The Regression of Liver Fibrosis and Risk for Hepatocellular Carcinoma (ROLFH) Study

Study Overview
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Brief Summary
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This study aims to demonstrate that patients with chronic hepatitis C (CHC) and B (CHB) experiencing regression of liver cirrhosis after effective antiviral therapy have decreased risk for hepatocellular carcinoma (HCC). Primary aim is to determine the incidence of HCC in patients with cirrhosis secondary to CHC and CHB, after treatment is provided, and to identify the magnitude of the decreased risk for HCC in patients experiencing regression of fibrosis. As a secondary aim, environmental risk factors for HCC development will be sought, in order to determine a subset of patients in whom it will be safe to stop surveillance.

Detailed Description
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Cirrhosis is the final pathway of chronic liver disease, and up to 30% of patients develop hepatocellular carcinoma (HCC) within 5 years of diagnosis of cirrhosis. Worldwide, chronic hepatitis C (CHC) and B (CHB) account for the majority of cases of cirrhosis. Successful antiviral treatment results in regression of fibrosis in the majority of patients. Surveillance programs for early detection of HCC mandate the use of imaging (ultrasound/CT-scan) every 6 months. It has been shown in CHC and CHB that the risk of HCC is greatly reduced after viral disease is eradicated/inactive. However, the impact that regression of fibrosis and other factors could have in abating the incidence of HCC has not been systematically investigated. Currently, all patients with eradicated/inactive viral disease continue to be enrolled in HCC surveillance programs, generating anxiety in patients and very high costs to our healthcare system. Fibrotest (FT) and transient elastography (TE) are noninvasive tools proven to be useful for serial assessment of liver fibrosis. OBJECTIVES: The proposed hypothesis is that patients with regression of liver fibrosis have decreased risk for HCC. Primary aim is to determine the incidence of HCC in patients with cirrhosis secondary to CHC and CHB, during the 3-7 years after treatment is provided, and to identify the magnitude of the decreased risk for HCC in patients experiencing regression of fibrosis. As a secondary aim, environmental risk factors for HCC development will be sought, in order to determine a subset of patients in whom it will be safe to stop surveillance. METHODS: Patients 18-70 year-old with cirrhosis will be identified from hepatology clinics in 4 academic centers in North America. FT/TE will be obtained before the start of antivirals and yearly thereafter (prospective arm). A retrolective arm of all patients treated no earlier than Jan/2009 will also be included. In this group, baseline FT/TE will be performed off treatment (CHC) or after initial phase of therapy (CHB), and yearly thereafter. During baseline and yearly visits other factors possibly affecting HCC development will be investigated (family history, comorbidities, BMI, diet, etc.). Patients will be classified as having or having not undergone regression of fibrosis after a 3-year follow up, depending on FT and TE evolution. During follow up, all patients will undergo 6-month imaging as part of their routine HCC surveillance. Based on power calculations, enrollment should stop after 924 patients have been recruited. Kaplan-Meier and Cox regression models will be used to analyze data. PATIENT OUTCOMES: ROLFH study uses state-of-the-art noninvasive markers of liver fibrosis to test whether reversed fibrosis decreases the risk of HCC. We believe this study will lead to a better understanding of HCC risk factors, improved patient counseling and decision making, optimized screening and allocation of health resources, and decreased healthcare costs.

Official Title
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The Regression of Liver Fibrosis and Risk for Hepatocellular Carcinoma (ROLFH) Study

Conditions
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Chronic Hepatitis C, Chronic Hepatitis B

Intervention / Treatment
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* Other: Regression of fibrosis
* Other: Specific risk factors related to hepatocellular carcinoma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 Chronic liver disease due to CHC or CHB. Starting of disease-specific treatment no earlier than January of 2010. Treatment could consist of: combination therapy with peginterferon and ribavirin, with or without a direct-acting viral agent in CHC; single or combination therapy containing peginterferon, entecavir, or tenofovir in CHB. Established cirrhosis on liver biopsy (METAVIR F4) obtained before starting disease-specific treatment. In patients without liver biopsy, any of the following criteria will be used as a surrogate to define cirrhosis: History of spleen >13 cm, bilirubin >2, albumin <3.5, INR >1.5 (2 of 3 criteria). History of APRI ([AST/ULN]/platelets x 100) >2, and esophageal varices or ascites. History of Fibrotest/Fibrosure >0.74, and TE >12.5 kPa (M-probe) or >10 kPa (XL-probe). Exclusion Criteria: Known diagnosis of hepatocellular carcinoma or portal vein thrombosis Conditions limiting Fibrotest/Fibrosure read: hemolysis, Gilbert's syndrome, autoimmune disease. Conditions limiting TE read: ascites, heart failure with retrograde vascular congestion, extrahepatic cholestasis. Pregnancy or implantable active medical device (such as pacemaker or defibrillator).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Regression of fibrosis<br>Group conformed by patients experiencing improvement in the noninvasive markers of fibrosis, Fibrotest/Fibrosure and transient elastography, while enrolled in the study. | Other: Regression of fibrosis<br>* Regression of fibrosis will be defined by assessing yearly evolution of noninvasive markers in patients who received antiviral therapy before start of the study, and by comparing baseline markers before start of antiviral therapy to those on subsequent yearly visits in patients prospective recruited (>50% of cases).<br>* Other names: FibroTest, FibroSure, FibroScan (transient elastography);Other: Specific risk factors related to hepatocellular carcinoma<br>* Such as: family history of liver cancer; body mass index; alcohol, smoking and recreational drug use status; dietary habits, including use of caffeinated drinks; comorbidities such as type 2 diabetes mellitus; use of medications for other chronic diseases such as statins and angiotensin-converting enzyme inhibitors.<br>|
| No regression of fibrosis<br>Group conformed by patients not showing the predefined improvement in the noninvasive markers of fibrosis, Fibrotest/Fibrosure and transient elastography, while enrolled in the study. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatocellular carcinoma | According to standard imaging surveillance protocol, and confirmatory CT/MRI/biopsy | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk factors for hepatocellular carcinoma | Positive family history of liver cancer, BMI, active/previous smoking, active/previous alcohol consumption, caffeine consumption in diet, diabetes mellitus, use of drugs for chronic medical conditions | Change from baseline to 3 years | 
| Profile with lowest risk for hepatocellular carcinoma | Composite of regression of fibrosis plus other specific conditions decreasing incidence of hepatocellular carcinoma to <1.5% / year | Change from baseline to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular carcinoma, Regressed cirrhosis, Hepatitis C, Hepatitis B, Noninvasive markers of fibrosis, FibroTest, FibroSure, FibroScan, Transient elastography