Clinical trial: comparison of weekly once versus twice half-dose weekly administration of pegylated interferon alpha 2b in combination with ribavirin for the treatment of HCV-1 positive patients with chronic hepatitis C.

BACKGROUND: Pegylated interferon (PEG-IFN) alpha2b is currently used as a once weekly injection in combination with ribavirin for the treatment of chronic hepatitis C. AIM: To test whether twice half-dose weekly administration may improve the virological response in difficult-to-treat hepatitis C virus-1 patients. METHODS: Thirty patients were treated with 1.5 microg/kg of PEG-IFN alpha2b given once weekly for 48 weeks (group A) and were compared with 30 patients treated with the same dose of PEG-IFN alpha2b divided in twice weekly doses of 0.75 microg/kg for the initial 4 weeks (group B). All patients were hepatitis C virus-1 positive and received weight-based ribavirin (800-1400 mg/daily). RESULTS: Weekly twice half-dose administration of PEG-IFN alpha2b for the first 4 weeks was associated with lower rates of biochemical and virological response at all time points compared with a once weekly schedule, and with significantly higher rates of in-therapy breakthrough leading to significantly lower rates of end of therapy response (week 48). The rate of sustained virological response was of 56.7% in group A and 36.7% in group B. CONCLUSIONS: Weekly twice half-dose administration of PEG-IFN alpha2b is not superior to the standard once weekly schedule, and might be less efficacious.

Fibrosis progression in initially mild chronic hepatitis C.

The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 +/- 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 +/- 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (DeltaF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.

Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C.

Hepatic iron has been described in hepatitis C virus (HCV) infection as an important cofactor of disease outcome. The mechanisms leading to hepatic iron deposits (HIDs) in HCV patients are partially understood. We investigated HIDs in the liver biopsies of a consecutive series of 242 HCV-infected patients with well-compensated liver disease. Serum ferritin was elevated in 20.7% and transferrin saturation in 19.0%, while 38.8% had stainable HIDs indicating that serum markers of systemic iron overload have low sensitivity in predicting HIDs in hepatitis C. A cut-off value of serum ferritin (350 microg/L in females and 450 microg/L in males) had good negative predictive value in excluding presence of mild-moderate HIDs (grade II-III). Hepatic iron deposits correlated by multivariate analysis with serum ferritin [odds ratio (OR) 1.008, 95% confidence interval (CI) 1.005-1.011] and albumin (OR 1.15, 95% CI 1.02-1.297). Hepatic iron deposits were more frequent in HCV-3-infected cases than in other genotypes (P = 0.027) while raised serum iron indices were more frequent in non-HCV-3 genotypes (P = 0.02). Furthermore, advanced fibrosis (F3-F4 by METAVIR) was more frequent in non-HCV-3 genotypes (P = 0.04). In HCV-3 cases there was a close association between HIDs and severe (grade II-III) steatosis (P < 0.00001). These results indicate that in well-compensated chronic hepatitis C HIDs are strongly associated with HCV-3 and viral-induced hepatic steatosis, while in the presence of other genotypes they might merely reflect a more advanced stage of liver disease and/or a systemic iron overload. Serum ferritin could identify a subgroup of patients in which the need of venesection could be excluded without liver biopsy.

Review article: chronic hepatitis C--natural history and cofactors.

Chronic hepatitis C is highly heterogeneous in clinical presentation and outcomes. This heterogeneity is largely related to host factors that have been clearly proven to affect the severity and rapidity of disease progression. The most relevant factors that have been shown to accelerate progression to cirrhosis include age at infection, alcohol abuse and the metabolic syndrome with insulin resistance, obesity and hepatic steatosis. Co-infection with HIV and/or HBV also increases the risk of progression to cirrhosis and to hepatocellular carcinoma. Surprisingly enough, viral related factors appear as less important and neither the virus genotype and load have been found to exert a clear influence on disease severity and progression, although more data in this field, and particularly on the role of different viral proteins in causing cytopathic effects, are awaited and may change this view in the near future.

