Publications (20)114.65 Total impact
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Article: Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of HCV genotype 1-infected patients.
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ABSTRACT: The preeminent mode of action of the broad-spectrum antiviral nucleoside ribavirin in the therapy of chronic hepatitis C is currently unresolved. Particularly under contest are possible mutagenic effects of ribavirin that may lead to viral extinction by lethal mutagenesis of the HCV genome. We applied ultradeep sequencing to determine ribavirin-induced sequence changes in the HCV coding region (nt 330-9351) of patients treated with six-week ribavirin monotherapy (n = 6) in comparison to placebo (n = 6). HCV RNA levels declined on average by -0.8 or increased by +0.1 log10 IU/mL in ribavirin versus placebo-treated patients, respectively. No general increase of nucleotide substitutions in ribavirin-treated patients was observed. However, more HCV genome positions with high G-to-A and C-to-U transition rates were detected between baseline and treatment week six in ribavirin-treated patients in comparison to placebo (rate = 0.0041 transitions per bp versus rate = 0.0022 transitions per bp; P = 0.049). Similarly, the sensitive detection of low-frequency minority variants by statistical filtering indicated significantly more positions with G-to-A and C-to-U transitions in ribavirin-treated patients relative to placebo (rate = 0.0331 transitions versus rate = 0.0186 transitions per G/C-containing position at baseline; P = 0.018). In contrast, non-ribavirin-associated A-to-G and U-to-C transitions were not enriched in the ribavirin group (P = 0.152). We conclude that ribavirin exerts a mutagenic effect on the virus in patients with chronic hepatitis C by facilitating G-to-A and C-to-U nucleotide transitions.Journal of Virology 03/2013; · 5.40 Impact Factor -
Article: Portal vein thrombosis as complication of romiplostim treatment in a cirrhotic patient with hepatitis C-associated immune thrombocytopenic purpura.
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ABSTRACT: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. During hospitalization, the platelet count was measured above 330,000/μl and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly.Journal of Hepatology 02/2011; 55(1):229-32. · 9.26 Impact Factor -
Article: Impact of ribavirin on HCV replicon RNA decline during treatment with interferon-α and the protease inhibitors boceprevir or telaprevir.
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ABSTRACT: Ribavirin increases early and sustained virological response rates in patients chronically infected with HCV who receive pegylated interferon-α and novel HCV protease inhibitors. To better characterize antiviral efficacies of these upcoming therapies, Huh7 cells harbouring a subgenomic HCV replicon system were cultivated with various doses and combinations of ribavirin, interferon-α, and the protease inhibitors boceprevir and telaprevir. Antiviral efficacy parameters were estimated from HCV RNA decay, and synergistic effects of combination therapies were analysed with the Bliss independency model. Single-drug antiviral activities showed dose-dependent HCV RNA reductions in replicon cells (50% inhibitory concentration of 386.16 μM, 81.67 IU, 0.44 μM and 0.81 μM after 48 h for ribavirin, interferon-α, boceprevir and telaprevir, respectively). For the dual combination of ribavirin with either boceprevir or telaprevir, no deviation from additivity was observed whereas the reduction of HCV RNA was synergistic for ribavirin with interferon-α (P<0.001). Triple combinations with ribavirin, interferon-α and protease inhibitors showed the most profound HCV RNA decay. The beneficial in vitro antiviral effect of ribavirin with interferon-α and novel HCV protease inhibitors demonstrates that ribavirin may be required as an antiviral backbone in the near future.Antiviral therapy 01/2011; 16(5):695-704. · 3.16 Impact Factor -
Article: Cost-effectiveness analysis of roadmap models in chronic hepatitis B using tenofovir as the rescue therapy.
