Interferon Therapy and Prevention of Hepatocellular Carcinoma in Hepatitis C

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and one of the leading causes of death among patients with cirrhosis. Its incidence is expected to continue increasing over the next 20 years and to peak around 2030 [1]. Although hepatitis B remains the most common risk factor worldwide, chronic hepatitis C virus (HCV) infection is the driving force for the increased incidence of HCC in Western countries and Japan [1]. Therefore, strategies aimed at eliminating the virus may provide opportunities for primary and secondary prevention of the development of HCC. The first evidence of primary prevention of HCC was from a small randomized controlled trial with 90 HCVinfected patients in which interferon (IFN) treatment was associated with a significant reduction in the incidence of HCC [2]. The beneficial effects of IFN therapy were thought to be related to its anti-proliferative, anti-angiogenic, and/or anti-tumor effects [3, 4]. Since that time, several studies have replicated the findings of a reduction in HCC risk among patients treated with IFN, particularly patients who achieved a sustained viral response (SVR). A meta-analysis found that SVR was associated with a 79% (95% CI 0.73–0.84) reduction in the risk of development of HCC by patients with HCV-related cirrhosis [5]. The primary preventive effect of IFN therapy may be even greater among non-cirrhotic HCV patients, given that SVR at earlier stages of fibrosis can prevent the development of cirrhosis. Given that the effect of IFN therapy was primarily seen among patients who had SVR, the utility of maintenance pegylated interferon (PEG–IFN) to prevent disease progression and HCC among non-responders was evaluated. Several randomized trials (HALT-C, COPILOT, and EPIC) have since demonstrated that maintenance PEG–IFN fails to prevent HCC in patients with HCV-related cirrhosis among non-responders [6–8]. Patients with HCC who are diagnosed at an early stage can be effectively treated by liver transplantation, surgical resection, or local ablative therapy [9]. Although liver transplantation effectively treats both the HCC and replaces the underlying cirrhotic liver, it is not possible for all patients, given rigorous selection criteria and a shortage of organs. Surgical resection and local ablative therapy are able to achieve high cure rates, but these patients remain at high risk of developing recurrent or de-novo cancers. Recurrence 5 years after resection of primary tumors is reported to be approximately 50% [10]. Early recurrence seems to be primarily driven by metastases and is associated with factors such as microvascular invasion and AFP level. Late recurrence, i.e., that occurring after 2 years, often appears as de-novo lesions and is associated with factors such as hepatitis activity and persistent HCV viremia [11]. Given the widespread implementation of HCC surveillance programs and increasing burden of HCC, a greater proportion of patients is expected to be diagnosed during early stages and be suitable for either resection or local ablation. Given the associated high incidence of recurrent or de-novo tumors, further studies that address prevention of HCC recurrence are crucial. Several studies, including five randomized controlled trials and subsequent meta-analysis, have demonstrated A. G.