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TNF α has been shown to play a role in hepatitis C virus ( HCV)-induced insulin resistance ( IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNF α. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNF α activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNF α (s TNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA- IR was positively correlated with serum levels of leptin ( r = 0.35, P < 0.0001) and s TNFR1 ( r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA- IR (means 1.6 ± 0.9 vs 1.7 ± 1.4) and had similar circulating levels of s TNFR1 and adipokines. Independent factors associated with IR were ferritin ( OR = 1.002, P = 0.02), leptin ( OR = 1.06, P = 0.02) and s TNFR1 ( OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA- IR or sTNFR1 level. HCV-related IR may be mediated through TNF α independent of IL28B genotype. [ABSTRACT FROM AUTHOR]

Ribavirin has a minor and transient effect on hepatitis C virus (HCV) replication and has been suggested to select a novel mutation, F415Y, in the RNA-dependent RNA polymerase of subtype 1a viruses. Twenty-nine patients with chronic hepatitis C (subtyped by INNO LiPA as 1a, 17; 1b, 11; 1a/1b, 1) who were nonresponders to interferon-based therapies were identified retrospectively and screened at Baseline, week 24 of treatment, and 24 weeks post-treatment. Selection of resistance mutations, including at amino acid position 415 of the polymerase, was investigated. Using clonal sequencing and pyrosequencing of the NS5B gene, we screened for the F415Y resistance mutation among patients who received combination therapy with ribavirin and interferon α. Of the 15 subtype 1a patients treated with interferon plus ribavirin, only one had the F415Y change at week 24, and an F/Y mixture was still present 24 weeks after therapy. Four additional patients in this group had the F415Y change 24 weeks post-therapy. The NS5B genes were sequenced in order to identify amino acid changes associated with ribavirin therapy, but no evidence was found that ribavirin selects for particular amino acids in the RNA-dependent RNA polymerase. Ribavirin, a weak inhibitor of HCV replication, does not select for resistance mutations in the sequence of the HCV RNA polymerase. [ABSTRACT FROM AUTHOR]

Prevention of hepatitis C virus (HCV) infection complications can be achieved by antiviral therapy based on the use of a combination of pegylated interferon (IFN)-α and ribavirin. The steady-state kinetics of HCV infection represents the treatment target. The goal is cure, which is achieved when all infected cells have been cleared from the body. Because of their intrinsic properties, real-time polymerase chain reaction (PCR) methods are rapidly replacing other technologies for routine quantification of HCV-RNA during antiviral therapy. The virological response at week 12 of therapy is currently used to tailor treatment duration in HCV genotype 1 infection only. Recent reports suggest that the virological response at week 4 could be used to tailor treatment duration, whatever the HCV genotype. [ABSTRACT FROM AUTHOR]

Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment. [ABSTRACT FROM AUTHOR]

Both absolute viral load and log decline in viral load from baseline were found clinically useful in predicting sustained virological response and lack of sustained virological response (non-sustained virological response, NSVR) to treatment. We assessed the clinical utility of hepatitis C virus (HCV) RNA quantitation and changes in viral load using the VERSANT® HCV RNA 3.0 Assay (bDNA) in 351 HCV-infected individuals treated with interferon plus ribavirin. We show that viral load decision thresholds provided negative predictive values (NPVs) of >95% at week 4 using a 100 000 IU/mL cut-off and at weeks 8 and 12 using 10 000 IU/mL cut-offs. A 2-log decline from baseline provided NPVs >95% at weeks 8 and 12. Combinations of absolute viral loads and changes in viral load from baseline did not enhance the performance of the decision rules for predicting NSVR. The positive predictive values (PPVs) at weeks 8 and 12 were 59.1 and 67.3%. This study highlights the critical importance of viral quantitation in gauging therapeutic response in patients with chronic HCV infection on antiviral therapy. Early changes in viral load, measured as absolute viral loads or change in viral load from baseline, are highly predictive of NSVR at 8 and 12 weeks. PPVs are modest but these data may provide encouragement to patients who are in the early phases of treatment when side effects are frequent. Additionally, we demonstrated the need for cautious interpretation of stopping rules when the values are at or near the decision thresholds. [ABSTRACT FROM AUTHOR]