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ABSTRACT: The roadmap approach is recommended to guide chronic hepatitis B treatment. We evaluated the cost-effectiveness of various treatment strategies in the global market. Lamivudine and telbivudine were tested in roadmap models with switch-to tenofovir if HBV was detectable at week 24 or add-on tenofovir if resistance developed at year 1. Tenofovir and entecavir were tested as continuous monotherapy. In the reference arm, lamivudine was used with add-on tenofovir if resistance developed at year 1. The primary measure of effectiveness was undetectable HBV DNA at year 2. Cost-effectiveness was measured by incremental cost-effectiveness ratio (ICER) in US dollars against the reference arm. In the US and Germany, costs of the reference arms were US $14,486 and US $9,998 for hepatitis B e antigen (HBeAg)-positive and US $11,398 and US $7,531 for HBeAg-negative patients, respectively. In HBeAg-positive patients, the lamivudine roadmap was most cost-effective (ICER US $15,260 in the US and US $29,113 in Germany) with comparable effectiveness (75.1%) to other strategies. In HBeAg-negative patients, tenofovir and entecavir monotherapies were most effective (91-96%) and cost-effective (ICER US $31,297-43,387 in the US and US $53,976-59,822 in Germany). In Asia, where telbivudine cost was lower, both telbivudine and lamivudine roadmaps were cost-effective in HBeAg-positive patients. Tenofovir would be most cost-effective in HBeAg-negative patients if its cost equaled that of telbivudine in Asia. In HBeAg-positive patients, lamivudine roadmap was most cost-effective; in Asia, telbivudine roadmap had comparable cost-effectiveness to lamivudine roadmap because of the relatively low price of telbivudine. In HBeAg-negative patients, entecavir and tenofovir monotherapies were more cost-effective than the roadmap models.Antiviral therapy 01/2010; 15(2):145-55. · 3.16 Impact Factor -
Article: Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function.
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ABSTRACT: Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End-Stage Liver Disease [MELD] score >or= 20). Lactic acidosis (lactate 26-200 mg/dL, pH 7.02-7.40, base excess -5 mmol/L to -18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child-Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function.Hepatology 12/2009; 50(6):2001-6. · 11.66 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 -
Article: Cognition in hepatitis C patients treated with pegylated interferon.
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ABSTRACT: Neuropsychiatric symptoms are frequently reported by patients with chronic hepatitis C during treatment with interferon (IFN)-alpha and may lead to treatment discontinuation. In order to assess the objective neuropsychiatric impairments we prospectively administered standardized neuropsychological testing before and 3 months after the initiation of antiviral treatment with pegylated IFN-alpha in 17 patients suffering from chronic hepatitis C. In addition depression and anxiety scores, social functioning and hepatological parameters were obtained. While depressive and anxiety symptoms increased significantly during treatment only subtle worsening in neurocognitive performance could be detected, indicating slight impairment in cognitive flexibility and psychomotor speed (Trail Making Test B; 69.6+/-23 s before vs. 80.7+/-31 s during therapy, P=0.011, not remaining significant after Bonferroni correction). We found no association between reduced neurocognitive performance and the severity of depression. Better neurocognitive performance in single domains was associated with better response to antiviral treatment measured as the decline of elevated liver enzymes (AST). We conclude that neurocognitive performance was influenced by antiviral IFN-alpha-based combination treatment only in single domains and not to a clinically relevant extent in contrast to the significant worsening of depression.The World Journal of Biological Psychiatry 01/2009; 10(4 Pt 3):819-26. · 2.38 Impact Factor -
Article: Clinical relevance of the 2'-5'-oligoadenylate synthetase/RNase L system for treatment response in chronic hepatitis C.
