Publications (9)44.04 Total impact
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Article: Low vitamin D serum concentration is associated with high levels of hepatitis B virus (HBV) replication in chronically infected patients.
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ABSTRACT: Vitamin D is an important immune modulator which plays an emerging role in inflammatory and metabolic liver diseases, including infection with hepatitis C virus (HCV). In contrast, the relationship between vitamin D metabolism and chronic hepatitis B is less well characterized. Therefore, we quantified 25-hydroxyvitamin D [25(OH)D3 ] serum levels in a cohort of 203 treatment-naïve patients with chronic hepatitis B virus (HBV) infection and tested for their association with clinical parameters of chronic hepatitis B. 69 (34%), 95 (47%), and 39 (19%) out of 203 patients had severe vitamin D deficiency [25(OH)D3 <10ng/mL], vitamin D insufficiency [25(OH)D3 ≥10ng/mL and <20ng/mL], or adequate vitamin D serum levels [25(OH)D3 ≥20ng/mL], respectively. In both uni- and multivariate analyses, HBV DNA viral load (log10 IU/mL) was a strong predictor of low 25(OH)D3 serum levels (p=0.0007 and p=0.000048, respectively), and vice versa. Mean 25(OH)D3 serum concentrations in patients with HBV DNA <2000 IU/mL vs. ≥2000 IU/mL were 17 vs. 11 ng/mL, respectively (p<0.00001). In addition, hepatitis B early antigen (HBeAg) positive patients had lower 25(OH)D3 serum levels than HBeAg negative patients (p=0.0013). Finally, 25(OH)D3 and HBV DNA serum levels showed inverse seasonal fluctuations. Conclusions: Low 25(OH)D3 serum levels are associated with high levels of HBV replication in patients with chronic hepatitis B. This represents a major difference to chronic hepatitis C, were numerous previous studies have shown a lacking correlation between HCV viral load vitamin D serum levels. Inverse seasonal fluctuations of 25(OH)D3 and HBV DNA serum levels are suggestive for a functional relationship between both variables. (HEPATOLOGY 2013.).Hepatology 05/2013; · 11.66 Impact Factor -
Article: New antiviral therapies in the management of HCV infection.
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ABSTRACT: Improved knowledge of the HCV life cycle and of structural features of HCV proteins have led to the discovery of numerous potential targets for antiviral therapy. Viral replication and polyprotein processing have been tagged as promising viral targets. Clathrin-mediated endocytosis, fusion of HCV with cellular membranes, translation of viral RNA, virus production and release as well as several host cell factors may provide alternative targets for future anti-HCV therapies. Several compounds are currently under investigation in clinical trials and showed high antiviral activity in patients with chronic hepatitis C. Recently, Phase III studies for two protease inhibitors, telaprevir and boceprevir, each given in combination with pegylated interferon (standard of care [SOC]), were completed. In HCV-genotype-1-infected patients, the addition of telaprevir or boceprevir to SOC increased sustained virological response rates from <50% to >70%. Nucleoside/nucleotide inhibitors of the HCV NS5B polymerase have shown antiviral activity against different HCV genotypes, and have a higher barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. Inhibitors of NS5A are potentially active against all HCV genotypes. Among the different host cell-targeting compounds, cyclophilin inhibitors have shown promising results. Future hope lies in the combination of direct-acting antiviral agents with the possibility of interferon-free treatment regimens.Antiviral therapy 05/2012; 17(5):771-83. · 3.16 Impact Factor -
Article: Nucleos(t)ide analogue treatment reduces apoptotic activity in patients with chronic hepatitis B.
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ABSTRACT: Reduction of necroinflammatory activity is a major goal of antiviral therapy of patients with chronic hepatitis B. Serum ALT does not detect all forms of cell death. To analyze dynamics of novel serum cell death markers for apoptosis and necrosis in association with virologic response to nucleos(t)ide (Nuc) analogue treatment. Quantification of the M30-apoptosis neoepitope and the cytokeratin-18 (M65-necrosis) serum levels before and during treatment of patients with chronic hepatitis B with Nuc (n = 26). Before treatment, M30-apoptotic activity was significantly correlated with M65-necrosis and fibrosis but not with serum ALT. During therapy with Nucs, cell death parameters M30-apoptosis, M65-necrosis, and ALT declined in association with virologic response. The most frequent cell death pattern was simultaneous decline of ALT and M30-apoptosis which occurred more frequently in patients with HBs-Antigen decline than in patients with HBs-Antigen increase during treatment (87.5% vs. 40.0%; p = 0.024). ALT decline in association with increase of M30 apoptosis was frequent in patients with HBs-Antigen increase during treatment (36.3%) but was not observed in patients with HBs-Antigen decline during treatment. Decline of cell death parameters in association with decline of HBV-DNA and HBs-Antigen indicates a reduction in overall cell death activity during Nuc treatment supporting the concept that response to Nuc therapy reduces necroinflammatory activity and progression of liver disease.Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 09/2011; 52(3):204-9. · 3.12 Impact Factor -
Article: Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection.
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ABSTRACT: Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively). We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.Journal of Hepatology 12/2010; 55(2):322-7. · 9.26 Impact Factor -
Article: Serum lipids in European chronic HCV genotype 1 patients during and after treatment with pegylated interferon-α-2a and ribavirin.
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ABSTRACT: Chronic hepatitis C alters the host's lipid metabolism and hepatitis C virus (HCV) eradication may be followed by an increase of serum cholesterol to adverse levels. We therefore aimed to determine the impact of chronic hepatitis C and its treatment on circulating lipids in a large European cohort of HCV genotype 1 patients. The serum lipid profile of 575 HCV genotype 1-infected patients was characterized before, during and after treatment with pegylated interferon-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks within a randomized controlled clinical trial. Total baseline cholesterol levels were significantly higher in patients with sustained virologic response (SVR) compared to nonresponders/relapsers (177 vs. 167 mg/dl, P=0.01), and low-cholesterol levels were an independent negative predictor of SVR (P=0.084). During the antiviral treatment, cholesterol levels substantially decreased as a putative marker of interferon-activity, but rebounded above baseline in patients with SVR (177-188 mg/dl, P=0.02), and to baseline in nonresponders/relapsers. Proportions of patients with cholesterol (>240 mg/dl) at baseline and after HCV eradication were 4 and 6%, respectively. Significant differences of triglyceride levels in patients with and without SVR were only observed at follow-up (136 and 117 mg/dl, respectively, P=0.028) but not at baseline. Our study reports a substantial pretreatment hypocholesterolemia in European HCV genotype 1 patients with nonresponse to interferon-α-based therapy and lower pretreatment cholesterol levels were an independent predictor of not attaining SVR. After treatment-induced HCV eradication median cholesterol levels increased above baseline, but the proportion of patients with high-risk cholesterol levels remained relatively low.European journal of gastroenterology & hepatology 11/2010; 22(11):1303-7. · 1.66 Impact Factor -
Article: Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C virus genotype 1 infection.
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ABSTRACT: Clinical trials provided conflicting results about whether extended duration of treatment with pegylated interferon-alfa (pegIFN-alfa) and ribavirin (more than 48 weeks) improves rates of sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 and slow virologic response. We performed a meta-analysis to determine the overall impact of extended treatment, compared with standard treatment, on virologic response rates in these patients. We performed a literature search to identify randomized controlled trials (RCTs) that included monoinfected, treatment-naive patients infected with HCV genotype 1; data were compared between slow responding patients treated with pegIFN-alfa-2a/b plus ribavirin for 48 weeks and those that received extended treatment (as much as 72 weeks). End points included SVR rates, end-of-treatment (EOT) response and relapse rates; they were calculated according to the DerSimonian-Laird estimate. Six RCTs assessed the benefits of extended treatment with pegIFN-alfa-2a/b and ribavirin in treatment-naive patients with HCV genotype 1 that were slow responders (n = 669). The extended treatment significantly improved SVR rates in slow responders, compared with the standard of care (14.7% increase in overall SVR; 95% confidence interval, 4%-25.5%; P = .0072). Rates of viral relapse were significantly reduced by extended treatment, but EOT response rates were similar. The frequency of voluntary treatment discontinuation, but not of serious adverse events, was significantly increased by extended therapy. Extending the duration of treatment with pegIFN-alfa-2a/b and ribavirin in patients with HCV genotype 1 and a slow response to therapy improves the rate of SVR.Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2010; 8(10):884-90. · 5.64 Impact Factor -
Article: Highly sensitive determination of HCV protease inhibitors boceprevir (SCH 503034) and telaprevir (VX 950) in human plasma by LC-MS/MS.