This cross-sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6-month period. HCV genotyping in the 5′-non-coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer-specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non-subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype ( P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies. [ABSTRACT FROM AUTHOR]

This study reports evidence that hepatocellular steatosis, a frequent histological feature of chronic hepatitis C, is principally metabolic in hepatitis C virus (HCV) genotype 1-infected patients, whereas it is principally virus-induced in HCV genotype 3-infected patients. Multivariate analysis of data on 176 patients with chronic hepatitis C revealed that the severity of steatosis was independently related to HCV RNA load alone in patients infected by HCV genotype 3, whereas it was independently related to the body mass index, daily alcohol intake and histological activity grade (but not viral load) in patients infected by HCV genotype 1. These findings suggest that steatosis is a cytopathic lesion induced by HCV genotype 3, whereas HCV genotype 1 is not steatogenicper seor at the usualin vivoexpression levels. [ABSTRACT FROM AUTHOR]

Background and aim: Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antivirol treatment in patients with chronic hepatitis C and paired liver biopsies. Methods: A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI) <28 kg/m²; absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies. Results: Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non- responders (NR) (64% v 31%; p<.0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p<0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p<0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (1 9% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61-22.9); p=0.01), severe steatosis (OR 5.50 (95% CI 1.54-19.6); p=0.01), HCV genotype 3 (OR 2.90(95% CI 0.85-10.0); p= 0.07), and BMI >25 kg/m² (OR 0.24 (95% CI 0.08-0.73); p=0.02). Conclusions: Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Examines the relationship between hepatitis C virus (HCV) infection and HCV host. Distribution of HCV genomes; Mechanisms of viral persistence and resistance to interferon therapy; Pathogenesis of liver injury in chronic HCV infection.

The author reflects on the development on the study and treatment of hepatitis C virus (HCV). He relates that the virus was discovered by Michael Houghton and colleagues in 1989. He says that a major progress in HCV treatment was the launch of ribavirin, which increases the sustained virological response (SVR) rates at a maximum of 40% when combined with interferon (IFN)-α. He mentions that the creation of HCV vaccine is still a challenge.

Organ transplantation recipients are exposed to the transmission of various viruses. Viral safety is based on careful selection of the grafts, based on both clinical criteria and systematic screening for the following markers: anti-human immunodeficiency virus antibodies and p24 antigen, anti human T-cell leukemia virus antibodies, anti-cytomegalovirus antibodies, anti-Epstein- Barr virus antibodies, HBs antigen, anti-HBs antibodies and anti-HBc antibodies, and anti-hepatitis C virus (HCV) antibodies. A residual risk of HCV transmission is theoretically associated with the "serological window" that can occur in an acutely infected patient before seroconversion, and that can last for up to 70 days. The objective of this study was to determine the value of HCV core antigen detection and of nucleic acid testing (NAT) to improve viral safety of organ grafts. We tested blood samples prospectively collected between may 1992 and may 2000 in 2000 consecutive organ donors from the Paris area for the presence of: i) HCV core antigen with a new enzyme immunoassay (Core Antigen ELISA Test System, Ortho-Clinical Diagnostics, Raritan, New Jersey), ii) HCV RNA using the Transcription-Mediated Amplification assay (Chiron Procleix[sup TM] TMA HIV-1/HCV Assay, Chiron). HCV core antigen positive results were confirmed by neutralization. Of 2000 samples tested, 5 were found to be positive for the HCV core on first determination, among which 4 were confirmed to be specific (prevalence 0.20%; 95% confidence interval: 0.10%-0.30%). These four donors were also anti-HCV antibody-positive. The donor with a nonspecific reaction was antibody-negative and HCV RNA negative in PCR. NAT preliminary results show that 1.2% of sample tested were reactive. In conclusion, the residual risk of HCV transmission by organ transplantation appears to be very small. HCV-infected patients are well identified by the detection of anti-HCV antibodies and implementation of HCV core antigen detection would increase the cost without clear benefit for viral safety. [ABSTRACT FROM AUTHOR]