Predilution haemofiltration--the Second Sardinian Multicentre Study: comparisons between haemofiltration and haemodialysis during identical Kt/V and session times in a long-term cross-over study.

BACKGROUND: The potential superiority of various renal replacement treatment modalities consisting largely of convective mass transfer as opposed to primarily diffusive mass transfer, is still a matter of debate. The objective of the present study was to evaluate acute and long-term clinical effects of varying degrees of convection and diffusion in a group of 24 clinically stable patients with end-stage renal disease. METHODS: The patients were prospectively assigned to three consecutive treatment schedules of 6 months each: phase I (HF1) (on-line predilution haemofiltration)-->phase II (HD) (high-flux haemodialysis)-->phase III (HF2; as phase I). We used the AK100/200 ULTRA monitor (Gambro), which prepares ultrapure dialysis fluid for HD and sterile, pyrogen-free substitution solution for HF. The membrane (polyamide), fluid composition, and treatment time were the same on HF and HD. The targeted equilibrated Kt/V was 1.2 for both treatment modes, creating a similar urea clearance. RESULTS: Fifteen patients, mean age 62.8+/-8.4 years, completed the study according to the above conditions. Urea kinetics, nutritional parameters, and dry weight were similar in the three periods. The frequency of intra-treatment episodes of hypotension/patient/month was significantly lower on HF1 (1.24) and HF2 (1.27) than on HD (1.80) (P<0.04). It decreased progressively on HF1, then increased on HD, and decreased again during HF2. Patients had fewer muscular cramps on HF than on HD (P<0.03) and required significantly less saline and plasma expander during HF than HD sessions. The prevalence of inter-treatment symptoms, including fatigue and hypotension, was lower on HF than on HD (score difference P=0.04). Quality of life, determined by the Laupacis method in all three periods, showed a tendency towards improvement during the study, reaching the best values during HF2. CONCLUSIONS: HF has a progressive stabilizing haemodynamic effect, producing a more physiological cardiovascular profile than HD. This long-term effect, observed in stable patients treated under strictly identical conditions, is probably due to the mechanism of convection, and is different from the acute effect observed mainly in unstable patients.

Adequacy in pre-dilution haemofiltration: Kt/V or infusion volume? The Sardinian Collaborative Study Group on Haemofiltration On-line.

Kt/V is the main index of adequacy for diffusive and diffusive convective methods of extracorporeal depuration, yet there exists no universally acceptable validation of an adequacy index for the solely convective methods such as haemofiltration (HF). The aim of the present study is to analyse which of the parameters of adequacy used in two multicentre HF studies, Kt/V for urea or infusion volume, correlate best with nutritional parameters and can therefore be utilized for the evaluation of treatment dose in on-line pre-dilution HF. Twenty-three clinically stable patients were enrolled in the first study [3 months of haemodialysis (HD)+ 3 months of HF]. In the second study, 24 stable patients were studied in three phases: 6 months in HF, 6 months in HD and a further 6 months in HF; in this study, a target of Kt/V= 1.2 in all three periods was preestablished: 15 patients completed the full study. In both studies, we utilized the same monitor (AK 100/200 Ultra, Gambro), the same membrane (polyamide) and the same on-line prepared ultrapure dialysis fluid and sterile infusion solution. In both studies, we ensured that HF fulfilled the following parameters of adequacy: urea kinetics, cardiovascular and blood pressure stability (better in HF than in HD), common haematochemical and nutritional parameters, reduction in beta2-microglobulin levels, a good intra- and extra-session clinical outcome, and a good quality of life with morbidity and mortality rates no different from those of HD. HF proved to be an efficacious method of ensuring adequate depuration and a good quality of life for uraemic patients. We have shown that in longer periods of HF, a notable correlation between Kt/V and normalized protein catabolic rate (nPCR) and an equally good correlation between total ultrafiltration (UF)/dry weight ratio and nPCR could be achieved. In both studies, the patients showed a good level of epuration adequacy when total UF per session was at least 1.3 times the dry body weight. The total UF/body weight ratio thus seems to be an easy method in HF because of its greater ease of predictability and measurement, also when it is used independently of the Kt/V index.