O4. Hepatocellular carcinoma among patients with chronic hepatitis C and cirrhosis in Denmark

Sofie Hallager1, Steen Ladelund2, Mette S. Kjær3, Lone G. Madsen4, Erika Belard5, Jan Gerstoft6, Birgit T. Røge7, Henrik B. Krarup8, Peer B. Christensen9, 10, Nina Weis1,11
Affiliates: Copenhagen University Hospital, Hvidovre, Department of Infectious Diseases, Denmark1, Copenhagen University Hospital, Hvidovre, Clinical Research Center, Denmark2, Copenhagen University Hospital, Rigshospitalet, Department of Hepatology, Denmark3, Køge Hospital, Department of Gastroenterology, Denmark4, Copenhagen University Hospital, Herlev, Department of Gastroenterology, Denmark5, Copenhagen University Hospital, Rigshospitalet, Department of Infectious Diseases, Denmark6, Kolding Hospital, Department of Internal Medicine, Denmark7, Aalborg University Hospital, Section of Molecular Diagnostics, Clinical Biochemistry and Department of Hepatology, Denmark8, Odense University Hospital, Department of Infectious Diseases, Denmark9, Clinical Institute, University of Southern Denmark, Denmark10, University of Copenhagen, Faculty of Health and Medical Sciences, Department of Clinical Medicine11.

Background
Approximately 20% of patients with chronic hepatitis C (CHC) develop cirrhosis which is associated with a high risk of hepatocellular carcinoma (HCC). Patients with HCC face a dismal prognosis if not diagnosed at an early tumor stage. Thus surveillance for HCC among CHC patients with cirrhosis with ultrasound of the liver (US) and measurement of alpha-fetoprotein (AFP) is recommended in Denmark. The aims of this study were to estimate the incidence rate (IR) of HCC among patients with CHC and cirrhosis in Denmark, describe HCC patients with regards to demographics, tumor stage and APF and to estimate the prognosis of patients with HCC.

Methods
This observational cohort study is based on prospectively collected data. Patients were identified in the Danish Database of Hepatitis B and C (DANHEP); a clinical database with ongoing enrollment of patients with chronic hepatitis B or C seen in outpatient clinics in Denmark since 1 January 2002. Patients with CHC and cirrhosis and enrollment in DANHEP prior to 31 December 2012 were eligible. Cirrhosis was based on liver biopsy (Metavir fibrosis score = F4), transient elastography median elasticity ≥ 17 kPa and clinical cirrhosis. Data were extracted from nationwide registries and the medical records of patients with HCC were checked for additional information on HCC stage and AFP. Tumor staging was based on Barcelona-Clinic Liver Cancer stage (BCLC), TNM classification and tumor size and number and combined into stage 0 (BCLC 0, 1 tumor 3 tumors or > 3 cm) and stage 3 (BCLC C/D, T4 and/or N≥1M≥1, disseminated). The Kaplan-Meier estimator was used to estimate the survival function of HCC patients stratified by HCC stage and tested for difference using the log-rank test.

Results
1,096 patients with CHC and cirrhosis, free of HCC and liver transplantation at baseline, were included. During 5,072 years of follow-up 121 HCC cases were diagnosed after a median of 3.9 years (range 0.02 – 11.9) corresponding to an IR of 2.39/100 person observation years [95% confidence interval 2.07 – 2.76]. For patients diagnosed with HCC the median age was 58 years (range 40 – 86), 87 (71.9%) were male, 77 (63.6%) had alcohol overuse, 3 (2.5%) and 2 (1.7%) were coinfected with hepatitis B virus and HIV, respectively, 46 (38.0%) had genotype 1, 47 (38.8%) genotype 3, and 2 (1.7%) had both genotype 1 and 3. Within 365 days before the HCC diagnosis 82 (67.8%) patients had AFP measured (median last AFP before HCC: 23.5 ng/mL, interquartile range 6.1 – 160.9) and 91 (75.2%) had US performed. Two (1.7%) patients presented with HCC stage 0, 25 (20.7%) stage 1, 50 (41.3%) stage 2, 29 (24.0%) stage 3 and 15 (12.4%) had unknown stage. Six-month survival after HCC was 73.1% [56.7 – 94.4], 59.3% [46.7 – 75.3] and 44.1% [29.2 – 66.8] for stage 1, 2 and 3, respectively (figure 1, log-rank test p = 0.019). No difference in median last AFP within 365 days before HCC was found between HCC stages (p = 0.87).

Conclusions
Among patients with CHC and cirrhosis in Denmark the HCC IR is high. Despite the national surveillance program the majority of patients have HCC diagnosed at a late stage and show a poor prognosis.

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