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Biomedical subjects

Christoph Sarrazin

Publications and source records attributed to Christoph Sarrazin.

At least 19 recordsLinked to original sources
PubMed2007

13C-methacetin breath test shortened: 2-point-measurements after 15 minutes reliably indicate the presence of liver cirrhosis.

BACKGROUND AND GOALS: The 13C-methacetin breath test (MBT) measures the activity of the cytochrome P450 dependent enzyme system and has been developed to assess the functional hepatic mass. We evaluated simple modifications of the 13C-MBT to further increase its practicability and therefore clinical acceptance. STUDY: One hundred and four patients with different chronic liver diseases (including 35 patients with histologically proven cirrhosis) and 65 healthy controls underwent the 13C-MBT. Breath test results of 2-point measurements were compared with conventional breath test results (cumulative recovery after 30 min) and liver histology. RESULTS: The 2-point-measurement at 0 and 15 minutes (with a cut-off <14.6 per thousand delta over baseline) had 92.6% sensitivity and 94.1% specificity in identifying the presence of cirrhosis compared with liver histology. The 2-point-measurements at 5 and 10 minutes also provided good discrimination between cirrhotic and noncirrhotic patients. CONCLUSIONS: The 13C-MBT using 2-point-measurement of breath samples at baseline and after 15 minutes reliably indicates decreased liver function in liver cirrhosis. This simplification of the 13C-MBT will increase practicability and cost efficiency, thus facilitating its clinical acceptability.

Acetamides↗
PubMed2007

Viral determinants of resistance to treatment in patients with hepatitis C.

Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-alpha) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-alpha is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-alpha-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

Amantadine↗
PubMed2006

Elevated plasma levels of N-terminal pro-brain natriuretic peptide in patients with chronic hepatitis C during interferon-based antiviral therapy.

AIM: To investigate plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), an established marker of cardiac function, in patients with chronic hepatitis C during interferon-based antiviral therapy. METHODS: Using a sandwich immunoassay, plasma levels of NT-proBNP were determined in 48 patients with chronic hepatitis C at baseline, wk 24 and 48 during antiviral therapy and at wk 72 during follow-up. RESULTS: Plasma NT-proBNP concentrations were significantly increased (P<0.05) at wk 24, 48 and 72 compared to the baseline values. NT-proBNP concentrations at baseline and wk 24 were closely correlated (r = 0.8; P<0.001). At wk 24, 7 (14.6%) patients had NT-proBNP concentrations above 200 ng/L compared to 1 (2%) patient at baseline (P = 0.059). Six of these 7 patients had been treated with high-dose IFN-alpha induction therapy. In multiple regression analysis, NT-proBNP was not related to other clinical parameters, biochemical parameters of liver disease or virus load and response to therapy. CONCLUSION: Elevated levels of NT-proBNP during and after interferon-based antiviral therapy of chronic hepatitis C may indicate the presence of cardiac dysfunction, which may contribute to the clinical symptoms observed in patients during therapy. Plasma levels of NT-proBNP may be used as a diagnostic tool and for guiding therapy in patients during interferon-based antiviral therapy.

Adult↗
PubMed2006

The hepatitis C virus NS5A protein and response to interferon alpha: mutational analyses in patients with chronic HCV genotype 3a infection from India.

The hepatitis C virus (HCV) non-structural (NS)5A protein is linked to interferon alpha resistance in vitro and higher numbers of NS5A amino acid (aa) variations in HCV 1a/b isolates are associated with virologic response to interferon alpha-based therapy in vivo. Here, we aimed to study NS5A aa variations in Indian patients undergoing interferon alpha/ribavirin treatment infected with HCV 3a. The NS5A region [aa 2194-2401, comprising interferon sensitivity determining region, protein kinase resource (PKR) binding domain, V3 region] was sequenced from pre-treatment sera of 24 patients with HCV 3a infection. Mean number and physicochemical properties of aa variations (conserved vs. non-conserved) were assessed. Additionally, published NS5A sequences [NS5A region (n = 61), PKR binding domain (n = 111)] of characterized HCV 3a isolates were analyzed. The mean number of NS5A aa variations was not correlated with treatment response in our cohort. When all available NS5A sequences were included, a higher number of non-conserved aa variations within PKR binding domain and an extended V3 region of NS5A was associated with virologic response (P = 0.004 and 0.05, respectively). Mutational analyses of a large number of NS5A sequences suggest, that a higher number of non-conserved aa variations within the PKR binding domain and the extended V3 region is correlated with virologic response in HCV 3a infected patients.

Adult↗
PubMed2006

Dynamics of CD81 expression on lymphocyte subsets during interferon-alpha-based antiviral treatment of patients with chronic hepatitis C.

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.

Adult↗
PubMed2006

Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy.

Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine-resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg+), viral breakthrough during lamivudine therapy, and persistent viral replication (>10(4) copies/mL) after 15 months of ADV monotherapy (range 4-28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow-up (median 12 months, range 3-24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti-HBs after 16 months of TDF therapy. Lamivudine-associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV-resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV-infected patients with altered responsiveness to treatment with lamivudine and ADV.

