Viral Kinetics and Liver Gene Expression in Response to Ribavirin and Peginterferon Therapy of Chronic Hepatitis C
Status:
Completed
Trial end date:
2014-08-19
Target enrollment:
Participant gender:
Summary
Up to 120 patients with chronic hepatitis C will be enrolled in a study of viral kinetics and
liver gene expression before and during combination therapy with peginterferon and ribavirin.
Adult patients with chronic hepatitis C virus (HCV) infection who have compensated liver
disease and have not received interferon in the past will be randomized into one of four
groups. Groups A and C will undergo liver biopsy before starting peginterferon therapy and
Groups B and D will undergo biopsy 6 hours after the initial dose of peginterferon.
Furthermore, Groups C and D will receive a run-in period of 4 weeks of ribavirin therapy
before starting peginterferon. All patients will receive the standard recommended doses of
peginterferon alfa 2a (180 mcg sc weekly) and ribavirin (1000 or 1200 mg daily for genotypes
1, 4-6 and 800 mg daily for genotype 2 and 3) for up to 48 weeks (24 weeks for genotype 2 and
3). All patients in Groups C and D, irrespective of genotype, will be pretreated with
ribavirin at a dose of 1000 or 1200 mg, depending on patient body-weight. After the initial
peginterferon injection, patients will have blood taken and symptoms recorded at 6, 24, 48,
72 hours and weekly thereafter for four weeks to assess viral kinetic response. Liver biopsy
tissue taken before or 6 hours after the initial dose of peginterferon will be assessed by
standard light microscopy and also subjected to RNA extraction and microarray analysis of
mRNA expression. Patients will be monitored carefully during therapy and tested regularly for
HCV RNA levels. Therapy will be given for 48 weeks, but will be discontinued early for
patients with genotype 1 infection if HCV RNA levels do not decline by at least 2 log IU/ml
by week 12 (lack of an early virological response) or do not decline to undetectable levels
by week 24 (lack of HCV RNA clearance). Patients with other genotypes with be treated for a
full course of therapy regardless of early responses. After completing therapy, patients will
be followed at 4 to 8 week intervals and undergo repeat medical evaluation with liver biopsy
24 weeks after stopping therapy.
The primary clinical criterion for success of therapy is a sustained virological response, as
marked by the absence of HCV RNA from serum at least 24 weeks after stopping. The focus of
this study, however, will be on viral kinetics comparing patients who were pretreated with
ribavirin (Groups C and D) to those who were not (Groups A and B) as well as on gene
expression studies assessing the effects of peginterferon on intrahepatic mRNA profiles by
comparing Group A and B and the effects of ribavirin by comparing Group A to Group C and
Group B to Group D. Results will also be compared between different HCV genotypes. These
studies are aimed at assessing the mechanisms of action of peginterferon and ribavirin
against HCV and evaluating the basis for the lack of virologic response to combination
therapy.
Phase:
Phase 1
Details
Lead Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)