Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period.

BACKGROUND & AIMS: Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS: Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS: Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS: Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.

Safety and efficacy of treatment with pegylated interferon alpha-2a with ribavirin in chronic hepatitis C genotype 4.

The hepatitis C virus (HCV) genotype is an important predictive outcome parameter for pegylated interferon plus ribavirin therapy. Most published therapeutic trials to date have enrolled mainly patients with HCV genotypes 1, 2 and 3. Limited studies have focused on genotype 4 patients, who have had a poor representation in pivotal trials. Our aim was to evaluate the efficacy and safety of treatment with standard dose pegylated interferon alfa-2a in combination with weight-based ribavirin in patients with chronic hepatitis C genotype 4. In this prospective observational study, 198 patients with HCV-4 were included in this study from February 2004 to August 2005,188 patients who received at least 1 dose of drugs were included in the ITT analysis and they were treated with pegylated interferon alfa-2a and ribavirin for 48 weeks. Baseline and demographic characteristics, response to treatment at weeks 12, 48 and 72, and the nature and frequency of adverse effects were analyzed. Virological response at week 12 was achieved in 144 patients (76.6%). Virological response at the end of treatment was present in 110 patients (58.5%). At week 72, 99 patients presented SVR (52.7%). The reported adverse events were similar to those found in the literature for treatments of similar dose and duration. In conclusion, combined treatment with pegylated interferon alfa-2a and ribavirin was well tolerated and effective in chronic hepatitis C genotype 4, yielding response rates between those reported for genotype 1 and those of genotypes 2-3.

Circulatory function and hepatorenal syndrome in cirrhosis.

The pathogenic mechanism of hepatorenal syndrome is not well established. We investigated the circulatory function in cirrhosis before and after the development of hepatorenal syndrome. Systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems were measured in 66 patients who had cirrhosis with tense ascites and normal serum creatinine levels; measurements were repeated at follow-up in 27 cases in whom hepatorenal syndrome had developed. At baseline, mean arterial pressure and cardiac output were significantly higher, and hepatic venous pressure gradient, plasma renin activity, and norepinephrine concentration were significantly lower in patients who did not develop hepatorenal syndrome compared with those presenting with this complication. Peripheral vascular resistance was decreased to the same extent in the two groups. Plasma renin activity and cardiac output were the only independent predictors of hepatorenal syndrome. Hepatorenal syndrome occurred in the setting of a significant reduction in mean arterial pressure (83 +/- 9 to 75 +/- 7 mmHg; P < .001), cardiac output (6.0 +/- 1.2 to 5.4 +/- 1.5 L/min; P < .01), and wedged pulmonary pressure (9.2 +/- 2.6 to 7.5 +/- 2.6 mmHg; P < .001) and an increase in plasma renin activity (9.9 +/- 5.2 to 17.5 +/- 11.4 ng/mL . hr; P < .001), norepinephrine concentration (571 +/- 241 to 965 +/- 502 pg/mL; P < .001), and hepatic venous pressure gradient. No changes were observed in peripheral vascular resistance. In conclusion, these data indicate that hepatorenal syndrome is the result of a decrease in cardiac output in the setting of a severe arterial vasodilation.