Adenine↗
PubMed2006

Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.

BACKGROUND & AIMS: The treatment of patients infected with hepatitis C virus (HCV) type 1 remains a challenge necessitating innovative strategies to improve treatment outcome. The extension of treatment duration beyond 48 weeks is one possible strategy to address this problem. METHODS: The efficacy and safety of 48 weeks (group A, N = 230) vs 72 weeks (group B, N = 225) of treatment with pegylated-interferon-alfa-2a (180 microg/wk) plus ribavirin (800 mg/day) were studied in treatment-naive patients with HCV type 1 infection. On-treatment and sustained virologic response (SVR) 24 weeks after stopping treatment was assessed by qualitative reverse-transcription polymerase chain reaction (sensitivity 50 IU/mL). RESULTS: Overall, no significant differences could be observed in the treatment outcome between both groups. End-of-treatment and SVR rates in groups A and B were 71% vs 63% and 53% vs 54%, respectively. Patients with undetectable HCV-RNA levels already at weeks 4 and 12 had excellent SVR rates ranging from 76% to 84% regardless of treatment group, whereas patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 instead of 48 weeks (29% vs 17%, P = .040). A particular benefit from extended treatment duration was seen in patients with low-level viremia (<6000 IU/mL) at week 12. The frequency and intensity of adverse events was similar between the 2 groups. CONCLUSIONS: Extended treatment duration generally is not recommended in HCV type 1 infection and should be reserved only for patients with slow virologic response defined as HCV-RNA positive at week 12 but negative at week 24.

Adult↗
PubMed2006

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.

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.

DNA, Viral↗
PubMed2006

Viral kinetics in patients with chronic hepatitis C treated with the serine protease inhibitor BILN 2061.

We analysed viral kinetics from a 2-day treatment with BILN 2061, a serine protease inhibitor of hepatitis C virus, in patients chronically infected with genotype 1 hepatitis C virus. The efficiency (E), describing inhibition of viral production, was above 99.45% in all patients with minor or moderate fibrosis receiving doses of 200mg and 500 mg twice daily and larger than in previous studies for interferon-based treatments. However, epsilon was slightly smaller in patients with cirrhosis given 200mg and markedly smaller in patients given 25 mg. Estimates of viral clearance and infected-cell loss support conclusions on these rates and on treatment mechanisms from previous studies on interferon-alpha-based treatments.

Adult↗
PubMed2006

Amino acid variations in hepatitis C virus p7 and sensitivity to antiviral combination therapy with amantadine in chronic hepatitis C.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Amantadine↗
PubMed2005

Clinical significance of in vitro replication-enhancing mutations of the hepatitis C virus (HCV) replicon in patients with chronic HCV infection.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2005

Current therapy for hepatitis C.

INTRODUCTION: Pegylated interferon alfa in combination with ribavirin has been established as standard therapy for chronic hepatitis C virus (HCV) infection with sustained virologic response rates of 54-63%. The duration of therapy depends on the HCV genotype with currently 48 weeks for genotype 1 and 24 weeks for genotypes 2 and 3. RESULTS AND DISCUSSION: The probability of sustained virologic response is very low (<1-2%) in genotype-1-infected patients without a 2-log decline of HCV RNA concentration after 12 weeks of therapy, and treatment can therefore be discontinued early. CONCLUSION: Efficient treatment of the multiple side-effects of interferon-based antiviral therapy is essential in order to improve compliance, prevent dose reduction or early discontinuation and therefore enhance the probability of sustained response. Future developments of interferon-based therapy aim at the individualisation of the duration of therapy according to the kinetics of viral reduction. Furthermore, direct antiviral drugs, which are currently under investigation in phase I/II clinical trials, will fundamentally expand the treatment options of HCV infection in the next few years.

Algorithms↗
PubMed2005

Spontaneous resolution of chronic hepatitis C virus infection after antiviral treatment and relapse.

Clearance of acute hepatitis C virus (HCV) infection is associated with strong and multi-specific cellular immune responses which are often weak in chronic hepatitis C. We here report a case of spontaneous and sustained resolution of chronic hepatitis C virus infection in the absence of apparent HCV-specific immunity. The patient received standard antiviral therapy for chronic HCV infection and was HCV-RNA negative at the end of treatment but relapsed between follow-up week 4 and 12. Surprisingly, from follow-up week 28 on, he persistently was HCV-RNA negative in serum, even when being tested with the highly sensitive TMA-assay (cut-off 5-10IU/ml). ALT levels were within the normal range throughout follow-up. Virus-specific CD4+ T cell responses were prospectively analysed during the relapse period and during spontaneous resolution by interferon-gamma ELISPOT assays. Importantly, no HCV-specific cellular immune responses were detectable at any time-point. The patient suffered from an acute respiratory tract infection before HCV clearance and serum IL-8 levels were significantly increased during this period. Thus, spontaneous resolution of hepatitis C after antiviral treatment and relapse may occur even in the absence of hepatitis flares and apparent HCV-specific immune responses in single cases. The role of heterologous infections for HCV clearance requires further investigation.