The hepatitis C virus (HCV) non-structural (NS) 5A protein appears to play an important regulatory role on viral replication and could also be involved in viral pathogenesis. HCV resistance to interferon is a complex mechanism involving multiple causes, among which certain NS5A functions could play a role. [ABSTRACT FROM AUTHOR]

Discusses the regulatory role of hepatitis C virus (HCV) non-structural 5A protein on viral replication. Viral pathogenesis; HCV resistance to interferon; Amino acid sequences.

Presents letter to the editor focusing on association of porphyria cutanea tarda and lichen planus in a patient with chronic hepatitis C virus infection.

Background & Aims: Single nucleotide polymorphisms (SNPs) associated with IL28B influence the outcome of peginterferon-α/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the kinetics of HCV RNA during therapy as a function of IL28B SNPs. Methods: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 242 HCV treatment-naïve Caucasian patients (67% genotype 1, 28% genotype 2 or 3) receiving peginterferon-α2a (180μg weekly) and ribavirin (1000–1200mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and early viral kinetics were assessed, accounting for relevant covariates. Results: In the multivariate analyses for genotype 1 patients, the T allele of rs12979860 (Trs12979860) was an independent risk factor for a less pronounced first phase HCV RNA decline (log10 0.89IU/ml among T carriers vs. 2.06 among others, adjusted p <0.001) and lower rapid (15% vs. 38%, adjusted p =0.007) and sustained viral response rates (48% vs. 66%, adjusted p <0.001). In univariate analyses, Trs12979860 was also associated with a reduced second phase decline (p =0.002), but this association was no longer significant after adjustment for the first phase decline (adjusted p =0.8). In genotype 2/3 patients, Trs12979860 was associated with a reduced first phase decline (adjusted p =0.04), but not with a second phase decline. Conclusions: Polymorphisms in IL28B are strongly associated with the first phase viral decline during peginterferon-α/ribavirin therapy of chronic HCV infection, irrespective of HCV genotype. [ABSTRACT FROM AUTHOR]

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-infectedpatient, 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. [ABSTRACT FROM AUTHOR]

Large-scale hepatitis C screening is required to prevent further spread of the infection, improve access to care in the context of new hepatitis C virus (HCV) drug regimens without interferon-alpha and subsequently reduce the risk of long-term complications of chronic liver disease. Rapid diagnostic tests (RDTs) represent an attractive alternative to enzyme immunoassay using blood from venepuncture. The aim of the present study was to prospectively assess the clinical performance of CE-marked RDTs detecting anti-HCV antibodies in fingerstick capillary whole blood and/or oral fluid. A total of 513 individuals, including 318 patients with chronic HCV infection, 25 patients with resolved HCV infection and 170 HCV-seronegative individuals, were prospectively enrolled. The specificity of RDTs with fingerstick whole blood varied from 98.8% to 100%. The clinical sensitivity was high for the OraQuick ® and Toyo ® tests (99.4% and 95.8%, respectively), but low for the Labmen ® test (63.1%). The specificity and clinical sensitivity in crevicular fluid were both satisfactory for the OraQuick ® test (100% and 97.6%, respectively). HCV antibody RDTs were easy and rapid to perform in the context of patient care. They were highly specific. Both the OraQuick ® and Toyo ® tests reached the expected level of performance for wide-scale use, with a performance advantage for the OraQuick ® HCV test. RDTs appear to be a promising new tool for wide-scale screening of HCV infection in high-risk to medium-risk populations. Hence, careful assessment of the performance of HCV RDTs must be recommended before they can be implemented in clinical practice. [ABSTRACT FROM AUTHOR]