Hepatocellular carcinoma in long-term sustained virological responders following antiviral combination therapy for chronic hepatitis C T.-M. Scherzer, 1 K. R. Reddy, 2 F. Wrba, 3 H. Hofer, 1 K. Staufer, 1 P. Steindl-Munda, 1 A. Gangl 1 and P. Ferenci 1 1 Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 2 Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; and 3 Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria Received November 2007; accepted for publication March 2008 SUMMARY. Antiviral treatment results in a sustained virologic response (SVR) in 50–75% of patients with chronic hepatitis C. Long-term follow up studies have observed ongoing SVR in the overwhelming majority of them. Thus chronic hepatitis C is considered ÔcuredÕ if an SVR is achieved. Consequently, it is expected that in sustained virologic responders long-term complications of hepatatic C virus (HCV) related chronic liver disease including hepatocellular carcinoma are eliminated or have a decreased incidence. We report on five patients (three from Austria, two from USA) who developed hepatocellular carcinoma during follow up (3–6 years) after achieving SVR. During follow up and at diagnosis all were HCV-RNA neg. None of the patients had other liver diseases. One patient presented with bilateral adrenal metastasis, the remaining four with large hepatic tumours. Three patients were non- cirrhotic at the start of treatment at the time of tumour diagnosis. Successful antiviral treatment in HCV patients does not prevent development of hepatocellular carcinoma even in non-cirrhotic livers. Long-term follow up of patients with SVR is mandatory and should include surveillance for hepatocel- lular carcinoma. Keywords: hepatatic C virus, hepatitis C, hepatocellular carcinoma, sustained virological response. INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most common carcinoma in men and the ninth in women and affects approximately half a million persons worldwide [1]. Main risk factors for HCC in the USA are cirrhosis due to chronic hepatitis C (47%), chronic hepatitis B (15%), and coinfection with HCV and HBV (5%) [2]. The risk factors for HCC in Austria are similarly dominated by viral hepatitis (HBV: 9.8%, HCV: 36.7% HBV/HCV: 1.6%) followed by alcoholic cirrhosis (35.1%) [3]. In the United States an estimated 3.9 million people are infected with the hepatitis C virus (HCV) [4], whilst in Western Europe the prevalence of chronic HCV infection varies from about 0.1% in the North to 1% of the population in the South and ranges from 0.4% to 4.5% (median 2%) in Eastern Europe. Chronic hepatitis C is a slowly progressive disease leading to liver cirrhosis [5]. Once cirrhosis is present the risk to develop HCC is high [6]. Chronic hepatitis C is considered a curable disease following combination therapy with peginterferon and ribavirin. Sustained virologic response (SVR) rates range between 45% and 60% in patients infected with genotypes 1 and 4 and up to 80–90% in patients with genotypes 2 and 3 [7–10]. Sustained virologic response is maintained in about 98–99% of patients over long observation periods [11,12] and is associated with improvement of liver fibrosis [13,14]. Hepatitis C is considered ÔcuredÕ if SVR in non-cirrhotic pa- tients is achieved [15]. Thus, successful antiviral treatment may substantially decrease the rate or even prevent the occurrence of HCC in patients with or without cirrhosis [13,16–19]. However, most of these studies observing a favourable impact on the incidence of HCC are from Asia, are retrospective and have a potential selection bias [17,18,20]. Overall the rate of HCC occurrence in sustained virologic responders was much lower than in nonresponders. In an Italian study the incidence of HCC in patients with HCV cirrhosis treated by interferon monotherapy was 2.59-fold higher in non responders than in sustained responders [19]. Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatatic C virus; PCR, polymerse chain reaction; RT-PCR, reverse transcrip- tase-polymerse chain reaction; SVR, sustained virologic response. Correspondence: Peter Ferenci, University of Klinik fu ¨ r Innere Medizin III, Medical University of Vienna, Vienna General Hospital (AKH), Waehringer Guertel 18–20, A 1090 Wien, Austria. E-mail: peter.ferenci@meduniwien.ac.at Journal of Viral Hepatitis, 2008, 15, 659–665 doi:10.1111/j.1365-2893.2008.01006.x Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Publishing Ltd