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Background: The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin., Methods: For 48 weeks, 388 "naïve"genotype 1 patients were treated weekly with PEG-IFN α-2a or PEG-INF α-2b combined with daily ribavirin (1000-1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR)., Results: The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR:7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI:3.2 to 7.4), were all independent predictors of SVR., Conclusion: Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance., Trial Registration: ClinicalTrials.gov Identifier: NCT01342003.

Background: Currently, the approved dosage of ribavirin has not been studied in patients with 'normal' alanine aminotransferase (ALT) levels., Methods: Modelling and simulations were performed using generalised additive models (GAMs) to predict the incidence of anaemia and rate of sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 1 and persistently 'normal' ALT levels treated with peginterferon alpha-2a (40KD) 180 microg/week plus ribavirin 1000/1200 mg/day for 48 weeks., Results: Model-based simulations predicted that SVR rates would increase from 39 to 48% if patients with genotype 1 and persistently 'normal' ALT levels had received the standard weight-adjusted dose of ribavirin. This was similar to the predicted 49% SVR rate for genotype 1 patients with elevated ALT levels. The incidence of anaemia was predicted to increase from 13% to 23% in patients with persistently 'normal' ALT activity and was higher than that predicted for patients with elevated ALT levels; however, the difference appeared to be largely explained by the higher proportion of women in the former group., Conclusions: Simulations based on GAM suggest that regimens for patients with HCV genotype 1 should include the standard weight-adjusted dose of ribavirin, as similar SVR rates are predicted to be achieved, regardless of patients' ALT status at baseline.

Background: Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression., Aims: To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features., Patients: A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C., Results: Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C., Conclusions: The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.

Background/aims: To evaluate demographic characteristics, liver histology and virological features of hepatitis C virus (HCV) carriers with normal alanine transaminase (ALT) levels., Methods: A nationwide prospective study was started in 1997. Four Italian centres have participated in this study., Results: Eight hundred and eighty subjects entered the study. One hundred and eighty-nine (21.5%) were excluded during the follow-up because of ALT increase. Among the 691 patients with persistent ALT normality, 72% were females. An overall prevalence of genotype 2 was found (52%). Normal liver was found in 17% of the patients; 34% had minimal chronic hepatitis, 44% mild hepatitis, 4% moderate to severe hepatitis, and 1% had cirrhosis. Clinical and virological features did not differ between subjects with ALT flares and those with persistently normal ALT. Baseline ALT levels have no effects on liver histology and clinical outcome., Conclusions: Many HCV carriers have significant chronic liver damage, although in the majority of them liver lesions are minimal or mild. Up to 60% of HCV carriers in Italy harbour non-1 HCV types. Current definition of HCV carriers with persistently normal ALT levels, based upon three normal ALT values over a 6-month period, is not adequate to discriminate between carriers with persistent ALT normality and those with transient biochemical remission. Longer follow-ups are needed.

Aims/background: Many HCV RNA positive subjects with normal aminotransferase levels have significant liver damage despite normal liver biochemistry. In these patients it is not possible to discriminate between "healthy" carriers and subjects with chronic liver damage, unless liver biopsy is performed. The aim of this study was to evaluate the usefulness of HCV RNA quantitation as a non invasive tool to predict the severity of liver injury in a group of HCV carriers with normal amino-transferase levels., Methods: 59 HCV RNA positive subjects (20 males) with persistently normal ALT levels were studied. All patients underwent HCV RNA quantitation and percutaneous liver biopsy., Results: No correlation was found between serum HCV RNA titers and grading, while viraemia did correlate with staging. Patients were categorized into four subgroups, according to arbitrary serum HCV RNA cut-offs. Grading was not different between the four groups. Staging was significantly higher among subjects with viraemia > 1000 x 10(3) copies/mL than in patients with HCV RNA titers < 1000 x 10(3) copies/mL., Conclusions: In HCV carriers with normal aminotransferase levels viraemia does not predict the grade of HCV-related chronic liver disease (CLD), although subjects with higher HCV RNA levels seem to have more severe fibrosis. Although these data suggest that patients with higher viraemia might have more intense architectural changes and more severe progression of liver disease than those with lower levels of HCV replication, the weak and imprecise correlation leads us to conclude that HCV RNA quantitation is not a useful indicator in clinical practice in the selection of patients for liver biopsy.

This study was aimed to evaluate demographic, clinical, histological, and virological characteristics of 46 hepatitis C virus (HCV) carriers with persistently normal alanine transaminase (ALT) levels and to compare the results with those obtained in a group of 52 HCV-RNA-positive patients with elevated ALT levels. Subjects with normal ALT were more often females (P < .001), were more likely to be asymptomatic (P < .001), and have a lower incidence of risk factors for HCV transmission (P < .01). All patients with normal ALT had significant histological liver damage. The mean grading and staging did not differ between patients with normal and those with raised ALT concentrations. Moderate to severe hepatitis was more frequently found among subjects with normal than with elevated ALT. HCV genotype 2a was far more common in subjects with normal (43%) than with abnormal ALT levels (6%; P < .002), genotype 1b being more frequent in these latter (50% vs. 17%; P < .001). Patients with normal ALT levels had similar serum HCV-RNA titers than subjects with raised ALT. Neither HCV genotype distribution nor viral load correlated with the severity of liver damage. We conclude that significant liver disease may occur irrespective of clinical symptoms, ALT levels, HCV genotypes, and viral load.