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ABSTRACT: Interferon-alpha induces 2'-5'-oligoadenylate synthetase which activates RNase L. Viral RNA is cleaved by RNase L at UU/UA dinucleotides. The clinical relevance of RNase L cleavage for response to an interferon-alpha-based therapy in chronic hepatitis C is unknown. RNase L cleavage sites within pre-treatment sequences coding for structural and non-structural hepatitis C virus proteins were compared between non-responders and responders to an interferon-alpha-based therapy. Furthermore, RNase L cleavage sites were analyzed in full length and partial genome isolates of hepatitis C virus genotype 1b infected non-responders before and during treatment and in different hepatitis C virus genotypes (1b, 2a/b, 3a/b). No differences in RNase L cleavage sites were observed between non-responders and responders within a given hepatitis C genotype. Non-responders with hepatitis C virus genotype 1b infection did not eliminate UA/UU dinucleotides during therapy. Hepatitis C virus genotype 1b isolates showed a lower number of UA/UU dinucleotides than hepatitis C virus genotypes 2/3 (p < 0.001). Response or non-response to an interferon-alpha-based therapy within a given hepatitis C virus genotype is not explained by differences for RNase L cleavage sites. General differences of interferon sensitivity between hepatitis C virus genotypes correlate significantly with frequencies of RNase L cleavage sites.Journal of Hepatology 12/2008; 50(1):49-58. · 9.26 Impact Factor -
Article: Virodynamic predictors of response to pegylated interferon and lamivudine combination treatment of hepatitis B e antigen-positive chronic hepatitis B.
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ABSTRACT: Early identification of non-responders to interferon-alpha and development of stopping rules are needed in patients with chronic hepatitis B to reduce treatment-related costs and morbidity. In total, 47 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B received pegylated interferon-alpha2b for 8 weeks, lamivudine plus pegylated interferon-alpha2b combination therapy for 24 weeks and lamivudine monotherapy for 28 weeks. Sustained virological response was defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10(5) copies/ml at the end of treatment and after 52 weeks of follow-up. The early HBV DNA data from the first 12 weeks of therapy were fitted by a viral kinetic model. Cutoff values for prediction of sustained virological response were defined as a rate of infected cell loss delta > or = 0.005 per day (negative predictive value [NPV] 100% and positive predictive value [PPV] 33.3%) and log values of the area under the mathematically predicted HBV DNA curve between baseline and week 12 of therapy < or = 8.9 log10 copies/ml x days (NPV 100% and PPV 50%). By the latter cutoff, 25/36 (69.4%) patients without sustained virological response could be identified after 12 weeks of therapy. In the present study, mathematical modelling of viral dynamics allowed prediction of sustained virological response after 12 weeks of therapy. Virodynamic predictors for sustained virological response should be further validated. The area under the mathematically predicted HBV DNA curve seems a promising candidate for potential cutoff values as it summarizes the influence of baseline HBV DNA and treatment effects.Antiviral therapy 01/2008; 13(8):1029-37. · 3.16 Impact Factor -
Article: Identification and in silico characterization of a novel compound heterozygosity associated with hereditary aceruloplasminemia.
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ABSTRACT: Hereditary aceruloplasminemia is an adult-onset autosomal recessive disease characterized by increased iron overload in the liver, pancreas, retina, and central nervous system. So far, 45 families with cases of aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. Here, we report the identification, clinical characterization, and in silico analysis of a novel compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload. Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and magnetic resonance imaging-based measurement of T2 relaxation times of the substantia nigra consistently suggested iron overload. By sequencing the ceruloplasmin gene, so far unknown nucleotide replacements G229C, and C2131A were detected in exons 2 and 12, respectively. In silico analyses showed that the resulting amino acid changes Asp58His and Gln692Lys are located at highly conserved positions. The Asp58His mutation is located on the surface of the protein, alters polarity, and may interfere with copper incorporation or ceruloplasmin trafficking. The Gln692Lys mutation is mapped to a beta-strand of domain 4 and may lead to conformational change of the cupredoxin fold. As causative for aceruloplasminemia, a formerly unknown compound heterozygosity in the ceruloplasmin gene was identified. In silico characterization suggests an impact on ceruloplasmin conformation and function.Scandinavian Journal of Gastroenterology 10/2007; 42(9):1088-94. · 2.02 Impact Factor -
Article: Mutagenic effect of ribavirin on hepatitis C nonstructural 5B quasispecies in vitro and during antiviral therapy.
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ABSTRACT: Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial. The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control. Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P < .05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P < .01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P < .01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P < .05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P < .01) were detectable. Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.Gastroenterology 04/2007; 132(3):921-30. · 11.68 Impact Factor -
Article: Dynamics of apoptotic activity during antiviral treatment of patients with chronic hepatitis C.
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ABSTRACT: Cell death during antiviral therapy of patients with chronic hepatitis C is not well understood. In the present study, apoptotic activity was monitored by quantification of apoptotic cytokeratin-18 neoepitopes in serum from patients with chronic hepatitis C before and 4, 12, 24 and 48 weeks after initiation of antiviral therapy with pegylated interferon-alpha2a and ribavirin and was compared with viral kinetic parameters. After 4 weeks of treatment apoptotic activity decreased significantly compared with baseline. Later during treatment, however, apoptotic activity increased again to levels similar to baseline. Alanine aminotransferase (ALT) activity also showed a significant decrease at week 4 compared with baseline but, in contrast to apoptotic activity, ALT remained at a reduced level during the treatment period. Baseline apoptotic activity was inversely correlated with the infected cell loss while an increase of apoptotic activity within the first 4 treatment weeks compared with baseline was positively correlated with the infected cell loss. Apoptosis appears to be an important form of cell death during interferon-alpha-based treatment and is associated with infected cell loss and underestimated by ALT activity.Antiviral therapy 02/2007; 12(5):779-87. · 3.16 Impact Factor -
Article: Dynamics of CD81 expression on lymphocyte subsets during interferon-alpha-based antiviral treatment of patients with chronic hepatitis C.
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ABSTRACT: CD81 is a hepatitis C virus (HCV) coreceptor with important functions in lymphocytes. During treatment, CD81 expression may be changed directly by the antiviral therapy or indirectly by reduction of the HCV serum level. The regulation of CD81 on lymphocyte subtypes has not been investigated so far and may be relevant for the control of viral infection and treatment response. CD81 was analyzed by flow cytometry in CD8(+), CD4(+), CD19(+), and CD56(+) lymphocyte subtypes from 20 patients with chronic hepatitis C before, during, and after antiviral treatment with pegylated interferon-alpha (IFN-alpha) and ribavirin. A sustained virologic response (SVR) was achieved in 11 patients. Dynamics of CD81 were investigated in correlation with HCV-RNA dynamics and the outcome of therapy. During treatment, the following typical patterns of CD81 regulation were observed: down-regulation on CD8(+) T cells (P = 0.022) and most significantly, on CD56(+) natural killer cells (P < 0.001), transient up-regulation on CD19(+) B cells (P = 0.006), and weak and late down-regulation on CD4(+) T cells (P = 0.028). During treatment, CD81 expression was not associated with the HCV-RNA serum level on all lymphocyte subtypes. After end of treatment, CD81 increased again in CD8(+) and CD56(+) cells (P = 0.001, P = 0.002). On CD8(+) T cells post-treatment, CD81 remained lower in patients who achieved a SVR compared with patients who failed to eliminate HCV after treatment (P = 0.033). Lymphocyte subsets show different patterns of CD81 response before and during antiviral treatment, which are associated with administration of IFN-alpha and antiviral response.Journal of Leukocyte Biology 08/2006; 80(2):298-308. · 4.99 Impact Factor -
Article: Comparison of conventional PCR with real-time PCR and branched DNA-based assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5.
