Chronic hepatitis C virus (HCV) infection leads to hepatocellular carcinoma (HCC) or liver cancer, which is the second leading cause of cancer-related death worldwide. HCV proteins, both structural and nonstructural, can influence directly on cell signaling pathways and metabolic mechanisms to promote HCC. Despite the advent of highly effective treatment option using direct-acting antiviral (DAA) agents, the morbidity and incidence of HCV-related HCC remain high. The HCV NS3/4A protease is a leading therapeutic target that has provided five FDA-approved drugs, e.g., telaprevir, boceprevir, simeprevir, paritaprevir, and grazoprevir, and several clinical candidates such as NS3/4A protease inhibitors for HCV infection, and potential for prevention and control of HCV-induced HCC. The six genotypes of HCV are linked to different level of risk for development of HCC and different potency against existing drugs as protease inhibitors. Meanwhile, there are emerging cases of viral resistance to all existing drugs mainly due to single-point mutations. Therefore, further research in this area targeting HCV NS3/4A protease as well as other targets is underway, and in fact, many candidate molecules are under clinical trials. This chapter covers the wide variety of HCV NS3/4A protease inhibitors that have been approved or under clinical investigation for the treatment of various HCV genotypes and thus have potential for the prevention of HCV-induced HCC.
