Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C/Hepatitis B Co-Infection and Chronic Hepatitis C

Hepatitis C, Chronic Clinical Trial

Official title: An Open Label, Comparative, Multi-Center Study, to Evaluate the Efficacy and Safety of Peginterferon Alfa-2a Plus Ribavirin in the Treatment of Patients With Chronic Hepatitis C/Hepatitis B Co-Infection and Chronic Hepatitis C

Status Recruiting

Clinical Trial Summary

The investigators' pilot study indicates that hepatitis C virus (HCV)- and hepatitis B virus (HBV)-coinfected patients with predominantly active hepatitis C and those with predominantly active hepatitis B may need different anti-viral regimens. Since in the majority of these coinfected patients the hepatitis activity is more likely due to HCV than to HBV, the optimal therapeutic regimen for HCV- and HBV-coinfected patients with predominantly active hepatitis C will first be investigated. The combination therapy using pegylated interferons (IFNs) such as PEG-IFN alfa-2a has been shown to have a superior efficacy than that using conventional IFN in the treatment of monoinfected chronic hepatitis C. This new combination therapy might also further enhance the treatment efficacy in HCV- and HBV- coinfected patients. The investigators therefore propose to initiate a trial comparing the efficacy of pegylated IFN plus ribavirin (RBV) in dual chronic hepatitis B and C versus that in chronic hepatitis C only, for both HCV genotype 1 and 2/3 patients. The efficacy using a 24-week combination therapy in the sustained clearance of serum HCV RNA is equivalent to that using a 48-week combination therapy in patients with HCV genotype non-1 [Hadziyannis et al, EASL 2002]. A 48-week course of pegylated IFN and RBV combination therapy, in contrast, has been shown to yield a better efficacy in the sustained clearance of serum HCV RNA in patients with HCV genotype 1 than a 24-week combination therapy in western countries [Hadziyannis et al, EASL 2002; Poynard et al, 1998]. The primary objective of the current proposal is to investigate and compare the efficacy of combination therapy using pegylated IFN plus RBV on the clearance of serum HCV RNA in both dually infected patients with a dominant HCV infection and HCV monoinfected patients. Therefore, in this proposal, the treatment duration will be 24 weeks for HCV genotype 2/3 in patients with dual chronic hepatitis C and B and in patients with monoinfected HCV, and will be 48 weeks for HCV genotype 1 in patients with dual chronic hepatitis C and B and in patients with monoinfected HCV.

Clinical Trial Description

Around the world, the majority of hepatitis C patients suffer a monoinfected chronic HCV infection. Current regimen on this group of patients received much attention and resulted in rapid advances [McHutchison et al, 1998]. However, there are certain understudied populations with chronic hepatitis C [Strader DB, 2002]. One important group of them is the patients co-infected by HBV. In hepatitis B or C endemic areas, the number of subjects with dual infections of both hepatitis C and B is substantial [Chen et al, 1990; Tsai et al, 1994; Liaw 1995; Pramoolsinsap et al, 1999]. For example, in Taiwan, anti-HCV was present in 11% of patients with HBV-related chronic liver diseases [Chen et al 1990; Liaw 1995], and HBsAg positive rate was 12% in anti-HCV-positive patients [Tsai et al, 1994]. In Italy, the prevalence of anti-HCV positivity can be as high as 40% in patients with chronic active hepatitis B in some cities [Sagnelli et al, 1997]. Such co-infected patients are rarely encountered in the developed countries, except in intravenous drug users, hemophiliacs or those receiving hemodialysis. Alarmingly, the HCV- and HBV- coinfected patients have been shown to carry a greater risk (1.5~5 folds) of developing LC or HCC than those with HCV or HBV infection only [Liaw 1995; Donato et al, 1998; Yang et al, 2002; Sun et al, 2003]. Therefore, the HBV and HCV dually infected patients also need active treatments. Unfortunately, current therapeutic targets and ongoing protocols of clinical trials recruit patients with HCV infection only and invariably exclude those co-infected with HBV. Thus, it is warranted to address this important issue and an effective treatment for these hepatitis C and B dually infected patients is desperately needed.

