Pegylated Interferon Alfa-2b Plus Ribavirin in Chronic Hepatitis B and Delta

Chronic Hepatitis B Clinical Trial

Official title:

A Pilot Study to Evaluate the Efficacy and Safety of Pegylated Interferon Alfa-2b Plus Ribavirin in the Treatment of Patients With Dual Chronic Hepatitis B and Delta

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00117533
• Other study ID #: 930904
• Status: Recruiting
• Phase: Phase 4
• First received: June 30, 2005
• Last updated: May 24, 2006
• Start date: September 2005
• Est. completion date: June 2007

Study information

• Verified date: September 2005
• Source: National Taiwan University Hospital
• Contact: Pei-Jer Chen, M.D., Ph.D.
• Phone: 886-2-23123456
• Email: peijer[@]ha.mc.ntu.edu.tw
• Is FDA regulated: No
• Health authority: Taiwan: Department of Health
• Study type: Interventional

Clinical Trial Summary

The treatment of choice for chronic hepatitis D is uncertain. The investigators hypothesize that pegylated interferon (IFN) alfa-2b in combination with ribavirin (RBV) may be effective in the treatment of chronic hepatitis D patients who are also infected by hepatitis B virus (HBV). The purpose of this study is to test this hypothesis. The investigators will use pegylated IFN alfa-2b in combination with RBV for the treatment of patients with dual chronic hepatitis D virus (HDV) and HBV infection. A 24-week course of combination therapy pegylated IFN+RBV will be used.

Description:

Recombinant IFN alfa possesses anti-viral and immunomodulatory effects and has been shown to be effective in chronic hepatitis B [Davis et al. 1989; Bisceclie et al, 1989]. Interferon alfa is also one of the approved treatments for chronic hepatitis B. Administration of IFN alfa-2b to adults leads to disappearance of HBV DNA with or without HBeAg seroconversion in 30-50% of patients, which is two to three times above the rate of yearly spontaneous HBeAg seroconversion (10-15%). Normalization of serum ALT occurs in most cases. Loss of HBsAg is observed in 10-15% of Caucasian patients during the prolonged post-treatment follow-up period. Recently, studies suggested that a higher proportion of patients receiving pegylated IFN could achieve HBeAg seroconversion and control of HBV replication [Marcellin et al, 2004; Lau et al, 2004; Jensen et al, 2004].

RBV is another antiviral nucleotide analogue with few adverse effects [Sidwell et al, 1972; Patterson et al, 1990]. RBV alone can modestly inhibit HDV or HBV replication [Choi et al, 1989]. The beneficial effect of combined IFN plus RBV in the treatment of chronic hepatitis B has also been shown in previous studies [Cotonat et al, 2000]. Why RBV can greatly enhance the treatment efficacy is not clear. It had been shown that ribavirin could inhibit interleukin-4, an inhibitor of cytotoxic T lymphocyte activity, and preserves the interleukin-2 and gamma IFN activities. Other studies revealed that the enhanced efficacy was associated with HBV- or other virus-specific type 1 cytokine-mediated T helper cell responses [Cramp et al, 2000; Tam et al, 1999; Hultgren et al, 1998; Fang et al, 2002; Fang et al, 2000; Rico et al, 2001]. Thus, the combination therapy may augment virus-specific cytotoxic T lymphocytes and non-specific immune response, and effectively shift the immune responses to the more potent antiviral type 1 T-helper profile [Hultgren et al, 1998].

HDV, like HCV, is a RNA virus. Indeed, RBV had also been shown to be active against HDV replication in cell cultures [Choi et al, 1989]. The investigators therefore hypothesize that pegylated IFN alfa-2b in combination with RBV can yield an efficacy in chronic hepatitis D patients who are dually infected by HBV. The purpose of this protocol is to test this hypothesis. A previous study found that high-dose IFN may improve the efficacy for chronic hepatitis D patients. Another pilot study using IFN alfa plus RBV also demonstrated that the seroclearance of HCV RNA was not affected by HBV coinfection [Liu et al, 2003]. The investigators thus use pegylated IFN alfa-2b in combination with RBV for the treatment of patients with dual chronic HDV and HBV infection.

The treatment choice for chronic hepatitis D was not clarified till now. In this proposal, the dosage and duration for the combination regimen are decided mainly by the experience from the treatment of chronic hepatitis B and chronic hepatitis C.

