Genetic Study of Peginterferon Treatment in Hepatitis B Patients: The GIANT-B Study
Background and rationale Chronic hepatitis B is the most common cause of liver cirrhosis and hepatocellular carcinoma worldwide.(1) Antiviral therapy with oral nucleoside analogs and interferon can reduce viral load and hepatic necroinflammation, and may reduce the risk of hepatocellular carcinoma and cirrhotic complications. (2-4) Peginterferon has both direct antiviral and immunomodulatory effects. The advantages of this drug include a finite course of treatment and the lack of drug resistance. However, it requires subcutaneous injections and carries some side effects. Besides, only 30% to 40% of treated patients have sustained response to treatment.(5-8) To reduce the costs and side effects of treatment, it is important to predict if a patient will respond to peginterferon. Genetic host studies on peginterferon response will provide a lot of knowledge on the interaction between the host and the virus to induce immune control, also outside the setting of immune modifying therapy. Recently, genome wide association studies (GWAS) identified genetic polymorphisms of the IL28B gene that were shown to be associated with treatment response to interferon and ribavirin in patients with chronic hepatitis C.(9-12) The same polymorphisms are also associated with natural clearance of hepatitis C virus. Whether the same phenomenon applies to patients with chronic hepatitis B is unclear. Furthermore, response to conventional interferon has shown to decrease the risk of hepatocellular carcinoma and to prolong survival.(13) Virological and serological response to PEG-IFN is durable in a substantial proportion of patients through 3 years of follow-up (14), but whether treatment benefits are sustained after that period and amount to clinically meaningful results is unknown. To date, a GWAS to predict the response to peginterferon in chronic hepatitis B patients has not been performed. Polymorphisms in genes such as IL28B can be identified through a GWAS and can be used to assess the chance of response to treatment and select patients who have a high probability of response to peginterferon.
We aim to perform a GWAS in chronic hepatitis B patients previously treated with peginterferon to identify polymorphisms in genes that are associated with response to this treatment regimen.
Chronic Hepatitis B
|Study Design:||Observational Model: Cohort
Time Perspective: Retrospective
|Official Title:||Genetic Study of Peginterferon Treatment in Hepatitis B Patients: The GIANT-B Study|
- Response to (PEG)IFN in relation to single-nucleotide polymorphisms identified by a GWAS [ Time Frame: 24 weeks off-treatment ] [ Designated as safety issue: No ]
HBeAg-positive patients: HBV DNA <2000IU/ml and HBeAg seroconversion; 24 weeks off-treatment.
HBeAg-negative patients: HBV DNA <2000IU/ml
- Response [ Time Frame: 24 weeks off-treatment ] [ Designated as safety issue: No ]HBV DNA <20IU/ml for both HBeAg positives as negatives sustainability of HBeAg seroconversion or HBeAg loss(only HBeAg+ patients) HBsAg loss and seroconversion, ALT normalization, data on survival, incidence of cirrhosis, hepatocellular carcinoma and liver transplantation.
|Study Start Date:||May 2010|
|Estimated Study Completion Date:||March 2015|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Patients who are treated for at least 12 weeks with (peg-)interferon for chronic hepatitis B
For the GWAS stage of this study, a cohort study will be conducted comparing hepatitis B patients with a response (see definitions below) versus patients who did not achieve a response to (peg)interferon treatment. Replication of SNPs identified by the GWAS will be performed in an independent cohort of patients with similar characteristics, treated with (peg)interferon. A large independent cohort of peginterferon treated HBV patients has already been identified guaranteeing a replication cohort.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01401400
|Erasmus Medical Centre|
|Rotterdam, Zuid-Holland, Netherlands, 3015 GE|
|Principal Investigator:||Harry LA Janssen, MD PhD||Foundation of Liver research (SLO), Rotterdam AND UHN liver clininc, Toronto Western & General Hospital|
|Study Chair:||Pietro Lampertico, MD PhD||IRCCS Ca' Granda, Ospedale Maggiore Policlinico, University of Milan|
|Study Chair:||Henry Chan, MD||The Chinese University of Hong Kong, Department of Medicine and Therapeutics|
|Study Chair:||Jin-Lin Hou, MD PhD||Nanfang Hospital, Southern Medical University, Hepatology Unit and Dept of Infectious Diseases|