were extracted from each paper and compiled for hypovitaminosis D and HCV antiviral response. Statistical analysis was performed using the Meta-Disc software 1.4[²⁴], considering: (1) a summary of data from individual studies; (2) an investigation of the homogeneity of the studies both graphically and statistically; (3) calculation of clustered indices; and (4) exploration of heterogeneity. The meta-analysis was performed using the random-effect model by the Der Simonian and Laird method. Heterogeneity was tested for each planned analysis using the Cochran-Q heterogeneity test and measured using χ² and I² tests, and statistical significance was considered to be present when P < 0.05.

RESULTS

Description of studies included in the meta-analysis

A flow diagram of the search process is shown in Figure 1. The total search yielded 61 articles and 15 abstracts, after accessing the title and abstract, 65 studies were excluded for the following reasons: 49 did not provide data on vitamin D level, HCV status and/or SVR; 5 were basic studies; 8 were reviews, letters or editorials; 3 were duplicate studies.

Figure 1 Prisma flowchart for the selection of publications for the systematic review and meta-analysis. HCV: Hepatitis C virus; 25(OH)D: 25-hydroxyvitamin D.

Eleven studies involving 1575 individuals were included in this study[^{17,18,20-23,25-29}]. The main characteristics of these studies are shown in Tables 1 and 2. Most of the studies were conducted in Europe and only one in North America. Eight studies evaluated vitamin D levels before and after antiviral therapy[^{17,18,21-23,25,28,29}], while three were interventional studies where vitamin D supplementation was conducted[^20,26,27]. Most of the studies included mono-infected HCV individuals with the mean age ranging from 38 to 56 years. Four studies were conducted in human immunodeficiency virus/HCV infected individuals[^22,25,28,29]. With regard to vitamin D measurement, most of the studies employed radioimmunoassays (n = 5) followed by chemiluminescence (n = 4) and just one study employed HPLC. Basal vitamin D levels varied from 17 to 43 ng/mL in the studies selected, and most of the HCV infected individuals had genotype 1 (1068/1575) with mean viral load ranging from log 4.5-5.9 UI/mL. With regard to HCV treatment, most of the studies (n = 8) included HCV individuals without previous treatment, where the pooled SVR rate was 46.4%.

Table 1 Summary of the general characteristics of the included studies regarding vitamin D and hepatitis C virus (mean ± SD)

Table 2 Summary of included studies regarding vitamin D and hepatitis C virus aspects

Figure 2 Meta-analysis of 8 observational studies regarding vitamin D levels and sustained virological response against hepatitis C virus infection.

Vitamin D levels and sustained virological response

Different cut-off values for vitamin D were employed and in order to reduce this heterogeneity, a value of 30 ng/mL was used as the cut-off value, as most of the studies used this value to define vitamin D. Among the observational studies, a total of 1411 individuals were included. Using 30 ng/mL as cut-off value, the χ² test of heterogeneity was high (P = 0.3799). There was a significant difference regarding vitamin D levels and SVR, where individuals with values higher than 30 ng/mL had a higher level of SVR. Using the random effects model by the Der Simonian and Laird method, the odds ratio was 1.57 (95%CI: 1.12-2.2) regardless of genotype (Figure 2).

A total of 1117 HCV infected individuals had low vitamin D levels (cut-off value of 30 ng/mL) representing 71% of the population studied, and most of these individuals were in the interventional studies (79.3%) as compared with the observational studies (69.9%). The highest association between vitamin D levels and SVR was observed in the study by Petta et al[¹⁷] as demonstrated by the OR and CI (OR = 1.96; 95%CI: 1.02-3.79).

Vitamin D supplementation and sustained virological response

With regard to vitamin D supplementation in HCV infected individuals in the interventional studies, the pooled estimation from 3 different studies indicated that SVR rates were higher in treated HCV individuals compared with non-treated HCV individuals. In the meta-analysis of SVR in the interventional studies where the cut-off value was 30 ng/mL, the OR was 4.59 (95%CI: 1.67-12.63) regardless of genotype (Figure 3). The test of heterogeneity (Cochran-Q = 2.86; df = 2; P = 0.2395), inconsistency I² = 30%, and t = 0.2454. Of these studies, the OR values were higher in the study where only genotype 1 HCV individuals were included[²⁷] (8.68) compared to the other 2 studies, one study included genotypes 1 and non-1[²⁰] (1.90) and the other study recruited genotype 2 and 3 HCV infected individuals (5.78)[²⁶].

