Efficacy of amantadine on quality of life in patients with chronic hepatitis C treated with interferon-alpha and ribavirin: results from a randomized, placebo-controlled, double-blind trial.

AIM: The aim of this study was to investigate whether amantadine reduces deterioration of quality of life in patients with chronic hepatitis C during and after treatment with interferon-alpha (IFN-alpha) and ribavirin. PATIENTS AND METHODS: In this randomized, prospective, placebo-controlled, multicenter trial, previously untreated patients with chronic hepatitis C were treated with IFN-alpha plus ribavirin [17] and randomized for treatment with amantadine (200 mg/day, orally, n=136) or placebo (n=131). Quality of life was assessed with the 'Profile of Mood States' scale and the 'Everyday Life' questionnaire at baseline, treatment week (TW) 8, TW24, TW48, and at follow-up. RESULTS: Early during treatment at TW8, quality of life was not different between patients in the control and the amantadine group. At TW24, the control group but not the amantadine group, however, showed significant deterioration of the modalities depression, fatigue, and vigor compared with baseline. Especially, nonresponders in the amantadine group showed significantly lower deterioration of depression, anger, mind function, everyday life, and zest for life than those in the placebo group. After treatment, the beneficial effects of amantadine disappeared. CONCLUSION: The addition of amantadine to IFN-alpha plus ribavirin combination therapy may reduce deterioration of depression, fatigue, and vigor during treatment but does not affect quality of life after treatment.

Distinct enzyme profiles in patients with cryptogenic cirrhosis reflect heterogeneous causes with different outcomes after liver transplantation (OLT): a long-term documentation before and after OLT.

BACKGROUND: Sound information is lacking about the clinical presentation of cryptogenic cirrhosis and its outcome after orthotopic liver transplantation (OLT). METHODS: Among 856 patients who have been transplanted at our center, 40 patients had no evidence of any known etiologies and were therefore defined as suffering from cryptogenic cirrhosis. Their median follow-up period before OLT was 78 months (range, 1-264), and after OLT 97 months (range, 1-132). Laboratory and histological data were evaluated according to features being compatible either with a toxic, hepatitic, or cholestatic condition. RESULTS: The clinical and histological findings differed specifically between these three groups. The toxic-like group (GGT 4-18 x upper limit of normal [ULN]) expressed significantly higher IgA levels, had histologically more often fatty liver changes, and risk factors for non-alcoholic steatohepatitis predominated (56% compared with 3% in the other groups, P=0.01). The hepatitic-like group (ALT 2-18 x ULN) showed histologically features of chronic hepatitis or hepatitic cirrhosis, and only among these patients a median International Autoimmune Hepatitis (IAH) score of 13 was found suggesting autoimmune hepatitis (AiH). In the cholestatic group (AP 2-8 x ULN) histology was compatible with a non-toxic inflammatory process but IAH score excluded AiH in all. After OLT, actuarial graft and patients survival was 90% at 5 years. Mild or moderate graft hepatitis occurred in 9 patients (23%) and was significantly associated with a pre-OLT IAH score >or= 10 (P =0.008). CONCLUSIONS: This study provides arguments that cryptogenic cirrhosis is a heterogeneous disease in which autoimmune mechanisms might be predominately involved and being responsible for recurrence of chronic liver disease observed in some instances after OLT.

Analysis of the effect of IL-12 therapy on immunoregulatory T-cell subsets in patients with chronic hepatitis C infection.

BACKGROUND/AIMS: Aim of this study was to investigate the influence of IL-12 therapy on the production of immunoregulatory type 1/type 2-cytokines by peripheral blood mononuclear cells from patients with chronic hepatitis C. METHODOLOGY: Peripheral blood mononuclear cells were isolated from 12 patients with chronic HCV infection before and after eight weeks of IL-12 application (0.03-0.5 micrograms/kg body weight). Peripheral blood mononuclear cells from 40 healthy blood donors served as a control group. The peripheral blood mononuclear cells were incubated for seven days with antigens stimulating specifically type 1 (tuberculin purified protein derivative) or type 2 T-cells (tetanus-toxoid). Furthermore, BCG (bacille Calmette-Guérin) was added to the cultures known to activate macrophages/antigen-presenting cells. Supernatants of peripheral blood mononuclear cells were analyzed for tuberculin purified protein derivative-induced production of the type 1 cytokine IFN-gamma, tetanus-toxoid-induced production of the type 2 cytokine IL-5 and the BCG-induced production of TNF-alpha by a double sandwich ELISA. RESULTS: IL-12 therapy hardly influenced the regulatory type 1/type 2 T-cell reactivity. In contrast, BCG induced secretion of TNF-alpha was significantly higher after eight weeks of IL-12 therapy (4348 +/- 3083 pg/mL) than before treatment (1559 +/- 988 pgmL, p < 0.01). Clinically, serum alanine transaminase levels significantly decreased during IL-12 treatment but HCV-RNA persisted in all patients. CONCLUSIONS: IL-12 therapy in patients with HCV does not alter the production of regulatory cytokines produced by type 1/type 2 TH cells. The significantly enhanced production of BCG-induced TNF-alpha may, however, indicate an activation of antigen presenting cells or natural killer cells.

Prediction of treatment outcome in patients with chronic hepatitis C: significance of baseline parameters and viral dynamics during therapy.

