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.

Condition	Intervention	Phase
Chronic Hepatitis B Chronic Hepatitis D	Drug: pegylated IFN alfa-2b plus ribavirin	Phase II Phase III

Further Study Details: 

Primary Outcomes: 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 Outcomes: the efficacy of pegylated IFN alfa-2b plus RBV in patients with dual chronic hepatitis D and B on: 1) The biochemical response rate; 2) The degree of histologic change
Expected Total Enrollment:  20

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.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

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

Please refer to this study by ClinicalTrials.gov identifier  NCT00117533

Pei-Jer Chen, M.D., Ph.D.      886-2-23123456  Ext. 7072    peijer@ha.mc.ntu.edu.tw

Taiwan
      National Taiwan University, Taipei,  100,  Taiwan
      National Taiwan University Hospital, Taipei,  100,  Taiwan

Study chairs or principal investigators

Pei-Jer Chen, M.D., Ph.D.,  Principal Investigator,  National Taiwan University Hospital   

Study ID Numbers:  931110
Record last reviewed:  June 2005
Last Updated:  July 25, 2005
Record first received:  July 6, 2005
ClinicalTrials.gov Identifier:  NCT00117533
Health Authority: Taiwan: Department of Health
ClinicalTrials.gov processed this record on 2005-07-26