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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00361179
First Posted: August 7, 2006
Last Update Posted: August 7, 2006
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Hoffmann-La Roche
Information provided by:
National Taiwan University Hospital
  Purpose

Chronic hepatitis C may relapse in simple chronic hepatitis C patients who initially obtained sustained virologic responses. Although the HCV SVR could be maintained in around 90%, the remaining 10% of these patients may develop hepatitis C relapse during follow-up. Therefore, it is important to follow up the long-term of these patients with dual chronic hepatitis B and C.

From another aspect, for the treatment of chronic hepatitis B, the virologic and serologic responses may also not be durable. Alternatively, previous studies suggested that the therapeutic efficacy might not be seen in the study period, and incremental response might occur during long-term follow-up. Therefore it is also important to clarify the long-term outcome of treatment in this dually infected population.

Evaluation of the long term effects of treatment with peginterferon alfa-2a plus ribavirin for patients with chronic hepatitis C/ hepatitis B co-Infection and chronic hepatitis C in the original study ML17862 is important. This present protocol is thus to assess whether the HCV SVR is sustained and to assess the durability of the HBV virologic and serologic responses or any incremental response during a 5-year follow-up period, including six months after end of the therapy in the original study and an additional 4 and half years in this project (5 years overall follow-up after the end of treatment). Specifically, we wish to assess the (1) sustained virologic response (SVR) of HCV in both populations, (2) incidence of HBsAg loss and HBsAg seroconversion (HBsAg loss and appearance of anti-HBs) in dually infected population, (3) ALT normalization or flare off-treatment during both populations, (4) reductions of HCV RNA from the original baseline levels in the two patient populations, and (5) reduction of serum HBV DNA off-treatment in the dually infected population.


Condition
Coinfection With Hepatitis B Virus and Hepatitis C Virus Monoinfection With Hepatitis C Virus

Study Type: Observational
Study Design: Observational Model: Defined Population
Observational Model: Natural History
Time Perspective: Longitudinal
Time Perspective: Prospective
Official Title: An Extension, Observational Protocol to Evaluate the Long Term Effects of Peginterferon Alfa-2a Plus Ribavirin for Chronic Hepatitis C/B Co-Infection and Chronic Hepatitis C in the Original Study ML17862

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Estimated Enrollment: 320
Study Start Date: May 2006
Estimated Study Completion Date: December 2011
  Hide Detailed Description

Detailed Description:

Pegylated IFNs (such as PEG-IFN alfa-2a, PEGASYS®) have been shown to possess a superior efficacy and convenience to conventional IFNs, either alone or in combination with RBV in patients with chronic hepatitis C only [Zeuzem et al, 2000; Heathcote et al, 2000; Fried et al, 2002; Hadziyannis et al, EASL 2002]. For patients with chronic hepatitis B, pilot study also revealed that the biochemical and virologic responses were better in HBeAg-positive patients receiving pegylated IFN than those receiving conventional IFN [24-week post-treatment combined virologic, HBeAg loss, and ALT normalization rate: 28% vs. 12%; Lai et al, APSAL 2002].

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 [SVR: 40~51% vs. 29~41%, Table 1, Hadziyannis et al, EASL 2002; Poynard et al, 1998]. Based on these findings, NIH Consensus Statement suggests that patients with genotype 1 need 48 weeks of combination treatment and standard doses of RBV [NIH 2002]. Previous study revealed that a 12-week RBV therapy was not effective for patients with chronic hepatitis B [Kakumu et al, 1993]. Therefore, in this proposal, the treatment duration will be 24 weeks for HCV genotype 2/3, and will be 48 weeks for HCV genotype 1, in patients with monoinfected chronic hepatitis C and dual chronic hepatitis C and B.

Increased RBV dosage has been considered as a contributory factor to the better efficacy in some previous studies. Recent studies suggested that using RBV 800 mg daily is adequate to treatment HCV genotype non-1 but standard dosage of RBV is required to treatment HCV genotype 1 [NIH 2002]. We follow the recommendations and use RBV 800 mg daily for HCV genotype non-1, both in dually infected patients and in monoinfected chronic hepatitis C patients. RBV with 1000-1200 mg daily will be used for HCV genotype 1 according the body weight of the patient, both in dually infected patients and in monoinfected chronic hepatitis C patients.

