Characteristics of direct acting antiviral agents for hepatitis C virus infection

	Protease inhibitors	Nucleos(t)ide polymerase inhibitors	Non-nucleoside polymerase inhibitors	NS5A inhibitors
Potency	High (varies by HCV genotype)	Moderate-to-high (consistent across HCV genotypes and subtypes)	Varies by HCV genotype	High (against multiple HCV genotypes)
Barrier to resistance	Low (1a <1b)	High (1a = 1b)	Very low (1a <1b)	Low (1a <1b)
Potential for drug interactions	High	Low	Variable	Low-to-moderate
Toxicity	Rash, anemia, ↑ bilirubin	Mitochondrial toxicity, interactions with HIV antiretrovirals (nucleoside reverse transcriptase inhibitors) and ribavirin*	Variable	Variable
Dosing	daily to three times daily	daily to twice daily	daily to three times daily	daily
Comments	Later generation protease inhibitors are expected to have higher barriers to resistance and be pan-genotype	Single target for binding at the active site	Many targets for binding at allosteric sites	Multiple antiviral mechanisms of action

The main targets of the direct acting antiviral agents are the HCV-encoded nonstructural (NS) proteins that are vital to the replication of the virus. Protease inhibitors block the function of the NS3/NS4A serine protease. Nucleoside and nonnucloside inhibitors block the function of the NS5B polymerase. The NS5A protein has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell.

* Such toxicities have plagued the nucleoside inhibitor class as a whole. However, the first available nucleoside polymerase inhibitor, sofosbuvir, has not been associated with serious toxicity.

Adapted from: Schaefer EA, Chung RT. Anti-hepatitis C virus drugs in development. Gastroenterology 2012; 142:1340.

Graphic 93884 Version 1.0

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Characteristics of direct acting antiviral agents for hepatitis C virus infection