Patterns of Early Hepatitis C Virus Decline Predict the Outcome of Interferon Therapy

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the outcome of interferon therapy on HCV infected patients can be early precisely predicted with a novel mathematic method with Chinese population.

Detailed Description
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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 6 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.

Official Title
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Study of Parameters of Early Hepatitis C Virus Dynamics for Predicting the Outcome of Standard Interferon Therapy With Chinese Cohort

Conditions
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Hepatitis

Intervention / Treatment
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* Drug: Interferon Alfa-2b, Ribavirin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Interferon and ribavirin<br>All the patients followed the standard treatment protocol. | Drug: Interferon Alfa-2b, Ribavirin<br>* 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.<br>* Other names: FDA Approval number:S20030032,H10940157;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood HCV RNA Copies | Blood HCV RNA copies were assayed with Roche - COBAS® AmpliPrep/COBAS® TaqMan® HCV Test. | 0h,8h,10h,12h,18h,24h,37h,43h,3d,7d,2w,4w,6w,12w,24w,48w | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IL-28B polymorphism | IL28 gene polymorphism,rs8099917,rs12979860,etc | Baseline | 
| Microarray Analysis of PBMC Gene Expression | During the first 3 days, blood samples are collected for PBMC separation and microarray analysis. | Baseline,8h,18h,3d | 
| HCV genotype | HCV NS5A is cloned into T vector and sequenced for evolutionary analysis. | Baseline | 
| Blood Anti-HCV,HBV Antibody | Co-infection status are analyzed. | Baseline | 
| HCV genome sequencing | Deep sequencing is used for blood serum HCV genome analysis. | 0h,8h,10h,12h,18h,24h,37h,43h,3d | 
| Alanine Aminotransferase (ALT) and Aspartate transaminase (AST) | ALT AST are assayed to detect the hepatic function. | Baseline,4w,6w,12w,24w,48w | 
| Fibrosis stage | Fibrosis is analyzed with Fibroscan. | Baseline,4w,12w,24w,48w | 
| Regular blood test | The distribution and absolute count of the different types of blood cells are assayed. | Baseline,4w,12w,24w,48w | 
| Electrocardiography | Electrocardiography is taken to avoid severe side effects. | Baseline,4w,12w,24w,48w | 
| Alcohol ,smoking condition | Patients are asked whether they take alcohol or smoke cigarettes during the therapy period. | Baseline,4w,12w,24w,48w | 
| Drug abuse history | Patients will be asked about their drug usage history. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV dynamics, Mathematical model, Interferon, Predict, Hepatitis C Virus