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ABSTRACT: The purpose of this study was to develop a specific and highly sensitive method based on fast sample preparation and LC-MS/MS techniques for the determination of the HCV protease inhibitors boceprevir (SCH 503034) and telaprevir (VX 950) in human plasma. Boceprevir, telaprevir and the internal standard dimethylcelecoxib were separated on a Luna C18 column (150 mm x 2.0 mm I.D., 5 microm particle size) under gradient conditions with a mobile phase A consisting of water/ammonia solution (25%) (100:0.05, v/v) and mobile phase B consisting of methanol/ammonia solution (25%) (100:0.05, v/v) and a chromatographic run time of 11 min. The lower limit of quantification (LLOQ) of boceprevir and telaprevir is 0.25 pg on column (25 pg/mL at injection volume of 10 microL). The method possesses a reliable calibration range of 0.025-2.5 ng/mL. Due to the dilution of real life plasma samples by a factor of 10 during the precipitation process the method is suitable to quantify boceprevir and telaprevir at a concentration range of 0.25-25 ng/mL. Variations in accuracy and intraday and interday precision (n=6 for each concentration) were <15% over the whole range of calibration. For the first time, a rapid, specific, sensitive, accurate and reproducible LC-MS/MS method in human plasma has been developed and validated. It is suitable to quantify the concentrations of the hepatitis C virus protease inhibitors boceprevir and telaprevir in human plasma.Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 10/2009; 877(31):4001-6. · 2.78 Impact Factor -
Article: Increased frequency of regulatory T cells and selection of highly potent CD62L+ cells during treatment of human lung transplant recipients with rapamycin.
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ABSTRACT: The currently available immunosuppressive agents applied in human transplantation medicine are highly potent in the protection from acute allograft rejection. However, long-term allograft survival is still poor as these drugs fail to sufficiently prevent chronic allograft rejection. Naturally occurring regulatory T cells have been postulated as the key players to establish long-lasting transplantation tolerance. Thus, the development of immunosuppressive regimens which shift the pathological balance of cytopathic versus regulatory T cells of human allograft recipients towards a protective T-cell composition is a promising approach to overcome limitations of current transplantation medicine. Thirty-three patients that received rapamycin (RPM) or calcineurin inhibitor treatment following lung transplantation were included and their T-cell compartments analysed. Twelve healthy volunteers without history of lung disease served as controls. In this article, we show that treatment of human lung transplant recipients with RPM is associated with an increased frequency of regulatory T cells, as compared with treatment with calcineurin inhibitors or to healthy controls. Moreover, regulatory T cells during treatment with RPM were CD62Lhigh, a phenotype that displayed an enhanced immunosuppressive capacity ex vivo. Our data support the use of RPM in human lung transplant recipients and undertaking of further prospective studies evaluating its impact on allograft and patient survival.Transplant International 10/2009; 23(3):266-76. · 2.92 Impact Factor -
Article: Optimal therapy in genotype 1 patients.
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ABSTRACT: Most infections with hepatitis C virus (HCV) fail to resolve spontaneously and progress to chronic hepatitis C. Genotype 1 HCV accounts for most hepatitis C infections in North America, Western Europe, and Japan. Patients infected with HCV genotype 1 are the most resistant to treatment, which results in poor treatment outcomes. Although sustained virologic response (SVR) rates have significantly improved with introduction of combination therapy with pegylated interferon alfa and ribavirin, the rates are still lower than those in genotype 2 or 3 infections. This review discusses how treatment outcomes in patients with HCV genotype 1 infection can be optimized by using the drugs currently licensed for treatment of hepatitis C: pegylated interferon alfa-2a/b and ribavirin. Dose modifications and variations of treatment duration are the two strategies that have been investigated best, so far. Treatment--naïve patients and non-responders and relapsers to prior antiviral therapy are discussed separately.Liver international: official journal of the International Association for the Study of the Liver 02/2009; 29 Suppl 1:23-30. · 3.82 Impact Factor
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Institutions
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2009–2012
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Goethe-Universität Frankfurt am Main
- Zentrum der Inneren Medizin
Frankfurt am Main, Hesse, Germany
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