Hepatitis C pharmacogenetics: state of the art in 2010.

In 2009, a correlated set of polymorphisms in the region of the interleukin-28B (IL28B) gene were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with pegylated interferon-alfa and ribavirin. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. The link between IL28B genotype and HCV clearance may impact decisions regarding initiation of current therapy, the design and interpretation of clinical studies, the economics of treatment, and the process of regulatory approval for new anti-HCV therapeutic agents.

Interpretation of real-time PCR results for hepatitis C virus RNA when viral load is below quantification limits.

Hepatitis C virus RNA quantification results obtained in 18 laboratories using real-time PCR methods with 10 negative samples and 22 sample dilutions (viral loads of 0.5 to 500 IU/ml) showed a score of correct results of up to 93.5%.

Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10.

Unlabelled: The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro.

Association of caffeine intake and histological features of chronic hepatitis C.

Background & Aims: The severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC.

Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections.

Background: Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B infection has a presentation and clinical course that is divergent from that of HBeAg‐positive infection. The former usually presents with lower viral levels but faster progression to liver disease. We sought to better understand the balance between replication and the immune response against hepatitis B virus (HBV).

Performance of version 2.0 of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B virus DNA quantification.

The detection and quantification of hepatitis B virus (HBV) DNA are essential for the diagnosis and treatment of chronic HBV infection. The use of real-time PCR assays for HBV DNA quantification is strongly recommended. The goal of this study was to evaluate the intrinsic characteristics and clinical performance of version 2.

[Chronic hepatitis B: antiviral treatment guidelines].

The main goals of chronic hepatitis B therapy are, sustained reduction of HBV DNA below the limit of detection of real-time PCR (10-15 IU/mL), biochemical remission (ALT normalization) and histological improvement, in order to prevent disease progression associated with cirrhosis and hepatocellular carcinoma. In HBeAg positive patients, the objective is to achieve durable HBe seroconversion and/or in all patients lost of HBsAg, with or without anti-HBs seroconversion. Antiviral treatment is recommended in patients with HBV DNA levels above 2000 IU/ml and/or elevated ALT values and histological findings in liver biopsy over A1F1.

Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest.

Members of the Gadd45 family play central roles in the cellular response to genotoxic stress and have been implicated in several human cancers, including hepatocellular carcinomas. Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of primary hepatocellular tumors, although the underlying mechanisms are unclear. Here, we show a novel link between diminished Gadd45beta expression and HCV infection.

Care of hepatitis C virus infection in human immunodeficiency virus-infected patients: modifications in three consecutive large surveys between 2004 and 2009.

Background & Aims: To analyze the care of HCV infection in HIV-HCV coinfected patients and its progression between 2004 and 2009.

Methods: Three hundred eighty HIV-HCV coinfected patients were prospectively included from November 22 to 29, 2004 (2004 survey), 416 patients from April 3 to 10, 2006 (2006 survey), and 419 patients from June 15 to 22, 2009 (2009 survey).

Results: The rate of liver biopsy decreased (14% vs.

Occupational transmission of hepatitis C virus resulting from use of the same supermarket meat slicer.

Tracing risk factors for acquiring hepatitis C virus (HCV) in an HCV-infected patient, the only identified risk was working at the same butcher's counter of a supermarket as another HCV-infected patient, using a common ham cutting machine, with frequent bleeding hand injuries. A phylogenetic analysis showed a high percentage of nucleotide homology between the two patients' strains.

Characterization of V36C, a novel amino acid substitution conferring hepatitis C virus (HCV) resistance to telaprevir, a potent peptidomimetic inhibitor of HCV protease.

We characterized a novel substitution conferring moderate resistance to telaprevir, a peptidomimetic inhibitor of hepatitis C virus protease. V36C conferred a 4.0-fold increase in the telaprevir 50% inhibitory concentration in an enzyme assay and a 9.

Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C.

Unlabelled: High systemic levels of interferon-gamma-inducible protein 10 kDa (IP-10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP-10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP-10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO-HCV). Low levels of plasma or intrahepatic IP-10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.

Lessons from HIV therapy applied to viral hepatitis therapy: summary of a workshop.

Therapies for hepatitis B virus (HBV) have continued to evolve, and new therapies for hepatitis C virus (HCV) will soon be available in clinical practice. These medications for hepatitis C will mark the first time that direct antivirals that target HCV functions have been used. When such drugs are used as single agents, previously existing mutants with reduced susceptibility to them are rapidly selected.

The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report.

Abstract Hepatitis C virus (HCV) genotypes 4, 5 and 6 represent >20% of all HCV cases worldwide. HCV-4 is mainly seen in Egypt, where it represents 90% of all HCV cases. Antischistosomal therapy was the main cause of contamination there, followed by procedures performed by informal providers and traditional healers such as dental care, wound treatment, circumcision, deliveries, excision and scarification.

Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug development and future clinical practice.

Background: With the development of new specific inhibitors of hepatitis C virus (HCV) enzymes and functions that may yield different antiviral responses and resistance profiles according to the HCV subtype, correct HCV genotype 1 subtype identification is mandatory in clinical trials for stratification and interpretation purposes and will likely become necessary in future clinical practice. The goal of this study was to identify the appropriate molecular tool(s) for accurate HCV genotype 1 subtype determination.

Methodology/principal Findings: A large cohort of 500 treatment-naïve patients eligible for HCV drug trials and infected with either subtype 1a or 1b was studied.

Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

Background & Aims: Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels.

Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: a meta-analysis.

Background & Aims: In hepatitis C virus genotype 1 (HCV-1) patients with a rapid viral decline within the first month of therapy, a 24-week course of pegylated interferon (PEG-IFN) alpha and ribavirin treatment has been claimed to be as efficient as the standard 48-week duration.

Methods: We performed a meta-analysis of 7 randomized controlled trials comparing less than 48 weeks to 48 weeks PEG-IFN alpha/ribavirin treatment in 807 HCV-1 patients with rapid viral decline.

Results: SVR was significantly less frequent with short treatment duration than with 48 weeks of therapy, with a mean difference of -13.

Hepatitis C virus proteins induce lipogenesis and defective triglyceride secretion in transgenic mice.

Chronic hepatitis C virus (HCV) infection is associated with altered lipid metabolism and hepatocellular steatosis. Virus-induced steatosis is a cytopathic effect of HCV replication. The goal of this study was to examine the mechanisms underlying HCV-induced lipid metabolic defects in a transgenic mouse model expressing the full HCV protein repertoire at levels corresponding to natural human infection.

Prediction of nonSVR to therapy with pegylated interferon-alpha2a and ribavirin in chronic hepatitis C genotype 1 patients after 4, 8 and 12 weeks of treatment.

In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment.