subcutaneous continuous infusion of interferon alfa-2b and ribavirin in hepatitis c genotype 1 nonresponders

Conditions: Chronic Hepatitis C

Summary: for chronic hepatitis c patients unresponsive to previous (peg-)ifn/rbv combination therapy we propose continuous subcutaneous administration of high-dose ifn-a2b (intron a®) for 48 weeks in combination with 15 mg/kg/day rbv (rebetol®) and optimal management of side effects in order to maintain the highest possible dosages of both ifn-a2b and rbv for 48 weeks. we expect improved tolerability with continuous subcutaneous pump delivery of ifn-a2b compared to thrice weekly or daily subcutaneous injection of ifn-a2b, and increased antiviral activity and biologic potency due to sustained and higher levels of a fully potent interferon protein.


Eligibility criteria:
inclusion criteria: * hepatitis c genotype 1 unresponsive to (peg)interferon /ribavirin therapy * in the past, peginterferon or conventional interferon plus ribavirin combination therapy for at least 12 weeks and less than 2-log hcv rna decrease at week 12, hcv rna positivity at week 24, breakthrough during therapy or relapse after therapy * at least 12 weeks between end of (peg)interferon/ribavirin therapy and start of high-dose ifn/ribavirin therapy * persistent indication for antiviral therapy such as persistently elevated serum alt or histological evidence of continuing or progressive fibrosis * age 18-60 years exclusion criteria: * signs of progressive liver disease since end of previous therapy, beyond generally accepted criteria for hcv antiviral therapy: * serum bilirubin \>35 μmol/l, albumin \ 4 sec prolonged or platelets \<100,000/mm3 * decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, gastric bleeding, esophageal varices or encephalopathy) * hepatic imaging (us, ct or mri) with the evidence of hepatocellular carcinoma (hepatic imaging should be performed within 3 months prior to screening) or an alpha fetoprotein \>50 ng/ml * other acquired or inherited causes of liver disease that could explain liver disease activity * co-infection with hepatitis b virus or human immunodeficiency virus (hiv) * other significant medical illness that might interfere with this study: significant cardiovascular, pulmonary or renal dysfunction, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g.: hiv positivity, steroid therapy, organ transplants other than cornea and hair transplant) * history of a severe seizure disorder or current anticonvulsant use * history of thyroid disease poorly controlled on prescribed medications * contra-indications for ifn and/or ribavirin: * severe psychiatric disorder, such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression during previous (peg)interferon therapy. severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions. subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject's mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient's mental status during the study * reactivation of immunological disorders during previous therapy * visual symptoms related to retinal abnormalities * pregnancy, breast-feeding or inadequate contraception * thalassemia, spherocytosis * substance abuse, such as alcohol (³80 gm/day) and i.v. drugs. if the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 2 years * any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study

Keywords: genotype 1 nonresponders