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

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.

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).