The Evolution of Clinical Trials for Hepatitis C

Abstract

The development of well-tolerated treatments that attain nearly universal cure of hepatitis C virus (HCV) infection, less than 30 years after the long-sought discovery of the causative agent, ranks as a landmark achievement of modern medicine. In the broadest sense, the international effort to address this global public health problem can be divided into an era of nonspecifically targeted therapy centering on interferon, a relatively brief “hybrid period” combining interferon and ribavirin with direct-acting antiviral agents (DAAs), and the latest era of DAA combination regimens. One of the most notable features of this story is the quantum leap in efficacy for DAA therapy to extraordinarily high levels instead of the years-long incremental steps that might have been anticipated. Similarly gratifying is the foundation on which the concept of curability, unique to HCV thus far in human virology, has been solidified based on the combination of our understanding of the molecular biology of the virus and the rarity, dating back to the interferon era, of virologic relapse after attainment of sustained virologic response. Although, at least until recently, the number of therapeutic agents was very limited, the combination of viral and host diversity ensured the development of a rich literature reflecting hundreds of treatment studies which dominated the scientific programs of the international liver meetings for many years. Viewed panoramically through a retrospective lens, the field developed in a logical sequence by first making the most out of the limited tools which were available and later by building on the remarkable elucidation of HCV biology by the scientific community and the paradigm of combination therapy for viral infection established in the HIV field to get us where we are today.