In patients with chronic hepatitis C virus (HCV) infection scheduled for a 48-week treatment period, premature discontinuation of treatment was previously recommended if HCV-RNA levels remained detectable at week 24 of therapy. Considering the number of side effects and treatment costs, measurement of initial viral decline during therapy may identify virologic nonresponse earlier than 24 weeks. We retrospectively analyzed 260 European patients treated with standard or pegylated interferon alfa (IFN-alpha) and ribavirin for 24 to 48 weeks. Early prediction of virologic response by HCV-RNA decline at weeks 4 and 12 (Versant Quantitative [branched DNA (bDNA) 3.0]; Bayer Diagnostics, Emeryville, CA; and Qualitative [transcription-mediated amplification (TMA)] HCV RNA assay; Bayer Diagnostics) as well as clinical, biochemical, virologic, and histologic baseline parameters were analyzed by logistic regression and receiver operating characteristic (ROC) curves. A viral load at treatment week 4 above 450,000 IU/mL and at week 12 above 30,000 IU/mL was 100% predictive for virologic nonresponse in all patients. From multivariate logistic regression analysis of all patients, independent predictors for sustained virologic response were: genotypes 2 and 3 (P <.0001), a low baseline gamma-glutamyltransferase (GGT) level (P <.0001), a high baseline alanine aminotransferase level (P =.002), and a low baseline viral load (P =.04). None of the latter 3 factors were predictive for sustained virologic response when analysis was restricted to the subgroup of genotypes 2- and 3-infected patients. In conclusion, virologic nonresponse can be predicted early at week 12 of treatment independent from the applied therapeutic regimen based on a cutoff level for HCV RNA of 30,000 IU/mL. This algorithm recognizes 53.7% of nonresponders previously identified at week 24 of treatment.

Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease.

Liver transplantation in patients with hepatitis B has been under discussion for 20 years because of inferior results without reinfection prophylaxis; therefore, we analyzed our overall experience with liver transplantation in hepatitis B patients with immunoprophylaxis, particularly the influence of the available antiviral treatment in different periods. From 1988 to 2000, 228 liver transplants in 206 hepatitis B patients were performed. Indications were acute liver failure (10%), hepatitis B virus (HBV) cirrhosis alone (67%) or with hepatitis D virus (HDV) (13%), or hepatitis C virus (HCV) coinfection (7%). All patients received long-term immunoprophylaxis (anti-HBs > 100 U/L). HBV DNA-positive patients were treated before and after surgery with famciclovir or lamivudine since 1993 and 1996, respectively. Since 1993, antivirals also were used for HBV reinfection. The 1-, 5-, and 10-year patient survival rates were 91%, 81%, and 73%. In patients with hepatocellular carcinoma (HCC) (60% 5-year survival, P <.01) or HBV reinfection (69% 5-year survival, P <.01) survival was significantly impaired. Those with HDV or HCV coinfection had a slightly better survival than with HBV monoinfection (P >.05, not significant). Preoperative positive HBV DNA (hybridization-assay) test results were associated with a slightly impaired patient survival (78% 5-year survival, P >.05, not significant versus DNA-negative). Preoperative positive hepatitis B e antigen (HBeAg) predicted significantly worse survival (P <.05 versus negative HBeAg). Graft loss caused by reinfection was most frequent before the availability of antiviral drugs. Two-year patient survival increased from 85% in era I (1988-1993) to 94% in era III (1997-2000, P <.05). The 2-year recurrence rates in these 2 periods were 42% and 8% (P <.05). In conclusion, excellent long-term results can be achieved in hepatitis B patients after liver transplantation with modern strategies, and survival rates are similar to other indications. Based on our experience, hepatitis B patients, including those with active viral replication, should not be excluded from liver transplantation.

Triple therapy with amantadine in treatment-naive patients with chronic hepatitis C: a placebo-controlled trial.

The antiviral efficacy of amantadine in patients with chronic hepatitis C is controversial. In this randomized, prospective, placebo-controlled, multicenter trial, triple therapy with interferon alfa (IFN-alpha)-2a plus ribavirin and amantadine (amantadine group) was compared with combination therapy IFN-alpha plus ribavirin (control group). Four hundred previously untreated patients with histologically proven chronic hepatitis C were randomly allocated to treatment with amantadine sulphate (100 mg twice daily orally) or a matched placebo together with IFN-alpha induction plus ribavirin (1,000-1,200 mg/day orally) for 48 weeks. The primary end point was sustained virologic response (SVR) defined as undetectable serum hepatitis C virus (HCV) RNA (<100 copies/mL) 24 weeks after the end of treatment. SVR was observed in 52% of the amantadine group and in 43.5% of the control group (P =.11). Among patients with HCV genotype 1 infection, the corresponding SVR rates were 39% and 31%, respectively. The virologic on-treatment response rate in week 24 was significantly higher in the amantadine group as compared with the control group (70% vs. 59%, respectively, P =.016). This beneficial effect was mainly related to HCV type 1-infected patients (63% vs. 47%, respectively, P =.012). Independent factors associated with SVR, according to multiple logistic regression analysis, were amantadine treatment, low baseline HCV RNA, platelet counts (>/=250/nL), pretreatment ALT quotient >/=3, and GGT level (<28 U/L) as well as HCV genotypes other than 1. In conclusion, although we could not demonstrate a significant advantage of the triple regimen in univariate analysis, multivariate analysis offers arguments that amantadine should be considered as a potential anti-HCV drug in future studies.