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