The Efficacy And Safety Of Peginterferon Plus Ribavirin In The Treatment Of Chronic Hepatitis C

Background and objectivesHepatitis C is a worldwide contagious disease. Transfusion and the product of blood are the major factors contributory to hepatitis C. There are approximately 170 million people with hepatitis C virus(HCV) infection in the world, 70 to 90 percent of them are attributed to chronic hepatitis, and near 20 percent are suffering to liver cirrhosis and HCV-associated complications. About 1 to 2 percent of the patients develop hepatocellular carcinoma. Hepatitis C has been one of the major disorders, which is paid attention by the medical world. The HCV infection is mid-high prevalent in China. From serum epidemic survey in 1992, the rate of the positive for anti-HCV was 3.2 percent in China, and the rate in midwest part was higher than that in the eastern apparently. The therapeutic approaches include either interferon alone or interferon plus ribavirin. Interferon alfa-2b plus ribavirin appears safe and effective to those patients who response to the initial therapy of interferon effectively but relapse thereafter. Histidine is the 34th amino acid in interferon alfa-2b which is covalently attached by a 12 KD branched polyethlene glycol molecule to interferon alfa-2b produces Peginterferon alfa-2b. Peginterferon improves the pharmacokinetics of interferon alfa-2b (half-life is 40 hours , clearance rate of kidney is 30 percent, the anti-virus activity is 28 percent of interferon alfa-2b, and its efficacy can last 168 hours by administering once per week after the maintaining of steady concentration.), enhances the activity in vivo, lessenes the associated toxic reaction, improves the compliance and the patients' quality of life, lowers the immunogenicity and antigenicity, and lowers the capability of inducing the antibody to interferon. Because RNA-dependent RNA polyerase has no function of repairing and checking in the course of HCV replication, the higher mutation rate of HCV will lead to more quasispecies. Quasispecies may be the mechanism to help HCV escape from immune monitoring of host. Peginterferon can clear up virus quickly and effectively, furthermore it can resist the formation of the drug fast quasispecies. Peginterferon alfa-2b (Pegintron) was developed by Schering-Plough Corporation, which had been ratified by FDA of USA and Euro Union in 2000. Currently, Pegintron has come to the market in 21 countries and areas. Peginterferon alfa-2b plus ribavirin is regarded as the best treatment for chronic hepatitis C which can replace interferon alfa-2b plus ribavirin. In the same safe situation, Peginterferon alfa-2b plus ribavirin shows better efficacy as compared to interferon alfa-2b plus ribavirin, especially for difficult-to-treat patients infected with HCV genotype 1. The aims of our study were designed to evaluate the efficacy and safety of Peginterferon alfa-2b plus ribavirin in the treatment for Chinese patients with chronic hepatitis C, and compare those with interferon alfa-2b plus ribavirin. MethodsOur study was an open, randomized in 2:1 ratio , positive controlled clinical trial. Patients with chronic hepatitis C who received no interferon therapy or received effective interferon therapy before six months but relapse were enrolled. All patients were either out- or in-patients of Henan Provincial People's Hospital. Based on body weight, patients in treatment group received subcutaneous, weekly injections of Peginterferon alfa-2b (<65kg: 40μg/w;≥65kg: 50μg/w) plus oral ribavirin (<65kg:750mg/d; 65～84kg: 900mg/d;≥85kg: 1050mg/d) ; patients in control group received subcutaneous, thrice a week injections of 3 million units of interferon alfa-2b plus ribavirin( Ribavirin usage was the same to treatment group). The essential stage of therapy was at least 24 weeks. Patients who had undetectable serum HCV RNA at the 20th week continued to receive the next 24 weeks therapy, otherwise the therapy was stopped at 24th week. All the patients were followed up for 24 weeks after cessation of therapy. Patients who had a sustained virologic response(with serum HCV RNA negatitive and normal level of ALT at 24 weeks after cessation of therapy) continued to be followed up at 48th ,96th, 144th week after cessation of therapy. The evaluation of clinical, hematology, virology and safety were carried out. Both Peginterferon alfa-2b and interferon alfa-2b were produced by Schering-Plough (Irish) Limited Company, and ribavirin capsule was produced by Chengyi Medicine Limited Company in zhejiang province. Results1 From March to August 2002, 30 patients who met