The investigators recent study using ribavirin and interferon (IFN) combination therapy for dual chronic hepatitis B and C suggested that combining ribavirin 1,200 mg daily for 6 months, together with 6 million units (MU) IFN-alpha 2a thrice weekly for 12 weeks and then 3 MU for another 12 weeks was effective for the clearance of HCV RNA [Liu et al, 2003]. Twenty-four patients with chronic hepatitis seropositive for both hepatitis B surface antigen and antibody to HCV received ribavirin 1,200 mg daily for 6 months, together with 6 million units (MU) IFN-alpha 2a thrice weekly for 12 weeks and then 3 MU for another 12 weeks. The serum HCV clearance rate was 43% 24 weeks posttreatment. The serum ALT normalization rate was 43% 24 weeks posttreatment. In hepatitis B and C dually infected patients, combination IFN with ribavirin can achieve a sustained HCV clearance rate comparable with hepatitis C alone. Furthermore, a previous study revealed that a 12-week RBV therapy was not effective for patients with chronic hepatitis B [Kakumu et al, 1993]. Therefore, a 24-week course of combination therapy pegylated IFN+RBV will be used.

Increased RBV dosage has been considered a contributory factor to the better efficacy in treating refractory genotype HCV. For example, recent studies suggested that using RBV 800 mg daily is adequate to treat HCV genotype non-1 while the standard dosage of RBV is required to treat HCV genotype 1 [NIH 2002]. The investigators thus propose to use RBV 1000-1200 mg daily according to the body weight of the patient.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: June 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Be positive for both anti-HDV and HBsAg for more than 6 months

• Present with elevated serum ALT levels at least 1.5 times the upper limit of normal, documented on two occasions (at least one month apart), within six months prior to enrollment

• Be HDV RNA positive by PCR (sensitivity: 103 copies/mL) [Yamashiro et al, 2004]

• Be HBV DNA positive by PCR

• Present with liver biopsy findings compatible with the diagnosis of chronic liver disease (the liver biopsy needs to be taken within 52 weeks prior to enrollment)

• Have adequate liver reserve (defined as equal to or better than Child-Pugh Class A)

• Present with WBC =3000/mm3, ANC =1500/mm3, and platelet =80,000/mm3

• Be able to and likely to attend regularly for treatment and follow-up

• Give their written informed consent

• Be negative for urine pregnancy test (for females of childbearing potential), documented once within the screening period and again within 24 hours prior to the first dose of study drug

• All male patients with female partners of childbearing age should use a barrier method of contraception

• All female patients of childbearing potential must use two reliable forms of effective contraception

Exclusion Criteria:

• Drug addicts or have any history or histological evidence of alcohol abuse, or currently receive prescriptions that may cause hepatotoxicity

• Have decompensated cirrhosis as coded by Child-Pugh classification (i.e. history of ascites, history of bleeding from esophageal varices, severe portal hypertension, serum albumin <30 g/l, serum bilirubin >30 mg/l)

• Present with WBC <3000/mm3, ANC <1500/mm3, or platelets <90,000/mm3

• Present with hemoglobin <12.0 gm/dl for female and <13.0 gm/dl for male

• Have been treated with immunosuppressive therapy within the past six months (e.g. steroids, azathioprine, cyclophosphamide)

• Have renal insufficiency (serum creatinine >150 µmol/l)

• Have clotting abnormalities which preclude a liver biopsy

• Have evidence of any serious neurological dysfunction

• Have obesity or diabetes mellitus-induced liver disease

• Have serological evidence of autoimmune chronic liver disease (e.g. antinuclear antibody titers >1:320, and/or smooth muscle antibody titers>1:160)

• Hemophiliacs

• Have evidence of inheritable disorders such as haemochromatosis, alpha-1-antitrypsin deficiency or Wilson's disease

• Have been exposed to hepatotoxic substances which might be the cause of hepatitis

• Pregnant, lactating or not practicing an adequate form of birth control, such as oral contraceptives or intrauterine devices

• Seropositive for anti-HIV or anti-HCV

• Have serious psychological or psychiatric problems disrupting daily activities

• Have AFP (alpha-fetoprotein) greater than 20 ng/ml; in case of elevated AFP, abdomen ultrasonography is required to exclude the possibility of HCC

• Have serious heart diseases (coronary heart disease, etc)

• Have a history of asthma or drug allergy which may lead to hypersensitivity to ribavirin

Study Design

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

Related Conditions & MeSH terms

• Chronic Hepatitis B
• Chronic Hepatitis D
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis D
• Hepatitis D, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• pegylated IFN alfa-2b plus ribavirin

Locations

Country	Name	City	State
Taiwan	National Taiwan University	Taipei
Taiwan	National Taiwan University Hospital	Taipei

Sponsors (3)

Lead Sponsor	Collaborator
National Taiwan University Hospital	National Health Research Institutes, Taiwan, National Science Council, Taiwan

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the efficacy of 24-week pegylated IFN alfa-2b plus RBV for SVR of HDV in patients with dual chronic hepatitis D and B
Secondary	the efficacy of pegylated IFN alfa-2b plus RBV in patients with dual chronic hepatitis D and B on: The biochemical response rate
Secondary	The degree of histologic change