Journal Article↗
PubMed2005

Hepatitis C virus-related resistance mechanisms to interferon alpha-based antiviral therapy.

Only 50-60% of the patients chronically infected with the hepatitis C virus (HCV) achieve a sustained virologic response to the current standard antiviral therapy consisting of pegylated interferon alpha in combination with ribavirin. The definite reasons for virologic response or non-response to interferon alpha-based therapy are unknown. Besides host and treatment efficacy factors, it is presumable that HCV is able to antagonize the antiviral activity of interferon alpha. So far, among the different HCV proteins, the envelope (E)2 protein, the non-structural (NS)3/4A protein, and the NS5A protein have been associated with interferon alpha resistance mechanisms in vitro. The clinical significance of amino acid mutations within these HCV proteins in HCV isolates from patients who did or did not respond to interferon alpha-based therapy was investigated in multiple studies. Within the E2 (HVR2, CD81 binding sites, PePHD) and the NS3/4A proteins no specific mutations in correlation with virologic response to interferon alpha-based therapy were observed. For the NS5A protein, mutations within the interferon sensitivity determining region (ISDR) and the complete NS5A protein may be of importance for response to interferon alpha-based treatment in patients infected with HCV subtype 1a/b.

Antiviral Agents↗
PubMed2005

Comparison of transcription mediated amplification (TMA) and reverse transcription polymerase chain reaction (RT-PCR) for detection of hepatitis C virus RNA in liver tissue.

BACKGROUND: Transcription mediated amplification (TMA) is known to be one of the most sensitive detection assays for hepatitis C virus (HCV) RNA in serum but has not yet been evaluated in liver tissue. It is unknown whether the higher sensitivity of TMA in comparison with polymerase chain reaction (PCR)-based assays is related to a higher efficiency of the extraction and/or amplification step. OBJECTIVES: The sensitivity of a TMA-based assay (Versant HCV RNA Qualitative assay, Bayer Diagnostics) and a standard RT-PCR-based assay (Cobas Amplicor HCV 2.0, Roche Diagnostics) was compared in formalin-fixed paraffin-embedded liver biopsy specimens of patients with chronic hepatitis C. STUDY DESIGN: After deparaffinization of 7.5 microm liver sections HCV RNA was extracted by standard phenol/chloroform. HCV RNA dilution panels were transferred in parallel to cDNA synthesis and amplification steps of PCR and TMA. Furthermore, TMA amplification from stepwise diluted HCV sera was performed following RNA extraction by either microcentrifuge colums (QIAmp Viral RNA spin Kit, Qiagen, Hilden, Germany) or magnetic microparticles (VERSANT HCV RNA Qualitative assay). RESULTS: The total number of HCV RNA positive liver specimens detected by TMA was higher compared with those detected by RT-PCR (P=0.032). The total number of TMA positive serum samples was higher when HCV RNA was extracted using magnetic microparticles in comparison with multicentrifuge column extraction (P=0.019). CONCLUSION: Our results suggest that both the extraction and amplification step of the TMA-based assay contribute to the higher sensitivity compared with standard RT-PCR.

Formaldehyde↗
PubMed2005

Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir-lamivudine combination therapy.

BACKGROUND/AIMS: Mathematical analysis of viral kinetics during lamivudine-adefovir combination therapy has not yet been performed in patients with lamivudine-resistant hepatitis B. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adenine↗
PubMed2005

GNB3 C825T polymorphism and response to interferon-alfa/ribavirin treatment in patients with hepatitis C virus genotype 1 (HCV-1) infection.

BACKGROUND/AIMS: The outcome of infection with the hepatitis C virus (HCV) has been shown to be influenced by genetic host factors. The G protein beta3 subunit (GNB3) C825T polymorphism has been shown to determine immune cell functions in vitro. We investigated the association of GNB3 genotypes with treatment response in HCV-infected patients. METHODS: We genotyped 1781 HCV-free blood donors and 232 HCV-infected patients treated with interferon-alfa/ribavirin. Sustained virologic response (SVR) was defined by undetectable HCV-RNA 24 weeks after discontinuation of therapy. Non-response (NR) was defined by positive HCV-RNA at the end of at least 24 weeks of treatment. GNB3 genotypes were determined by DNA restriction enzyme analyses. RESULTS: Genotype distribution was not significantly different in healthy controls and HCV-infected patients. Only in HCV genotype 1-infected patients a significant correlation between GNB3 CC genotype and NR could be observed (6 TT, 42 TC, 54 CC) versus SVR (11 TT, 25 TC, 19 CC) patients (P = 0.004). In a logistic regression analysis including biochemical and virologic characteristics, only GNB3 CC genotype was significantly associated with NR (OR 4.9; 95% CI = 1.4-16.5; P = 0.011). CONCLUSIONS: The GNB3 825 CC genotype is associated with NR in HCV-1-infected patients.

Antiviral Agents↗