Treatment for hepatitis C virus (HCV) infection has progressed at remarkable speed. From
poorly tolerated injectable therapy with very low cure rates, treatment has moved to highly effective
well-tolerated all oral direct-acting antiviral therapies with cure rates above 90% for almost all patients
populations. Direct-acting antivirals have developed out of an improved understanding of the
viral lifecycle with recognition of targets that could be inhibited by small molecules. To date protease
inhibitors, non-structural 5a inhibitors and nucleotide and non-nucleotide polymerase inhibitors have
been developed. These agents have been used initially with peginterferon and ribavirin and subsequently
in combination without the need for interferon. Rational combinations have overcome the major
challenge of rapid emergence of drug resistance and second-generation agents in each class have
improved safety and efficacy profiles with fewer drug-drug interactions and very few adverse effects.
The progress of direct-acting antiviral development is outlined with a review of each class of agent as
well as a discussion of challenges for the future.
Keywords: Direct-acting antivirals, resistance, cirrhosis, difficult-to-cure, hepatitis C virus.
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