Previous studies suggested that chronic hepatitis C may relapse in simple chronic hepatitis C patients who initially obtained sustained virologic responses at 6 months after end of the treatment [Chemello et al, 1996; Marcellin et al, 1997]. Although the HCV SVR could be maintained in around 90%, the remaining 10% of these patients may develop hepatitis C relapse during follow-up. Chemello et al followed up 107 patients with chronic hepatitis C who maintained normal aminotransferase levels as long as 12 months after interferon-alpha therapy [Chemello et al, 1996]. Hepatitis C virus RNA was detected in 27 (25%) patients with sustained biochemical response; 80 (75%) patients were negative for HCV RNA. Patients positive for HCV RNA were older (P < 0.001), had received a smaller interferon-alpha dose (P = 0.02), and were more frequently infected with HCV genotype 2 (P < 0.01). Liver histologic findings were active in 57% of patients positive for HCV RNA, despite normal alanine aminotransferase levels, compared with only 12% of patients who were negative for HCV RNA (P = 0.01). The estimated probability of hepatitis relapse by 4 years after therapy was 53% in viremic patients and 0% in patients negative for HCV RNA (P < 0.001). Marcellin et al followed up 80 patients who had chronic hepatitis C and received interferon-alpha therapy [Marcellin et al, 1997]. The 80 patients had follow-up 1 to 7.6 years (mean +/- SD, 4.0 +/- 2.0 years) after interferon-alpha treatment. The follow-up period was 1, 2, 3, 4, 5, 6, and more than 6 years in 11, 13, 14, 18, 10, 12, and 2 patients, respectively, after the end of therapy. During the entire follow-up period, 93% (95% CI, 84% to 97%) of patients had persistently normal serum ALT levels. Serum HCV RNA remained undetectable in 96% (CI, 89% to 99%) of patients. A comparison of liver histologic findings before and 1 to 6.2 years after interferon-alpha treatment showed a clear improvement in 94% (CI, 83% to 99%) of patients. In 62% of patients, the last biopsy done showed normal or nearly normal histologic findings. Liver HCV RNA was detectable before treatment in all 13 patients tested and was undetectable 1 to 5 years after treatment in all 27 patients tested. They thus concluded that in patients with chronic hepatitis C who have persistently normal serum ALT levels and no detectable serum HCV RNA 6 months after interferon-alpha therapy, long-term sustained biochemical and virologic response is generally seen. Similar finding was noted in one reported case with dual chronic hepatitis B and C [Yalcin et al, 2003]. To be noted, this dually infected patient had reactivation of hepatitis B accompanied by severe flare of hepatitis activity during treatment and had relapse of hepatitis C after end of the treatment. Therefore, it is important to follow up the long-term of these patients with dual chronic hepatitis B and C.

From another aspect, for the treatment of chronic hepatitis B, the virologic and serologic responses may also not be durable [Liaw et al, 2005; Lok et al, 2004; Hadziyannis et al, 2003; Janssen et al, 2005]. Alternatively, previous studies suggested that the therapeutic efficacy might not be seen in the study period, and incremental response might occur during long-term follow-up as learned from previous experiences of using antiviral agents including interferon for the treatment of chronic hepatitis B [Saruc et al, 2003; Carreno et al, 2001]. Therefore it is also important to clarify the long-term outcome of treatment in this dually infected population.

This present protocol is thus to assess whether the HCV SVR is sustained and to assess the durability of the HBV virologic and serologic responses or any incremental response during a 5-year follow-up period, including six months after end of the therapy in the original study and an additional 4 and half years in this project (5 years overall follow-up after the end of treatment). Specifically, we wish to assess the (1) sustained virologic response (SVR) of HCV in both populations, (2) incidence of HBsAg loss and HBsAg seroconversion (HBsAg loss and appearance of anti-HBs) in dually infected population, (3) ALT normalization or flare off-treatment during both populations, (4) reductions of HCV RNA from the original baseline levels in the two patient populations, and (5) reduction of serum HBV DNA off-treatment in the dually infected population.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who were randomized, treated and returned for follow up in the ML17862 protocol will be eligible for inclusion in this protocol

Exclusion Criteria:

  • Patients unwilling to provide informed consent or abide by the requirements of the study.
  • Patients who have already initiated anti-HCV or HBV treatment, approved or investigational since completion of the original protocol
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00361179


Locations
China, Taiwan
Pei-Jer Chen
Taipei city, Taiwan, China, 100
Sponsors and Collaborators
National Taiwan University Hospital
Hoffmann-La Roche
Investigators
Principal Investigator: Pei-Jer Chen, M.D.; Ph.D. National Taiwan University Hospital
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00361179     History of Changes
Other Study ID Numbers: 9561706020
First Submitted: August 4, 2006
First Posted: August 7, 2006
Last Update Posted: August 7, 2006
Last Verified: August 2006

Keywords provided by National Taiwan University Hospital:
Observation
Post-treatment

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Hepatitis B
Hepatitis C, Chronic
Hepatitis, Viral, Human
Coinfection
Liver Diseases
Digestive System Diseases
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepadnaviridae Infections
DNA Virus Infections
Infection
Parasitic Diseases
Ribavirin
Peginterferon alfa-2a
Interferon-alpha
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs