This study will evaluate the safety and effectiveness of a long-acting form of alpha interferon called pegylated interferon in treating hepatitis D virus (HDV) infection. HDV only infects people who already have hepatitis B infection. HDV is often severe and progressive. Alpha interferon is the standard treatment for HDV, given by injection once a day or three times a week for up to 12 months. However, this treatment does not work for everyone, and those who respond usually relapse when the drug is stopped. The sustained-release form of the drug, pegylated interferon, is given just once a week. Pegylated interferon is more effective than standard interferon in hepatitis C patients, with patients experiencing longer-term improvement. This study will evaluate the effects of pegylated interferon on hepatitis D and hepatitis B. It will determine whether long-term therapy with this drug improves inflammation and scarring of the liver, thereby delaying or reversing cirrhosis, and whether the improvement can be maintained.

Patients with chronic hepatitis D over 6 years old may be eligible for this study. Participants will have a medical evaluation, including a history and physical examination, blood tests, routine urinalysis and 24-hour urine collection. Chest X-ray, electrocardiogram, abdominal ultrasound and liver biopsy will be done if these tests have not been done within the last year. In addition, depending on their age and individual health status, some patients may have exercise stress testing, an eye examination, hearing test, and psychiatric consultation. All patients will fill out a health-related quality of life questionnaire.

Patients will receive pegylated interferon by injection once a week and have blood tests to measure the effects of treatment on the liver and on HBV and HDV levels. The medical examination and liver biopsy will be repeated at the end of 12 months. Patients who improved with treatment may continue therapy long-term. Medical evaluations and liver biopsies will be repeated at 3 years and at 5 years.

Condition	Treatment or Intervention	Phase
Hepatitis D	Drug: Peginterferon Alpha-2a	Phase II

Further Study Details: 

Expected Total Enrollment:  20

We propose to treat between 10 and 20 patients with chronic delta hepatitis with pegylated alpha interferon for up to five years. Patients with chronic delta hepatitis with raised serum aminotransferases, HBsAg and HDV RNA in serum, and moderate-to-severe chronic hepatitis on liver biopsy with HDV antigen will be enrolled. Patients will be monitored for at least three months with regular testing for ALT levels and will undergo admission for a thorough medical evaluation, portal pressure measurement and percutaneous liver biopsy before treatment. Pegylated interferon will then be started in a dose of 180 mcg weekly. At each clinic visit, patients will be questioned about side effects and symptoms and have blood taken for complete blood counts and routine liver test (ALT, AST, alkaline phosphatase, direct and total bilirubin, and albumin). At 12-24 week intervals patients will undergo a physical examination and be tested for HBsAg, anti-HBs, HDV RNA, and prothrombin time. The dose of pegylated interferon will be adjusted based upon side effects and changes in ALT levels, aiming for optimal suppression of ALT elevations with acceptable tolerance. At 48 weeks (one year) and every 96 weeks (two years) thereafter, patients will be readmitted to the NIH Clinical Center for repeat thorough medical evaluation, portal pressure measurement and liver biopsy. The Primary endpoint of therapy will be improvements in hepatic histology on liver biopsy done after 3 years of pegylated alpha interferon therapy. Several secondary endpoints will be measured, including changes in HDV RNA, loss of HBsAg, HDV staining in the liver biopsy, ALT levels, changes in portal pressures, quality of life, all at 1.3 and 5 years, and hepatic histology at 1 and 5 years. Patients will be maintained on pegylated interferon if it is adequately tolerated and there is an adequate "histological response," as defined by at least 3 point improvement in inflammatory score or 1 point improvement in fibrosis score of the HAI at each liver biopsy. Therapy will be stopped for: (1) intolerance to alpha interferon (which will be carefully defined), (2) lack of improvement in hepatic histology after 1, 3, or 5 years of therapy (histological nonresponse), or (3) a "complete response," i.e. loss of HDV RNA and HBsAg and development of anti-HBs.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA
Age greater than or equal to 18 years, male or female
Serum alanine or aspartate aminotransferase activities that are above the upper limit of normal (ALT greater than 41 or AST greater than 31 U/L) on an average of three determinations taken during the previous 6 months. The mean of the three determinations will be defined as 'baseline' levels.
Presence of anti-HDV in serum.
Evidence of chronic hepatitis on liver biopsy done within the previous 12 months with a necroinflammatory score in histology activity index of at least 5 (out of a maximum of 18) and at least 1 for hepatic fibrosis (out of a maximum of 6).
Presence of HDV antigen in liver tissue.
Written informed consent.
Previous standard alpha interferon or other antiviral activity will not exclude patients.
Active HBV replication will not exclude patients.
All ethnicities.
Patients will need to meet the first six entry criteria to enroll.
EXCLUSION CRITERIA
Decompensated liver disease, as marked by bilirubin greater than 4 mg%, albumin less than 3.0 gm%, prothrombin time greater than 2 sec prolonged, or history of bleeding esophageal varices, ascites or hepatic encephalopathy. Patients with ALT levels greater than 1000 U/L (greater than 25 times ULN) will not be enrolled but may be followed until three determinations are below this level.
Pregnancy or, in women of child-bearing potential or in spouses of such women, inability to practice adequate contraception defined as vasectomy in men, tubal ligation in women, or use of condoms and spermacide, or birth control pills, or an intrauterine device, or Depo-Provera, or Norplant.
Significant systemic or major illnesses other than liver disease, including, but not limited to, congestive heart failure, renal failure (creatinine clearance less than 50 ml/min), organ transplantation, serious psychiatric disease or depression (only if felt to be at high risk by the NIH psychiatric consultation service), and angina pectoris.
Immunosuppressive therapy within the last 6 months.
Evidence of another form of liver disease in addition to viral hepatitis (for example autoimmune liver disease, Wilson's disease, alcoholic liver disease, hemochromatosis, and alpha-1-antitrypsin deficiency).
Any evidence of coronary artery disease or cerebral vascular disease, including abnormalities on exercise stress testing in patients with defined risk factors who will be screened for evidence of underlying coronary artery disease.
Active substance abuse, such as alcohol, inhaled or injection drugs within the previous year.
Evidence of hepatocellular carcinoma; either alphafetoprotein (AFP) levels greater than 200 ng/ml (normal less than 9 ng/ml) and/or ultrasound (or other imaging study) demonstrating a mass suggestive of liver cancer.

Maryland
      National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  010247; 01-DK-0247
Record last reviewed:  July 2, 2004
Last Updated:  November 23, 2004
Record first received:  September 3, 2001
ClinicalTrials.gov Identifier:  NCT00023322
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08