Patterns of Early Hepatitis C Virus Decline Predict the Outcome of Interferon Therapy (sIFN-pred2) (sIFN-pred2)

Study of Parameters of Early Hepatitis C Virus Dynamics for Predicting the Outcome of Standard Interferon Therapy With Chinese Cohort (Second Phase)

The purpose of this study is to validate the first round HCV early dynamics discovery within a larger population.

Study Overview

• Status: Unknown
• Conditions: Liver Diseases; Hepatitis C, Chronic; Interferon Deficiency
• Intervention / Treatment: Drug: interferon alpha 2b

Detailed Description

Hepatitis C virus (HCV) infection rate in China is about 3%, which means about 30 million patients. Combination therapy of ribavirin and interferons (IFN) is the standard clinical treatment of HCV chronical infections. However, overall rate of sustained virological response (SVR) still do not exceed 60% even with ribavirin and peg-IFN. Due to several virus- and patient-related factors, treatment is even less successful in certain populations, especially in HCV genotype 1 infection. Thus the standard therapy duration is optimized according to the virus genotype in the clinical practice. Nowadays, two direct antiviral agents (DAAs) have been approved by Food and Drug Administration (FDA) of USA this year, which increases the SVR rate. However, high price, side effects and long duration render people to hesitate about the addition of the third drug in the traditional prescription.

Predicting the outcome of traditional therapy is the cornerstone of the personalized therapy for HCV infected patients. In order to obtain an accurate prediction, different methods have been tried. Several indicators have been suggested to predict the final treatment outcomes. Rapid Virus Response (RVR), which indicates the non-detectable virus at the forth week since therapy starts, has been used to predict the final treatment outcome.Other indicators, including virus genotype, host genotype of IL-28B, human race and interferon stimulated genes (ISG) expression have also been shown to relate to and be able to predict the treatment outcomes to some extent. Here the investigators propose that the HCV virus dynamics analysis will give a more precise prediction for the therapy outcome.

The general idea is that blood HCV titration data is obtained continuously in the early treatment period (first 2 weeks) of the patients who have strictly followed the therapy method. These titration data will be used to draw virus dynamics curve and calculate the corresponding parameters individually. The parameter(s) that can distinguish patients who reach the therapy evaluation standard from those who failed to reach the evaluation standard will be selected out, and such parameter(s) may be used to predict the therapy outcome of a new patient in the early stage of his/her treatment.

• Study Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

Study Locations

• China
  • Jilin
    • Changchun, Jilin, China, 130061
      • Recruiting
      • First Hospital Jilin University
      • Contact: Yu Pan, PhD/MD; Phone Number: 0431-88782120; Email: panyu20000@yahoo.com.cn
      • Contact: Xiumei Chi, PhD/MD; Phone Number: 0431-88782222; Email: xiumeichi@hotmail.com
      • Principal Investigator: Yu Pan, PhD/MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients are from the northeast of China. Most of the patients have been infected by the hepatitis c virus due to the drug abuse. Many of them share the same syringe for drug intravenous injection. However, HIV infection has been rarely detected.

Description

Inclusion Criteria:

• Serologic evidence of chronic hepatitis C infection by an anti-HCV antibody test
• Serum HCV-RNA > 3 log IU/ml
• Has been infected by HCV for more than 6 months
• ALT,AST have been elevated continuously, inflammation and necrosis have been observed according to the histology diagnosis (G>=2),modest liver fibrosis (S>=2)For those patients whose ALT are normal,treatment accord to the liver biopsy. If obvious fibrosis has been detected (S2,S3),treatment should be done.For those S0,S1 stage patients, treatment could be delayed, but ALT/AST should be assayed every 3-6 months.
• Compensated liver disease
• Patients have never been treated with traditional interferon plus ribavirin or peginterferon plus ribavirin

Exclusion Criteria:

-

History:

• Has history of decompensated liver diseases
• Has been treated with other anti-virus drugs,or anti-tumor drugs,immuno-suppression drugs
• Has a history of autoimmune hepatitis
• History of a severe seizure disorder or current anticonvulsant use
• History or other evidence of a medical condition associated with chronic liver disease other than HCV which would make the patient, in the opinion of the investigator, unsuitable for the study (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures)
• Patients with documented or presumed coronary artery disease or cerebrovascular disease should not be enrolled if, in the judgment of the investigator, an acute decrease in hemoglobin by up to 4g/dL (as may be seen with ribavirin therapy) would not be well-tolerated
• History of thyroid disease poorly controlled on prescribed medications, elevated thyroid stimulating hormone (TSH) concentrations with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease

Current condition:

• Pregnant women or women during the lactation period
• Co-infected with hepatitis b virus or human immunodeficiency virus
• Liver cancer or alpha-fetoprotein > 100ng/ml
• Blood neutrophils count < 1500/mm3, or platelets count < 90000/mm3
• Female hemoglobin <11.5g/dL, male hemoglobin <12.5g/dL
• Blood creatinine > 1.5 ULN
• Have severe mental diseases,especially depression
• Severe pulmonary dysfunction
• Severe cardiovascular disease
• Uncontrolled diabetes
• Uncontrolled thalassemia
• Evidence of alcohol abuse (alcohol consumption>40 g/day)
• Unwillingness to provide informed consent or abide by the requirements of the study
• Local or System malignancy unstable status

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Interferon and ribavirin; All the patients followed the standard treatment protocol.