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ABSTRACT: The key parameter for diagnosis and management of hepatitis C virus (HCV) infection is HCV RNA. Standardization of HCV RNA assays to IU is mainly based on genotype 1 panels. Little is known about the variability of commercially available HCV RNA assays for quantification of different genotypes. Two real-time reverse transcription (RT)-PCR assays (COBAS TaqMan HCV Test for use with the High-Pure System [HPS/CTM] and COBAS Ampliprep/COBAS TaqMan HCV Test [CAP/CTM]), one standard RT-PCR assay (COBAS Amplicor HCV Monitor 2.0 [CAM]), and one signal amplification assay (Versant Quantitative 3.0 [branched DNA [bDNA]]) were compared for quantification of genotypes 1 to 5 (n = 108). Using CAM as a reference assay for genotype 1-infected patients, the mean interassay differences compared with CAP/CTM, HPS/CTM, and bDNA were 0.16, -0.13, and -0.48 log(10) IU/ml HCV RNA, respectively. Comparison of CAM with CAP/CTM, HPS/CTM, and bDNA for the remaining genotypes showed the following results, respectively: 2a/c, -0.24, -0.78, and -0.49; 2b, -0.21, -0.18, and -0.64; 3a, 0.13, -1.04, and -0.55; 4, -0.52, -1.51, and -0.05; and 5, -0.28, -1.00, and -0.24 log IU/ml HCV RNA. A correct decision for treatment discontinuation in genotype 1 patients at week 12 was possible only when the same assay was used at baseline and week 12. Comparison of CAM with the CAP/CTM assay showed equal quantifications of genotype 1, 2, 3, and 5 samples, while genotype 4 samples were slightly underestimated. For the HPS/CTM assay, a significant underestimation of the HCV RNA concentrations of genotypes 2a/c, 3, 4, and 5 was observed. For the bDNA assay, a constant lower quantification of genotypes 1 to 3 was detected.Journal of Clinical Microbiology 04/2006; 44(3):729-37. · 4.15 Impact Factor -
Article: Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C.
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ABSTRACT: Formation of transmembrane ion channels by hepatitis C virus (HCV) p7 and abrogation of channel function by amantadine was demonstrated in vitro. The relevance of HCV p7 amino acid (aa) variations for response to antiviral therapy with amantadine is unknown. HCV p7 was sequenced in 86 individuals who were infected with HCV genotype 1. Thirty-six of 86 patients received amantadine within an interferon-alpha (IFN-alpha)-based antiviral therapy. Helical wheel modelling for HCV p7 was performed. No significant correlation of overall aa variations within HCV p7 was observed with response to IFN-alpha-based therapy with amantadine in HCV genotype 1alpha/b infected patients. When analysis was restricted to non-conservative aa variations, a higher number of aa substitutions within complete HCV p7 and transmembrane helix 2 was associated with non-response in HCV-1b-infected patients receiving therapy with amantadine (P=0.015 and P=0.037, respectively), without amantadine (P=0.106 and P=0.118, respectively), and in the total cohort of HCV-1b-infected patients (P=0.00007 and P=0.011, respectively). Furthermore, substitution L20F was observed more often in non-responders than responders with HCV-1b infection and therapy with amantadine (P=0.099). By in silico modelling, aa 20 was located toward the p7 channel lumen. Substitution L20F may impair amantadine action by altering the shape of the ion channel pore. Substitution L20F within HCV p7 may be associated with non-response to combination therapy specifically with amantadine in HCV-1b-infected patients. Non-responders with HCV-1b infection showed higher numbers of non-conservative aa variations within HCV p7 than responders, irrespective of the application of amantadine.Antiviral therapy 02/2006; 11(4):507-19. · 3.16 Impact Factor -
Article: Clinical significance of in vitro replication-enhancing mutations of the hepatitis C virus (HCV) replicon in patients with chronic HCV infection.
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ABSTRACT: Mutations in nonstructural (NS) hepatitis C virus (HCV) proteins enhance replication in HCV-1a/b replicons. The prevalence of such mutations and their clinical significance in vivo are unknown. Parts of HCV NS3 and NS4B-NS5B genes that included 31 in vitro replication-enhancing sites were sequenced for 26 patients with chronic HCV genotype 1 infection. Five patients showed specific mutations within NS3 at sites enhancing replication in the replicon. Those mutations were associated with a slower decrease in HCV RNA concentration during interferon (IFN)- alpha -based therapy (P = .007). Neither specific nor other mutations within NS3 and NS4B-NS5B were associated with baseline HCV RNA concentrations. Within NS5A, fewer mutations in the major HCV strain (P = .001) and increased quasi-species complexity (P = .02) and diversity (P = .02) correlated with increasing baseline HCV RNA concentrations. In silico analyses of NS3 protein structures suggested that the majority of observed mutations did not lead to major conformational changes. Specific mutations leading to enhanced replication in the replicon system were detected in 5 of 26 patients in vivo and were not associated with baseline HCV RNA concentrations but were associated with a slower decrease in HCV RNA concentration during IFN- alpha -based therapy. Quasi-species heterogeneity of NS5A correlated with baseline HCV RNA concentrations.The Journal of Infectious Diseases 12/2005; 192(10):1710-9. · 6.41 Impact Factor -
Article: Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir-lamivudine combination therapy.
