[Treatment of chronic hepatitis C by bicyclum, a randomized double-blind placebo controlled trial]. Long-term follow-up of patients with chronic hepatitis C treated with different doses of interferon-alpha 2b. Evaluation of ribavirin efficacy and tolerance in subjects with chronic hepatitis C virus infection. High sustained response rate in patients with histologically mild (low grade and stage) chronic hepatitis C infection. A randomized, double blind, placebo controlled trial of interferon alpha-2b with and without ribavirin. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study. Treatment of chronic hepatitis C with interferon with or without ursodeoxycholic acid: a randomized prospective trial. A prospective and randomized study using ribavirin as monotherapy for the treatment of naïve patients with chronic hepatitis C. Fixed versus titrated interferon-alpha 2B in chronic hepatitis C. A randomized controlled multicenter trial. The Swiss Association for the Study of the Liver.
To evaluate the efficacy and safety of bicyclum, a China made new hepatocyte protecting agent, in the treatment of chronic hepatitis C (CHC).
                Thirty-nine CHC patients matched demographically and clinically were randomized into two groups: bicyclum group (group A, n = 20) and placebo/bicyclum crossovergroup (group B, n = 19). Bicyclum 75mg/d or placebo was administered to these two groups respectively for 3 months. Then the patients in group A received bicyclum for further 3 months and were observed for 3 months after the treatment discontinued; and the patients in group B received bicyclum 75mg/d for six months and were observed for 3 months after the treatment discontinued. Investigation items included clinical manifestations,liver function, serum HCV RNA and anti-HCV.
                In group A, the serum ALT was 120 +/- 43 U/L before treatment and was 57 +/- 32 U/L after treatment ( P < 0.01) In group B the baseline serum ALT was 126 U/L +/- 48 U/L. After the placebo administration the serum ALT was 127 U/L +/- 97 U/L (P > 0.05) and the clinical feature showed no improvement. After bicyclum treatment for 6 months, the serum ALT in group B was 68 +/- 45 U/L, significantly lower than that before bicyclum treatment ( P < 0.01) and clinical symptoms improved. The overall ALT normalization response rate were 64.1% and 48.7% at the end of bicyclum treatment and 3 months after the treatment discontinued respectively for the total 39 patients. The serum HCV-RNA became negative in 5 and 2 patients at end of treatment and 3 months after the treatment discontinued. Adverse drug reactions were mild and uncommon. Mild dizziness occurred in 1 patient in each group.
                Bicyclum is effective in improving ALT and clinical manifestations of CHC patients. It is safe and well tolerated and shows few adverse reactions. Eighty patients with chronic hepatitis C who completed a previously reported randomized controlled trial on the efficacy of interferon-alpha 2b were followed up for at least 36 mo after therapy discontinuation. Seventeen patients (21.2%) maintained normal ALT values throughout the follow-up; 63 (78.8%) either did not normalize the levels of ALT or relapsed during the follow-up. A significantly greater proportion of patients treated with 3 million units of interferon three times a week subcutaneously for 48 wk were long-term responders compared with patients treated for 24 wk. Sex, age, hepatitis C virus antibody status, source of infection and pretreatment levels of ALT were not predictive of long-term response. Cirrhosis was found to be an unfavorable predictive factor. After 3 yr of follow-up, clearance of viremia was observed in 58.9% of the 17 long-term responders but in none of the non-responders (p = 0.002). E2-NS1 antibody tested negative in 88.2% of long-term responders and in 14.3% of nonresponders (p = 0.001). Fifty-nine percent of long-term responders tested negative for C100-NS4 antibody compared with 14.3% of nonresponders (p = 0.031). No significant change was observed in other antibodies. Four long-term responders underwent liver biopsy 2 yr after discontinuation of therapy. All four patients had normal liver histology compared with baseline assessment of chronic active hepatitis in three and chronic persistent hepatitis in the other. Three of the four were negative for serum hepatitis C virus RNA. 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. To evaluate the efficacy and safety of therapy for patients with histologically mild hepatitis C virus (HCV) liver disease.
                A randomized, double blind, placebo controlled trial of interferon alpha-2b with or without ribavirin.
                Regional and university hospitals.
                One hundred and sixteen treatment naive patients with mild chronic HCV infection. Mild HCV infection was defined according to Knodell as a grade score of > or = 1 and < or = 6 and a stage score of < or = 1.
                Interferon alpha-2b (3 MU three times weekly) for 52 weeks in combination with either ribavirin or a matched placebo.
                The study endpoint was the absence of HCV RNA in plasma and liver tissue 26 weeks post-treatment. In addition, liver histology was compared pre- and post-treatment.
                Combination therapy was superior to interferon monotherapy, with a virological sustained response rate of 54% (31/57) and 20% (12/59), respectively, in both serum and liver tissue (P = 0.001). The sustained response rate was higher with combination therapy than monotherapy both in genotype non-1 (81% vs 36%) and in genotype 1 (28% vs 4%). There was a significant improvement in mean grade score in all sustained responders, irrespective of treatment arm.
                Combination therapy with interferon and ribavirin was safe and as effective in patients with histologically mild HCV infection as previously reported for more advanced disease. 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. Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation.
                Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment.
                Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement.
                The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored. The only effective and approved therapy for chronic hepatitis C is interferon-alpha. Because sustained response rates with interferon alone are disappointingly low, multidrug treatment regimens are currently being investigated. Ursodeoxycholic acid has been used in other chronic liver diseases and can limit hepatocyte injury. To evaluate the potential benefit of ursodeoxycholic acid in combination with interferon-alpha for the treatment of chronic hepatitis C, we conducted a prospective, double-blinded, randomized, placebo-controlled trial comparing the combination therapy of interferon-alpha 2b and ursodeoxycholic acid with interferon alone. Thirty-one patients with chronic hepatitis C were randomized to receive 3 million units of interferon-alpha 2b subcutaneously three times per week and either 13 to 15 mg/kg/day ursodeoxycholic acid or placebo orally for 6 months. The 6-month treatment period was followed by 6 months of observation. Biochemical normalization at the end of treatment occurred in 5 of 14 (36%) patients receiving monotherapy versus 8 of 15 (53%) patients (p = 0.34) receiving combination therapy. No patient treated with interferon alone had a sustained biochemical response 6 months after therapy; however, 3 of 12 patients (25%) treated with combination interferon and ursodeoxycholic acid maintained biochemical normalization at 6 months after therapy (p = 0.08). No difference in liver histology or clearance of hepatitis C viral RNA was noted 6 months after treatment. We conclude that combination therapy with ursodeoxycholic acid and interferon-alpha 2b was no more effective than interferon monotherapy in inducing a biochemical response in previously untreated patients with chronic hepatitis C. Ursodeoxycholic acid, however, may be useful in prolonging the biochemical response to interferon therapy. In order to evaluate the response to ribavirin in previously untreated patients with chronic hepatitic C, 39 patients were selected for a double-blind prospective and randomized trial, and divided into two groups: ribavirin-group (19 patients) and placebo-group (20 patients). Ribavirin was administered orally for 24 weeks (600 mg/day, followed by 1,000 mg/day and 1,200 mg/day each one for 8 weeks). After 3 months of drug administration, the patients were evaluated by measuring biochemical, virologic and histologic responses. After this phase, ribavirin was offered to the patients who had received placebo (second phase). The results showed that the patients who received ribavirin showed a higher reduction in serum alanine aminotransferase (ALT) activity than patients in the placebo group. Among the patients in the ribavirin-group, a complete biochemical response (ALT levels normalized) was observed in 3 patients (16%), and a partial response (reduction greater than 50% of the initial value of ALT activity) in 4 (21%). In the 20 patients in the placebo group, only 1 showed a partial response (5%). In the second phase of the study, among 16 patients who received ribavirin, 4 (25%) showed a complete and 5 (31%) a partial biochemical response. HCV-RNA did not become negative in any patient during the two phases. A reduction in the score of portal and lobular activity was observed in patients who received ribavirin, but statistical analysis did not identify differences. This study showed that ribavirin alone induces a biochemical response (ALT reduction) in some patients with chronic hepatitis C, which may be associated with a reduction in hepatic inflammatory activity reduction, but the changes are not sufficient to recommend initial monotherapy with ribavirin. Interferon has become the mainstay of treatment of chronic hepatitis C; however, duration of treatment and dose remain unresolved questions. The present study aimed to compare standard dose interferon with a titrated dose regimen carried out for 1 year.
                This was a randomized, controlled multicenter trial. Patients with chronic hepatitis C were randomly allocated to a control group (n = 30), to a fixed dose group (n = 31) where interferon-alpha 2b 3 MU thrice weekly was given for 1 year or a titrated group (n = 34) where interferon was titrated starting at 5 MU thrice weekly to the lowest dose keeping the patient in remission as assessed by a normal ALT value. Liver biopsies were obtained before and at the end of treatment; in addition, galactose elimination capacity was measured as a measure of cytosolic function.
                In the control, fixed and titrated groups a complete response was achieved in 2/29, 10/28 and 15/31, respectively (p < 0.001 in favor of treatment, p = n.s. for the two treatments). The corresponding figure for sustained response was 1/29, 5/28 and 6/ 31 (p = n.s). In the titrated group, a complete (sustained) response was achieved with 5 MU in 2 (2), with 4 MU in 1 (0), with 3 MU in 4 (0), with 2 MU in 3 (0) and with 1 MU in 5 (4). Liver biopsy score and galactose elimination capacity improved significantly in responders but not in treatment failures.
                Both fixed and titrated dosing of interferon given for 1 year induced virus clearance in only a minority of treated patients. However, in a small number of patients, a complete and sustained response can be achieved with low doses of interferon. Dose titration could be an interesting approach to decreasing the cost and side effects in the treatment of chronic hepatitis C.
Only one randomised clinical trial has examined bicyclol for patients with chronic hepatitis C. This small, short-term trial found no evidence to support or refute its use. Large, randomised, double-blind clinical trials with long-term follow-up are needed to examine the possible benefits and harms associated with bicyclol. Bicyclol can only be recommended for use in randomised trials.