Drug: interferon alpha 2b; Interferon:dosage,5 million units/person;frequency,every other day (qod);duration,48 weeks;Subcutaneous injection. Ribavirin: dosage,15mg/kg/day;frequency,three times a day (t.i.d);duration,48 weeks;take orally.; Other Names: Other Names:IFN+Ribavirin; Generic: Recombinant Human Interferon alpha-2b,Ribavirin; Brand: Kaiyinyisheng,Weilake; FDA Approval number:S20030032,H10940157

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Blood HCV RNA Copies at designed time points	Blood HCV RNA copies were assayed with Roche - COBAS® AmpliPrep/COBAS® TaqMan® HCV Test.	0hr,24hr,1wk,2wk,4wk,6wk,12wk,24wk,48wk,72wk

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HCV genotype	HCV NS5A is cloned into T vector and sequenced for evolutionary analysis.	Baseline
Drug abuse history	Patients will be asked about their drug usage history.	Baseline
IL-28B polymorphism	IL28 gene polymorphism,rs8099917,rs12979860,etc	Baseline
Alanine Aminotransferase (ALT) and Aspartate transaminase (AST)	ALT AST are assayed to detect the hepatic function.	Baseline,4wk,12wk,24wk,48wk
Fibrosis stage	Fibrosis is analyzed with Fibroscan.	Baseline,4wk,12wk,24wk,48wk
Regular blood test	The distribution and absolute count of the different types of blood cells are assayed.	Baseline,4wk,12wk,24wk,48wk
Electrocardiography	Electrocardiography is taken to avoid severe side effects.	Baseline,4wk,12wk,24wk,48wk
Alcohol ,smoking condition	Patients are asked whether they take alcohol or smoke cigarettes during the therapy period.	Baseline,4wk,12wk,24wk,48wk

Collaborators and Investigators

• Sponsor: Junqi Niu
• Collaborators: Chinese Academy of Sciences
• Investigators: Study Chair: Bing Sun, Doctor, Chinese Academy of Sciences; Study Director: Chen Yang, Doctor, Chinese Academy of Sciences

Publications and helpful links

General Publications

• Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001 Sep 22;358(9286):958-65. doi: 10.1016/s0140-6736(01)06102-5.
• Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998 Oct 2;282(5386):103-7. doi: 10.1126/science.282.5386.103.
• Dahari H, Ribeiro RM, Perelson AS. Triphasic decline of hepatitis C virus RNA during antiviral therapy. Hepatology. 2007 Jul;46(1):16-21. doi: 10.1002/hep.21657.
• Snoeck E, Chanu P, Lavielle M, Jacqmin P, Jonsson EN, Jorga K, Goggin T, Grippo J, Jumbe NL, Frey N. A comprehensive hepatitis C viral kinetic model explaining cure. Clin Pharmacol Ther. 2010 Jun;87(6):706-13. doi: 10.1038/clpt.2010.35. Epub 2010 May 12.
• Dixit NM, Layden-Almer JE, Layden TJ, Perelson AS. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature. 2004 Dec 16;432(7019):922-4. doi: 10.1038/nature03153.
• Dill MT, Duong FH, Vogt JE, Bibert S, Bochud PY, Terracciano L, Papassotiropoulos A, Roth V, Heim MH. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology. 2011 Mar;140(3):1021-31. doi: 10.1053/j.gastro.2010.11.039. Epub 2010 Nov 25.
• Araujo ES, Dahari H, Neumann AU, de Paula Cavalheiro N, Melo CE, de Melo ES, Layden TJ, Cotler SJ, Barone AA. Very early prediction of response to HCV treatment with PEG-IFN-alfa-2a and ribavirin in HIV/HCV-coinfected patients. J Viral Hepat. 2011 Apr;18(4):e52-60. doi: 10.1111/j.1365-2893.2010.01358.x.

Helpful Links

• Hospital's homepage
• Cooperator's homepage
• The software used
• Coperator's Homepage
• Homepage of Jilin University

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Anticipated): February 1, 2014
• Study Completion (Anticipated): March 1, 2014

Study Registration Dates

• First Submitted: September 8, 2012
• First Submitted That Met QC Criteria: January 1, 2013
• First Posted (Estimate): January 4, 2013

Study Record Updates

• Last Update Posted (Estimate): January 4, 2013
• Last Update Submitted That Met QC Criteria: January 1, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: HCV; Hepatitis C Virus; Interferon; Prediction; SVR; Sustained Virus Response
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Liver Diseases; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Interferons; Interferon-alpha; Ribavirin; Interferon alpha-2
• Other Study ID Numbers: 2012ZX10002007; 2009ZX10004-105-jida02 (Other Grant/Funding Number: Ministry of Science and Technology); 2008ZX10002-014-jida02 (Other Grant/Funding Number: Ministry of Science and Technology)