Source Duke Clinical Research Institute, Duke Univesity Medical Center, Durham, NC, USA; The Kirby Insitute for Infection, Immunity and Society, University of New South Wales, Sydney, Australia; Department of Gastroenterology, St Vincent's Hospital (Melbourne), The University of Melbourne, Australia; Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne, Australia.

In 2009, an association between IL28B polymorphism and treatment outcome for genotype 1 (G1) hepatitis C virus (HCV) infection, as well as spontaneous clearance of HCV, was reported(1-5) . Since the initial publications, over one hundred articles have appeared in the peer reviewed literature, with many more manuscripts in press and abstracts presented at scientific meetings. Despite the proliferation of data concerning IL28B polymorphism and HCV infection, there remain many critical unanswered questions about clinical implications and the underlying biological mechanisms. In this review we discuss the basic principles of GWAS methodology that are important for interpreting the results of genetic association studies. We then review the current literature concerning the association between IL28B variants and IFN treatment response in patients with chronic HCV infection, as well as spontanteous HCV clearance. We consider the relevance of IL28B polymorphism to non-G1 HCV, as well as the special treatment populations of HIV/HCV coinfection and recurrent HCV post-liver transplantation. We review current knowledge of the biological mechanisms underlying this genetic association, including the link to liver interferon stimulated gene expression and identify continuing gaps in our knowledge and key research priorities. Finally, pegIFN and RBV is no longer the standard-of-care for the treatment of G1 HCV, and we conclude by considering the relevance of IL28B polymorphisms in the era of direct acting antivirals (DAA).