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ABSTRACT: Mathematical analysis of viral kinetics during lamivudine-adefovir combination therapy has not yet been performed in patients with lamivudine-resistant hepatitis B. In 8 patients with lamivudine-resistant hepatitis B, adefovir dipivoxil (10 mg/day) was added to ongoing lamivudine. Viral decay during the first 8 weeks of combination therapy was described by a biphasic model to determine the efficacy: epsilon, of blocking viral production, the clearance: c, of free virus, and the loss of infected cells: delta. Median epsilon was 98%, median c was 0.7/day, and median delta was 0.07/day. No significant association was found between viral kinetic and baseline parameters and virologic and biochemical treatment response. When compared with viral kinetic constants reported for higher dose adefovir dipivoxil monotherapy, epsilon was lower (P=0.026) and delta was higher (P=0.008) in this study whereas c did not differ between both studies. Although a recent study did not show any differences in the reduction of HBV DNA comparing monotherapy with adefovir dipivoxil to adefovir-lamivudine combination therapy in patients with lamivudine-resistant chronic hepatitis B, mathematical analysis of early viral kinetics suggests an additional effect of lamivudine on the infected cell loss during adefovir-lamivudine combination therapy.Journal of Hepatology 09/2005; 43(2):217-24. · 9.26 Impact Factor -
Article: Highly sensitive hepatitis C virus RNA detection assays for decision of treatment (dis)continuation in patients with chronic hepatitis C.
Journal of Hepatology 05/2005; 42(4):605-6. · 9.26 Impact Factor -
Article: Association of serum interleukin-8 with virologic response to antiviral therapy in patients with chronic hepatitis C.
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ABSTRACT: Upregulation of interleukin-8 by the hepatitis C virus non-structural-5A-protein leads to inhibition of the antiviral activity of interferon-alpha in vitro. The clinical significance of interleukin-8 levels for virologic response to interferon-alpha-based treatment in patients with chronic hepatitis C is unknown. We investigated serum interleukin-8 in 59 healthy controls and 214 patients with chronic hepatitis C (genotype 1, n=152; genotype 2, 3, n=62) and different outcome to interferon-alpha-based therapy. In patients with chronic hepatitis C higher interleukin-8 levels were observed compared with healthy controls (P<0.0001). Hepatitis C genotype 1-infected patients with early and overall virologic response to interferon-alpha-based therapy showed lower interleukin-8 levels than non-responders (P=0.025 and P=0.035, respectively). In all patients, elevated interleukin-8 levels were associated with cirrhosis (genotype 1, P=0.0003; genotype 2, 3, P=0.009). Interleukin-8 levels in sustained virologic responders were still higher 24 weeks after the end-of-therapy compared with healthy controls (P<0.0001). In genotype 1 infected patients, low pretreatment serum interleukin-8 is associated with virologic response to interferon-alpha-based therapy. Thus, the conclusion from in vitro studies that the upregulation of interleukin-8 by the hepatitis C virus contributes to the inhibition of the antiviral actions of interferon-alpha may also be applicable in vivo.Journal of Hepatology 05/2004; 40(5):845-52. · 9.26 Impact Factor -
Article: Somatic hypermutation and mRNA expression levels of the BCL-6 gene in patients with hepatitis C virus-associated lymphoproliferative diseases
Journal of Viral Hepatitis, v.14, 484-491 (2007).
Top co-authors
Top Journals
Institutions
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2008–2013
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Goethe-Universität Frankfurt am Main
- Zentrum der Inneren Medizin
Frankfurt am Main, Hesse, Germany
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2005–2007
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Universität des Saarlandes
Homburg, Saarland, Germany
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