Sporadic studies showed that IFN alone was not effective in clearing HCV or HBV in patients dually infected with hepatitis B and C [Liaw 1995; Liaw et al, 1997; Weltman et al, 1995; Mazzella et al, 1999; Guptan et al, 1999]. A recent study reported that dose augmentation of IFN to 9 MU thrice weekly for 6 months could clear HCV in 31% of the patients [Villa et al, 2001]. Apparently, the efficacy was still not adequate. Because combining IFN with RBV has been shown to yield much better results in the treatment of chronic hepatitis C than IFN alone [Poynard et al, 1995; Davis et al, 1998; Reichard et al, 1998; McHutchison et al, 1998; Lai et al, 1996; Liaw et al, 1997; Schalm et al, 1999], the combination therapy might also be more effective in treating dual hepatitis B and C patients. To test this, we conducted a pilot study using conventional IFN alfa plus ribavirin to treat 24 patients coinfected with HCV and HBV. The 24-week combination regimen with IFN and ribavirin cleared HCV in 43% (9/21) of the patients dually infected with hepatitis B and C. The result was comparable to that in patients with monoinfected chronic hepatitis C. Normalization of serum ALT was obtained in 38% of the patients 24 weeks after the end of the treatment. In addition, we found that although the end-of-treatment clearance rate of HCV RNA was comparable between patients infected with genotype 1b and those with genotype 2a or 2b, the clearance of HCV RNA sustained much less commonly in those infected by HCV genotype 1b (21% vs. 86%, P<0.05). Actually, two recent studies from southern Taiwan also demonstrated that the efficacy of combination therapy using interferon plus ribavirin on the clearance of serum HCV RNA was comparable between HBV and HCV coinfected patients versus HCV monoinfected patients [Wang et al., 2003; Yu et al., 2003]. Based on these findings, we suggested that comparable efficacy of combination therapy using interferon plus ribavirin on the clearance of serum HCV RNA can be achieved in patients with HBV and HCV coinfected patients versus HCV monoinfected patients. Nevertheless, a more effective regimen is still needed for those dually infected patients, particularly for those with HCV genotype 1.

In our pilot study, we treated 24 patients coinfected with HCV and HBV as a single group. The majority of these patients had detectable hepatitis C viremia, but were anti-HBe positive and with a lower serum HBV titer. Therefore, hepatitic activity was more likely due to HCV than to HBV. Nevertheless, a few patients were HBeAg positive and had a higher serum HBV titer (>105 copies/mL) but with a low or undetectable serum HCV RNA. In them, the hepatitis was likely due to active hepatitis B. Importantly; none of the dually infected patients with predominantly active hepatitis B had biochemical and HCV virologic response both at the end of combination therapy and at 24 weeks post-treatment follow-up. These two groups of patients may need different anti-viral regimens according to the major offending virus in the liver. To treat dual hepatitis C and B patients with dominantly active hepatitis C, we may use IFN (conventional or pegylated form) and RBV, and the treatment schedule may be extended to one year to enhance the efficacy for those with HCV genotype 1. However, to treat dually infected patients with a dominant HBV infection, the treatment strategy may be different.

Our pilot study indicates that HCV- and HBV-coinfected patients with predominantly active hepatitis C and those with predominantly active hepatitis B may need different anti-viral regimens. Since in the majority of these coinfected patients the hepatitis activity is more likely due to HCV than to HBV, the optimal therapeutic regimen for HCV- and HBV-coinfected patients with predominantly active hepatitis C will first be investigated. The combination therapy using pegylated IFNs such as PEG-IFN alfa-2a has been shown to have a superior efficacy than that using conventional IFN in the treatment of monoinfected chronic hepatitis C. This new combination therapy might also further enhance the treatment efficacy in HCV- and HBV- coinfected patients. We therefore propose to initiate a trial comparing the efficacy of pegylated IFN plus RBV in dual chronic hepatitis B and C vs. that in chronic hepatitis C only, for both HCV genotype 1 and 2/3 patients. The efficacy using a 24-week combination therapy in the sustained clearance of serum HCV RNA is equivalent to that using a 48-week combination therapy in patients with HCV genotype non-1 [Hadziyannis et al, EASL 2002]. A 48-week course of pegylated IFN and RBV combination therapy, in contrast, has been shown to yield a better efficacy in the sustained clearance of serum HCV RNA in patients with HCV genotype 1 than a 24-week combination therapy in western countries [Hadziyannis et al, EASL 2002; Poynard et al, 1998]. The primary objective of the current proposal is to investigate and compare the efficacy of combination therapy using pegylated IFN plus RBV on the clearance of serum HCV RNA in both dually infected patients with a dominant HCV infection and HCV monoinfected patients. Therefore, in this proposal, the treatment duration will be 24 weeks for HCV genotype 2/3 in patients with dual chronic hepatitis C and B and in patients with monoinfected HCV, and will be 48 weeks for HCV genotype 1 in patients with dual chronic hepatitis C and B and in patients with monoinfected HCV. ;

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

• NCT number: NCT00154869
• Study type: Interventional
• Source: National Taiwan University Hospital
• Contact: Pei-Jer Chen, M.D.; Ph.D.
• Phone: 886-2-23123456
• Email: peijer@ha.mc.ntu.edu.tw
• Status: Recruiting
• Phase: Phase 3
• Start date: June 2004
• Completion date: August 2007