Figure 3 Meta-analysis of 3 interventional studies regarding vitamin D levels and sustained virological response against hepatitis C virus infection.

Quality of the studies

Low heterogeneity was observed in the studies included in this meta-analysis according to the Q value for the observational (7.49) and interventional studies (2.86). The possible sources of heterogeneity across the studies were also explored using meta-regression analysis with the following co-variates as predictor variables: HCV genotype (1 and non-1); previous treatment (yes or no); Origin (Europe or America); method of vitamin D determination (HPLC, chemiluminescence or radiomunoassay). None of these variables interfered with the levels of vitamin D according SVR (data not shown). It is likely that this occurred because most of the studies were from Europe, including HCV genotype I individuals without previous treatment.

Although low heterogeneity was found, it was not possible to ensure high quality of all studies included in this meta-analysis. Some studies did not provide relevant data such as, mean age of the population included[^23,28], mean basal vitamin D measurement[^20,23,28], or mean HCV viral load[^23,26-28].

DISCUSSION

Our review and meta-analysis summarize the results of eleven studies, which included a total of 1575 cases with hepatitis C, where basal 25(OH)D levels and 25(OH)D supplementation were associated with SVR in HCV patients. This updated review confirms and extends earlier results of a systematic review conducted by Cholangitis[⁶], who reported that vitamin D deficiency is very frequent before liver transplantation and ranges between 51% and 92%, whereas, in the liver transplantation setting, the prevalence of vitamin D deficiency is also high.

Vitamin D is metabolized by the liver and converted to 1,25-dihydroxyvitamin D₃, which is the active form of the vitamin[^29,30]. Individuals with chronic liver disease may have poor conversion from vitamin D3 or any of its other biologically active metabolites[³¹]. Severe liver disease may increase the risk of vitamin D deficiency and/or there might be a relationship between vitamin D deficiency and fibrosis. Putz-Bankuti et al[³²] and Baur et al[³³] also showed that low levels of 25(OH)D are associated with fibrosis and suggested that low 25(OH)D levels may predict hepatic decompensation and mortality in patients with chronic liver failure. More recently, Gal-Tanamy et al[³⁴] showed that vitamin D₃ increased the expression of the VDR and inhibited viral replication in cell culture.

Due to the observation of vitamin D deficiency in chronic liver disease patients, some studies have been conducted to evaluate vitamin D supplementation in these patients[^20,26,27]. In some of these studies, it is reported that higher sunlight exposure or vitamin D supplementation should be recommended in patients with CHC[^20,26,27]. In the present meta-analysis, vitamin D supplementation was related to higher SVR rates in HCV infected individuals, where the highest level was observed among genotype 1 HCV infected individuals. Although only a few studies regarding vitamin D supplementation fulfilled the eligibility criteria, different patterns were observed. The first study included only genotypes 2 and 3, the second included only genotype 1 and the third study involved genotypes 1, 2 and 3. Moreover, two of these studies were prospective and one was retrospective. Some limitations of these studies included the small number of patients, lack of vitamin D level assessment during therapy in the treatment and control groups, the design of prospective and randomized studies which were not placebo-controlled in one study[²⁷], and the retrospective design of the study where immunocompromised HCV patients were supplemented with low-dose vitamin D (800 IU/d) after liver transplantation and most of the HCV patients (75%) had low vitamin D levels despite treatment[²⁰].

In this meta-analysis, the levels of vitamin D were also associated with SVR, although different methods of vitamin D determination were used. Lai et al[⁸] demonstrated bias and variability in 25(OH)D measurements between laboratories and between different assays [quimioluminescence and liquid chromatography-tandem mass spectrometry (LC-MS/MS)] which can significantly affect clinical decision-making. In this situation, the adoption of common standards to allow assay calibration is urgently required.

Our study is the first meta-analysis of serum 25(OH)D levels and HCV infection in observational and interventional studies. Given the very small numbers of studies available to date, additional studies, ideally from different countries and populations are needed to assess potential differences in the associations between 25(OH)D and SVR for HCV. Large differences can be observed in different populations, depending on exposure to sunlight or vitamin D supplementation, and genetic differences[²³]. Moreover, patients of African and Hispanic descent are less likely to respond to standard therapy[²³] probably due to polymorphisms of the interleukin (IL)-28B gene, polymorphism of the VDR or vitamin D deficiency[^17,35,36]. In this meta-analysis, all the individuals were Caucasian and most lived in Europe, which could explain vitamin D deficiency in this population resulting from possible low exposure to sunlight.

Meta-analysis is an important tool for revealing trends that may not be apparent in a single study. Pooling of independent, but similar studies increases precision and therefore the confidence level of the findings. A particular strength of our study is the application of advanced statistical techniques which allowed a summary of adjusted associations across studies and over the entire range of serum 25(OH)D values, despite the very heterogeneous categorization of 25(OH)D levels in the individual studies. Our study also has important limitations. First, as data on serum 25(OH)D in individuals were not available in each study, median, midpoints and mean of the groups were used for pooling. As a result, estimates of risk may have been less accurate than if data points on each individual had been used. Second, our meta-analysis was limited by the data provided in the individual studies, and although the authors tried to obtain the raw data from the articles, not all were available. Finally, although our review searched the MEDLINE database, recent Congress of Hepatology and Gastroenterology articles, and extensive checks for completeness by cross-referencing were employed, we cannot exclude the possibility that relevant studies may have been missed.

Despite its limitations, our review and meta-analysis support previous suggestions and provide the most comprehensive empirical evidence to date that basal serum 25(OH)D levels and vitamin D supplementation improves SVR in HCV infected individuals. However, available data are still sparse and in-depth analyses of these associations, in the context of additional longitudinal and prospective studies, are highly desirable to enable more precise estimates and a better understanding of the role of vitamin D in HCV infection.

ACKNOWLEDGMENTS

The authors would like to thank Christian Lange, Raymond T Chung, Assy Nimer, Andrea Branch, Eric Trépo, Mattias Mandorferk, Kian Bichoupan, Markus Peck, Alison Jazwinski, Laura Milazzo, and Salvatore Petta who kindly answered questions regarding their manuscripts in order to provide more information for this meta-analysis.

COMMENTS

Background

Hepatitis C virus (HCV) is a serious public health problem worldwide infecting more than 130 million individuals. Recently, studies have been conducted to analyze the influence of genetic and metabolic factors on antiviral response, and a recent review showed that vitamin D levels can influence HCV treatment.

Research frontiers

Vitamin D itself is considered biologically inactive and is hydroxylated to 25-hydroxyvitamin D [25(OH)D] in the liver. Some studies have suggested that vitamin D deficiency is associated with an increased risk of cancer, cardiovascular, autoimmune and infectious diseases. However, due to the limitations of previous reviews, the authors conducted an updated systematic review and meta-analysis to comprehensively assess vitamin D deficiency with regard to antiviral therapy and the influence of vitamin D supplementation on sustained virological response.

Innovations and breakthroughs

Previous individual studies demonstrated that high levels of vitamin D (above 30 ng/mL) or supplementation are associated to sustained virological response (SVR) in HCV infected individuals. In the present study, a meta-analysis of observational and interventional studies was conducted which proved that high levels of vitamin D (above 30 ng/mL) or supplementation are associated with SVR in HCV infected individuals.

Applications

By showing that basal vitamin D levels or suplementation are important for high rates of SVR in HCV patients, this study may provide a future strategy for therapeutic intervention in the treatment of HCV patients.

Terminology

HCV is an infection caused by a virus transmitted by the parenteral route. Vitamin D itself is considered biologically inactive and is hydroxylated to 25(OH)D in the liver. In the kidney, 25(OH)D is converted to 1,25(OH)₂D by 1-alpha-hydroxylase, however, it has been demonstrated that this conversion can occur in many extra-renal tissues including the liver. Finally, 25(OH)D or 1,25(OH)₂D bind to the ubiquitously expressed vitamin D receptor, which regulates approximately 3% of the human genome.

Peer review

The authors examined the influence of vitamin D levels or supplementation among HCV infected individuals. It was observed that high levels of vitamin D or supplementation are strongly associated to SVR among HCV infected individuals. The results are interesting and may represent the role of metabolic factors in HCV infection.

Footnotes

Supported by Coordination of Improvement of Higher Education Personnel in part

P- Reviewers Cuevas-Covarrubias SA, Kent L S- Editor Zhai HH L- Editor Webster JR E- Editor Ma S

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