A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Evaluation of ribavirin efficacy and tolerance in subjects with chronic hepatitis C virus infection. Intravenous glycyrrhizin for the treatment of chronic hepatitis C: a double-blind, randomized, placebo-controlled phase I/II trial. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Antioxidant therapy for chronic hepatitis C after failure of interferon: results of phase II randomized, double-blind placebo controlled clinical trial. Successful glucocorticoid treatment for patients with abnormal autoimmunity on in vitro fertilization and embryo transfer. Daily interferon therapy for hepatitis C virus infection in liver transplant recipients.
Chronic hepatitis C is the most common indication for liver transplantation, but viral recurrence is universal and progressive graft injury occurs in most recipients. Our aim was to assess the safety, pharmacokinetics (PK), and antiviral effects of high doses of a human hepatitis C antibody enriched immune globulin product (HCIG) in patients undergoing liver transplantation for chronic hepatitis C. This was a multicenter, randomized, open-label, controlled trial conducted at 4 transplant centers in the United States. A total of 18 patients with chronic hepatitis C, who underwent liver transplantation, were randomized to receive low-dose HCIG (75 mg/kg) or high-dose HCIG (200 mg/kg), or no treatment. A total of 17 infusions of HCIG were administered in each treated patient over 14 weeks using a time-dependent dosing strategy based on the PK of anti-hepatitis B immune globulin in liver transplant recipients. Hepatitis C virus levels, liver enzymes, and liver biopsies were obtained serially throughout the study period. PK profiles of HCV antibodies were determined on days 4, 10, and 98. HCIG infusions were safe and tolerated. The infusion rate could not be maximized because of symptoms for 18% to 30% of the doses. The half-life of HCIG was extremely short immediately after transplantation but was gradually prolonged. In the high-dose group, serum alanine aminotransferase (ALT) levels normalized in most subjects and no patient developed hepatic fibrosis. However, serum HCV RNA levels were not suppressed at either dose. In conclusion, HCIG, an anti-HCV enriched immune globulin product, appears to be safe in patients with chronic hepatitis C undergoing liver transplantation. Further studies are required to determine whether the drug has beneficial effects in this group of patients. In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.
                We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.
                We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).
                Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)
                2008 Massachusetts Medical Society Reports by hepatologists indicated that anti-HCV antibodies might be detected in 71% to 84% of cases of post-transfusion hepatitis and in up to 50% of cases of sporadic non-A non-B hepatitis. Anti-HCV antibodies were detected in 0.05-1% of blood donors with normal alanine transaminase (ALT) levels and negative anti-HBc screening. Anti-HCV antibodies were found in 67% of patients with a history of intravenous drug abuse or autoimmune hepatitis, and in 10-30% of patients with hepatocellular carcinoma. This indicated that hepatitis C virus was a major cause of the acute and chronic hepatitis throughout the world.
                This was a multicenteric, international, double-blind, randomized, placebo-controlled study. After the eight-week screening period, patients were randomized to receive daily ribavirin 1200 mg or placebo, during the 48-week treatment period. Follow-up observations were performed during a 16 week post-treatment period. Up to 80 male and female outpatients with mild to moderate chronic active hepatitis C virus infection were enrolled in this study.
                During the treatment period ALT values were significantly lower in the ribavirin group. Neither in the ribavirin group, nor in the placebo group significant statistical differences of the HCV RNA values were found. Significantly lower portal inflammation was noticed in ribavirin group after the treatment. Analysis of laboratory data demonstrated that ribavirin therapy was associated with mild to moderate reversible anemia. Investigator's evaluation of the effect of the therapy on patient's well being showed statistically significant differences in the benefit of the ribavirin group.
                In this study ribavirin was more effective than placebo in reducing ALT levels during the treatment period of the applied therapy in patients with chronic active hepatitis C. In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C and reportedly reduces the progression of liver disease to hepatocellular carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on serum alanine aminotransferase (ALT), hepatitis C virus (HCV)-RNA and its safety in European patients.
                Fifty-seven patients with chronic hepatitis C, non-responders or unlikely to respond (genotype 1/cirrhosis) to interferon therapy, were randomized to one of the four dose groups: 240, 160 or 80 mg glycyrrhizin or placebo (0 mg glycyrrhizin). Medication was administered intravenously thrice weekly for 4 weeks; follow up also lasted for 4 weeks.
                Within 2 days of start of therapy, serum ALT had dropped 15% below baseline in the three dosage groups (P < 0.02). The mean ALT decrease at the end of active treatment was 26%, significantly higher than the placebo group (6%). A clear dose-response effect was not observed (29, 26, 23% ALT decrease for 240, 160 and 80 mg, respectively). Normalization of ALT at the end of treatment occurred in 10% (four of 41). The effect on ALT disappeared after cessation of therapy. During treatment, viral clearance was not observed: the mean decrease in plasma HCV-RNA after active treatment was 4.1 x 10(6) genome equivalents/mL (95% confidence interval, 0-8.2 x 10(6); P > 0.1). No major side-effects were noted. None of the patients withdrew from the study because of intolerance.
                Glycyrrhizin up to 240 mg, thrice weekly, lowers serum ALT during treatment, but has no effect on HCV-RNA levels. The drug appears to be safe and is well tolerated. In view of the reported long-term effect of glycyrrhizin, further controlled investigation of the Japanese mode of administration (six times weekly) for induction appears of interest. To examine the effects of interferon (IFN) therapy on clinical, biochemical, and histological features in patients with compensated hepatitis C virus (HCV)-related cirrhosis, we have conducted a randomized, controlled trial of IFN therapy versus observation. Eight centers included a total of 99 patients with biopsy-proven cirrhosis. IFN-alpha2b, 3 million units three times per week, or no antiviral therapy was given for 48 weeks. Twenty-three patients dropped out. End-of-treatment biochemical response was not observed in any of the 39 controls but was observed in 6 of the 47 treated patients (P <.02); sustained biochemical response was obtained in only 2 treated patients. Controls and treated patients did not significantly differ with regard to the changes in serum level of albumin, bilirubin, alpha-fetoprotein, in plasma prothrombin, in histological activity, or liver collagen content. During trial or follow-up (160 +/- 57 weeks), hepatocellular carcinoma developed in 9 controls and 5 treated patients (NS); decompensation of cirrhosis occurred in 5 controls and 7 treated patients. Seven controls and 10 treated patients died. In conclusion, in patients with compensated HCV-related cirrhosis, a 48-week course of IFN therapy is safe and is able to induce end-of-treatment biochemical response in a significant proportion of patients. However, a 48-week course of IFN therapy usually fails to achieve sustained response and, within the limit of this study, did not significantly improve the 3-year outcome. Therefore, a longer course of IFN therapy or combination therapy with ribavirin should be evaluated in patients with HCV-related cirrhosis. Several studies have reported that low doses of interferon can delay the development of hepatocellular carcinoma (HCC) and progression of chronic hepatitis C. We investigated the incidence of clinical events among participants of the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis (EPIC)3 program.
                Data were analyzed from an open-label randomized study of patients with chronic hepatitis C who had failed to respond to interferon alfa plus ribavirin. All patients had compensated cirrhosis with no evidence of HCC. Patients received peginterferon alfa-2b (0.5 μg/kg/week; n=311) or no treatment (controls, n=315) for a maximum period of 5 years or until 98 patients had a clinical event (hepatic decompensation, HCC, death, or liver transplantation). The primary measure of efficacy was time until the first clinical event.
                There was no significant difference in time to first clinical event among patients who received peginterferon alfa-2b compared with controls (hazard ratio [HR], 1.452; 95% confidence interval [CI]: 0.880-2.396). There was no decrease in the development of HCC with therapy. The time to disease progression (clinical events or new or enlarged varices) was significantly longer for patients who received peginterferon alfa-2b compared with controls (HR, 1.564; 95% CI: 1.130-2.166). In a prospectively defined subanalysis of patients with baseline portal hypertension, peginterferon alfa-2b significantly increased the time to first clinical event compared with controls (P=.016). There were no new safety observations.
