February 14, 2014

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)2D3. 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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