pegylated interferon alfa-2b plus ribavirin in chronic hepatitis b and delta

Conditions: Chronic Hepatitis B; Chronic Hepatitis D

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.

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.

Eligibility 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 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

Keywords: chronic hepatitis b; chronic hepatitis delta; treatment; pegylated interferon alfa-2b; ribavirin