Responses to venlafaxine treatment in major depressive disorder were stratified by COMT genotypes (Val158Met, rs4680) in a randomized, double-blind, placebo-controlled clinical trial. Improvements in depression scores among subjects with Val/Val genotypes were larger than those in Met/Met genotypes, suggesting that venlafaxine may alter noradrenergic flux differentially according to COMT activity.

The critical analysis of baseline factors has been found to be useful to predict virologic nonresponse (NR), relapse, or sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) who receive antiviral therapy. In the present retrospective study we tried to find out whether gamma-glutamyltranspeptidase (GGT) may be one of the baseline factors which are of special predictive power. We analyzed, in patients with different treatment outcomes, the predictive power of established baseline factors either in combination with GGT or by evaluating the predictive value of GGT independently.

This study demonstrates that a more precise prediction of the individual relapse risk in chronic hepatitis C virus genotype 1 infection can be obtained by kinetics of minimal residual viremia at weeks 4, 8, and 12 in combination with levels of baseline viremia. These data may also help to further individualize new protease inhibitor-based triple therapy regimens.

Background & Aims The adaptive immune response against hepatitis C virus (HCV) is significantly shaped by the host s composition of HLA-alleles with the consequence that the HLA phenotype is a critical determinant of viral evolution during adaptive immune pressure In the present study we aimed to identify associations of HLA class I alleles with HCV subtypes la and 1b genetic variantsMethods The association between HCV genetic variants and specific HLA-alleles was investigated in a cohort of 159 patients with chronic HCV genotypes 1a- and 1b-infection who were treated with pegylated interferon-alfa 2b and ribavirin in a prospective controlled trial for 48 weeks by direct sequencing of the genes encoding the HCV proteins E2 NS3 and NS5B and by HLA class I-genotyping of patients HCV genetic variants were associated with specific HLA-alleles and the binding strength of accordant amino acid sequences to the corresponding HLA-allele was assessed by using the SYFPEITHI-algorithmResults Overall associations between HLA class I alleles and HCV sequence variation were rare Five unknown HLA class I-associated viral genetic variations were identified which in part affected the binding of predicted HCV CD8+ T cell epitopes to the respective HLA-allele In addition different patterns of HLA class I-allele/HCV sequence associations between the two subtypes were observedConclusions We identified several unknown HIA class I-restricted HCV variants which in part impair binding to predicted HCV CD8+ T cell epitopes with remarkable differences between HCV subtypes la and 1b quasispecies (C) 2010 European Association for the Study of the Liver Published by Elsevier B V All rights reserved

Objective: The „EsCItalopram for the Prevention of PEGASYSΘ Associated Depression study“ (CIPPAD-study) is a prospective multicentre, randomized, double-blind, placebo-controlled clinical trial with the primary objective to evaluate the impact of a 2-week antidepressant pretreatment with Escitalopram on the incidence and severity of interferon-alpha associated depression. Study design: Patients without any history of psychiatric or substance abuse disorder either received escitalopram 10mg/day 2 weeks prior to commencement of HCV therapy and or received placebo. All patients were treated with pegylated interferon-alpha-2a (PEG-IFN-α-2a) plus ribavirin. The frequency and severity of depressive episodes were defined according to DSM-IV criteria for a „major depression“ and by using the Montgomery Asperg Depression Scale (MADRS). Results: According to preliminary data from 189 patients highly significantly more patients in the placebo group (48.9%) were diagnosed from clinicians as having a major depressive episode if compared to the verum group (p<0.001). Evaluation of the severity of depressive syndromes by MADRS-scores showed that significantly more patients in the placebo group reached moderate to severe depressive symptoms during antiviral treatment (34.7%) if compared to the verum group (p=0.004). Patients in the placebo group had a 2.6 fold increased risk to reach MADRS depression scores over 15 (OR=2.57). Significantly more patients in the placebo group needed an antidepressive rescue medication with mirtazapine (p=0.004). So far no significant differences between both groups were found regarding genotype distribution and sustained virological response. Discussion: Our preliminary results clearly indicate that an antidepressive pre-treatment with escitalopram was able to significantly reduce the frequency and severity of depressive episodes during antiviral therapy with PEG-IFN-a-2a in patients without psychiatric risk factors.

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type I-infected patients represents one possible strategy. Four hundred thirty-three patients were randomly assigned to receive either 1.5 mu g/kg peginterferon alfa-2b weekly plus 800-1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18-48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription-mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P < 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of > 80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009;50:369-377.)

Aims: Recently based on a genome-wide scan, a novel "gene signature" consisting of 7 single nucleotide polymorphisms (SNPs) has been proposed to identify patients at risk for cirrhosis in chronic hepatitis C virus (HCV) infection (Huang et al. Hepatology 2007;46: 297–306). However, this cirrhosis risk score (CRS) has yet to be replicated in an independent sample. Thus, our aim now was to evaluate the gene signature in a large independent cohort of patients with chronic HCV infection.

Background/Aims: Intercross studies in inbred mice susceptible or resistant to liver fibrosis revealed complement factor 5 as a quantitative trait gene associated with the development of fibrosis. In 277 patients with hepatitis C, two C5 SNPs, rs17611 and rs2300929, have been associated with advanced fibrosis.Methods: We investigated the association of these C5 SNPs with advanced fibrosis in 1435 HCV infected patients and in 1003 patients with other liver diseases. We performed genotyping with melting curve analysis using fluorescence resonance energy transfer probes in the LightCycler.Results: The defined high-risk genotypes (AA and TT) and alleles (A and T) were not associated with advanced fibrosis in HCV patients when Chi square testing and logistic regression analysis were applied (rs17611A 0.45 in F0-1 vs. 0.43 in 1724, P = 0.31; rs2300929T 0.91 F0-1 and 0.91 in F2-4, P = 0.82). In the group of patients with liver diseases other than HCV we neither found an association of the C5 SNPs with advanced fibrosis nor an overrepresentation of the SNPs in patients with cirrhosis.Conclusions: We found no evidence that these C5 SNPs are genetic risk factors for the development of advanced fibrosis in chronic HCV infection or other chronic liver diseases. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Low-density lipoprotein receptor (LDLR) is involved in the entry of hepatitis C virus (HCV) in host cells. We investigated whether three single-nucleotide alterations within LDLR might be associated with the course of hepatitis C infection and response to antiviral therapy. We enrolled 651 individuals with chronic HCV infection who had received interferon-based combination therapy, 174 individuals with self-limited HCV infection, and 516 healthy controls. LDLR c.1171G>A, c.1413G>A, and c.*52G>A genotyping was performed by real-time PCR-based assays. HCV genotype 1-infected individuals who were homozygous for 3'UTR c.*52G were at increased risk for virologic non-response to antiviral therapy compared to virologic responders (66.3% vs. 51.0%, p=0.001). Furthermore, compared to healthy controls, self-limited HCV genotype 1 infection was significantly associated with c.1171A (15.1% vs. 6.6%, p=0.006) and negatively associated with c.1413G>A heterozygosity (33.0% vs. 46.1%, p=0.023). The data indicate that LDLR alterations are correlated with response to interferon-based combination therapy and with self-limitation of HCV 1 infection.

We investigated and compared the results of treating the chronic hepatitis C (HCV) infection of different groups of psychiatric‐risk patients and controls with pegylated interferon alpha (pegIFN‐α) plus ribavirin. Seventy patients were prospectively screened for psychiatric disorders. Seventeen patients without psychiatric diseases or drug addiction (controls), 22 patients with psychiatric disorders, 18 patients who had received methadone substitution treatment and 13 patients who were former drug users were treated with pegIFN‐α plus ribavirin. Sustained virological response (SVR), adherence, and psychiatric side effects (using the Montgomery‐Asberg Depression Rating Scale and the Brief Psychiatric Rating Scale) in the groups were compared. An SVR was found in 58.6% of all patients: 58.8% of the controls, 50% of psychiatric patients, 72.2% of methadone patients, and 53.8% of former drug users. Methadone‐substituted patients and former drug users had significantly higher dropout rates. Scores for neither depressive nor psychotic symptoms differed significantly between groups during treatment. However, the controls had lower pretreatment scores, followed by a significant higher increase to maximum scores. A stepwise logistic regression model showed that only genotype, not group (control, psychiatric, methadone, or former drug abuse), type of psychiatric diagnosis (affective disorder, personality disorder, or schizophrenic disorder), depression scores before and during treatment, change in depression score, antidepressive treatment, sex, or liver enzymes before treatment, was associated with SVR. Conclusion: In an interdisciplinary treatment setting psychiatric diseases and/or drug addiction did not negatively influence psychiatric tolerability of and antiviral response rate to HCV treatment with pegIFN‐α and ribavirin. (HEPATOLOGY 2007.)