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Viral Kinetics and Liver Gene Expression in Response to Ribavirin and Peginterferon Therapy of Chronic Hepatitis C

2014-09-19 13:53:23 | BioPortfolio

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.

Description

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 two groups; group A will undergo liver biopsy before starting peginterferon therapy and groups B will undergo biopsy 6 hours after the initial dose of 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). 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 log10 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 and gene expression studies assessing the effects of peginterferon on intrahepatic mRNA profiles by comparing Group A and B. 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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Hepatitis C, Chronic

Intervention

Liver Biopsy, Peginterferon & amp; Ribavirin for Hepatitis C, Pre-treatment Ribavirin

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda
Maryland
United States
20892

Status

Completed

Source

National Institutes of Health Clinical Center (CC)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-09-19T13:53:23-0400

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Medical and Biotech [MESH] Definitions

INFLAMMATION of the LIVER in humans due to infection by VIRUSES. There are several significant types of human viral hepatitis with infection caused by enteric-transmission (HEPATITIS A; HEPATITIS E) or blood transfusion (HEPATITIS B; HEPATITIS C; and HEPATITIS D).

INFLAMMATION of the LIVER in humans caused by HEPATITIS DELTA VIRUS, a defective RNA virus that can only infect HEPATITIS B patients. For its viral coating, hepatitis delta virus requires the HEPATITIS B SURFACE ANTIGENS produced by these patients. Hepatitis D can occur either concomitantly with (coinfection) or subsequent to (superinfection) hepatitis B infection. Similar to hepatitis B, it is primarily transmitted by parenteral exposure, such as transfusion of contaminated blood or blood products, but can also be transmitted via sexual or intimate personal contact.

INFLAMMATION of the LIVER in humans that is caused by HEPATITIS C VIRUS lasting six months or more. Chronic hepatitis C can lead to LIVER CIRRHOSIS.

A family of hepatotropic DNA viruses which contains double-stranded DNA genomes and causes hepatitis in humans and animals. There are two genera: AVIHEPADNAVIRUS and ORTHOHEPADNAVIRUS. Hepadnaviruses include HEPATITIS B VIRUS, duck hepatitis B virus (HEPATITIS B VIRUS, DUCK), heron hepatitis B virus, ground squirrel hepatitis virus, and woodchuck hepatitis B virus (HEPATITIS B VIRUS, WOODCHUCK).

INFLAMMATION of the LIVER in humans caused by HEPATITIS C VIRUS, a single-stranded RNA virus. Its incubation period is 30-90 days. Hepatitis C is transmitted primarily by contaminated blood parenterally, and is often associated with transfusion and intravenous drug abuse. However, in a significant number of cases, the source of hepatitis C infection is unknown.

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