New horizons in hepatitis C antiviral therapy with direct-acting antivirals


  • Alessio Aghemo,

    1. A.M. e A. Migliavacca Center for the Study of Liver Disease 1st Division of Gastroenterology, Fondazione IRCCS Cá Granda Ospedale Maggiore Policlinico Milan Italy
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  • Raffaele De Francesco

    Corresponding author
    1. Istituto Nazionale Genetica Molecolare, Milan, Italy
    • INGM - Istituto Nazionale Genetica Molecolare, via Francesco Sforza 35, 20122 Milan, ItalyIstituto Nazionale Genetica Molecolare Milan Italy===

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  • Potential conflict of interest: Alessio Aghemo has received speaking and teaching honoraria from Roche, Janssen, and Merck, has received travel support from BMS, Janssen, Roche, and Merck and has received an unrestricted research grant from Gilead and Roche. Raffaele De Francesco has received consulting fees from Boehringer Ingelheim and Rottapharm Madaus.


Most direct-acting antivirals (DAAs) that are being developed as therapy against hepatitis C virus target the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers different target sites: the catalytic domain for nucleos(t)ide analogues as well as a number of allosteric sites for nonnucleos(t)ide inhibitors. Two NS3/4A protease inhibitors have been approved recently, and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development. These agents can achieve very high cure rates when combined with pegylated interferon-β and ribavirin and show promising clinical results when administered in all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small-molecule drug development are emerging, such as p7 or NS4B and viral entry. Future research will need to define well-tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication in all patients (including those with advanced liver disease), the broadest spectrum of action on viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration. (Hepatology 2013)