the selection criteria were randomly assigned to treatment group (20 cases )and control group(10 cases ).There were no difference between treatment group and control group in sex, age, weight, duration of illness, course of past therapy, serum level of ALT and HCV genotype.There were 15 cases in treatment group and 7 cases in control group who had received effective interferon therapy before six months but relapse after cessation of the therapy(P= 0.405). Both treatment and control group lost 1 case at 48th week in the treatment period. At 24th week of follow-up period, there were 3 cases lost in two groups (2 cases in treatment group; 1 case in control group). Twenty one cases achieved sustained virologic response (undetectable serum HCV RNA and normal level of ALT at 24 weeks after cessation of therapy) at the 24th week in the stage of follow-up in two groups (17 cases in treatment group; 4 cases in control group), and all the 21 cases completed follow-up at week 48,96, and 144.2 Each group had 1 case with serum HCV RNA positive at 20th week, whose treatment stoped at 24th week and continued to complete 24 weeks follow-up. One case with negative HCV RNA in each group required to exit this study because of adverse events after therapy for 24 weeks. The end-of-treatment response rate was 90.00 %(18/20) in the treatment group and 40.00% (4/10) in the control group, and the difference was statistically significant (P=0.007). The sustained virologic response rate was 85.00% (17/20) in the treatment group and 40.00% (4/10) in the control group, and the difference had statistically significant (P=0.030).3 Among of those who had received effective interferon therapy before six months but relapse, the sustained virologic response rate was 86.67%( 13/15) in treatment group and 28.57%( 2/7) in control group. The difference had statistically significant (P=0.014).4 Followed up for 24 weeks after cessation, the rate of HCV RNA reversal positive was 0.00% in treatment group and 10.00%( 1/10) in control group, but the difference of two groups had not statistically significant (P= 0.310). In patients with sustained virologic response, all of the ALT sustained normal level when they were followed up after cessation by week 48th, 96th, and 144th, and HCV RNA sustained last negativity. However no one was seronegative for anti-HCV. The average time of ALT normality was 4 weeks ,and the normal recover rate after 4 weeks therapy was 85.71% (18/21).5 During therapy, the two groups had no death or severe adverse events. The adverse event rate in two groups was similar. The frequently happened adverse events were fever (75.00% vs 80.00%), fatigue (60.00% vs 60.00 %), leukopenia (95.00% vs 80.00%), lower hematoglobulin (35.00 % vs 30.00 %), and thrombocytopenia (25.00 % vs 40.00 %). Two cases with acouesthesia lower were found after treatment for 24 weeks (both of them were in the treatment group, one recovered after cessation and the other recovered in the treatment period ) , and three patients suffered thyroidea disfunction 48 weeks after treatment ( all of them were in the treatment group). The difference of two groups was not statistically significant (P>0.05). In the followed up period of 24 weeks, one patient suffered severe adverse event ( hepatic failure after operation for intestinal obstruction), but it was not related with medicine; 5 cases with thyroidea disfunction, four in treatment group, and one in control group. The difference was not statistically significant (P>0.05). The abnormal hematology criteria recovered normality when followed up for 48 weeks.Conclusions1 The efficacy of treatment group with Pegintron plus oral ribavirin for the therapy of chronic hepatitis C was significant higher than that in control group with interferon alfa-2b plus oral ribavirin.2 Pegintron plus oral ribavirin was superior to interferon alfa-2b plus oral ribavirin in the treatment of chronic hepatitis C who had received effective interferon therapy before six months but relapse after therapy.3 When using interferon or Pegintron in combination with ribavirin in the management of chronic hepatitis C, the sustained virologic response in 24 weeks after the end of treatment can better reflect the long-term efficacy. The ALT sustained normal rate in 4 weeks of therapy stage can better predict the sustained virological responses.4 The safety of Pegintron plus ribavirin was similar to interferon alfa-2b plus ribavirin for the therapy of chronic hepatitis C.5 The treatment with Pegintron plus ribavirin for chronic hepatitis C was regarded as safety and efficacy, especially for the relapse patients.