                Maintenance therapy with peginterferon alfa-2b is not warranted in all patients and does not prevent HCC. However, there is a potential clinical benefit of long-term suppressive therapy in patients with preexisting portal hypertension.
                Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. To assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus (HCV) infection.
                One hundred chronic HCV infection patients failed in interferon treatment were enrolled and randomly assigned to receive combined intravenous and oral antioxidants or placebo, or oral treatment alone. Primary end points were liver enzymes, HCV-RNA levels and histology.
                Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52% of patients who received antioxidant therapy vs 20% of patients who received placebo (P = 0.05). Histology activity index (HAI) score at the end of treatment was reduced in 48% of patients who received antioxidant therapy vs 26% of patients who received placebo (P = 0.21). HCV-RNA levels decreased by 1-log or more in 28% of patients who received antioxidant therapy vs 12% who received placebo (P = NS). In part II of the trial, oral administration of antioxidants was not associated with significant alterations in any of the end points.
                Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon. Combined antiviral and antioxidant therapy may be beneficial for these patients. To analyze the effects of glucocorticoid treatment for patients with abnormal autoimmunity on IVF-ET outcomes, low-dose predonisolone or dexamethasone was administered in 51 IVF-ET cycles of 41 patients with positive antinuclear antibody (ANA), anti-DNA antibody, and/or lupus anticoagulant (LAC). Rates of clinical pregnancy and implantation in these patients were compared with those in 48 cycles without corticosteroid therapy. Autoantibody-negative patients were also treated with IVF-ET combined with (29 cycles) or without (57 cycles) glucocorticoid administration, and the pregnancy and implantation rates were investigated.
                Without glucocorticoid treatment, the pregnancy rate per cycle and implantation rate per embryo in antibody-positive patients were 10.4 and 3.8%, respectively. Significant increases in pregnancy (35.3%) and implantation (13.2%) rates were observed with corticosteroid treatment. In antibody-negative patients, the rates of pregnancy and implantation showed no significant differences with versus without the glucocorticoid administration.
                Our results indicate that because autoimmune abnormalities may be at least one cause of implantation failure following IVF-ET, the combined use of low-dose corticosteroid can be effective for autoantibody-positive women. Hepatitis C virus infection persists after liver transplantation and causes recurrent liver injury in the majority of patients. Standard dose interferon therapy has been largely unsuccessful for hepatitis C in transplant recipients.
                Twelve patients, at least 7 months posttransplant, with detectable hepatitis C virus RNA in serum and features of hepatitis C on liver biopsy were randomized to interferon-alpha2a, 3 mU daily for 12 months (n=8) or no treatment (n=4). The tolerability of daily interferon dosing in liver transplant recipients was evaluated and effects on hepatitis C virus RNA level, quasispecies evolution, and liver histology were studied.
                Treated patients had an improvement in histological activity index at the end of therapy relative to controls (median reduction of 2 versus median increase of 1.5) (P=0.04). Four treated patients had a virological response (all bDNA negative, one qualitative polymerase chain reaction negative) compared with none of the untreated patients. Only two of six treated patients tested had evidence of quasispecies diversification on therapy. Seven of eight patients in the treatment group required dose reduction for fatigue and/or depression. They tolerated 1.5 mU of interferon-alpha2a daily. Two treated patients developed graft dysfunction, one of who had histological evidence of rejection and subsequent graft loss.
                Low daily doses of interferon were tolerated by liver transplant recipients and provided histological benefit without associated quasispecies diversification in most cases. These findings provide a rationale to study low dose daily or pegylated interferon maintenance therapy for the management of hepatitis C posttransplant.
There is insufficient evidence neither to confirm nor exclude both beneficial and harmful effects of glucocorticosteroids for chronic hepatitis C with or without autoimmune disorders. This Review is not able to rule out potential serious adverse effects of glucocorticosteroids. Therefore, this Review cannot establish whether glucocorticosteroids treatment can be safely administrated for indications requiring glucocorticosteroids without analysing for hepatitis C virus. The effect of glucocorticosteroids for acute hepatitis C has not been examined in randomised trials.