Direct-acting antiviral agents for hepatitis C virus infection

Abstract

Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin. These drugs, boceprevir and telaprevir, received regulatory approval in 2011 and are the first direct-acting antiviral agents (DAAs) that selectively target HCV. During 2012, at least 30 additional DAAs were in various stages of clinical development. HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors (among others) can achieve high cure rates when combined with peginterferon alfa and ribavirin and demonstrate promise when used in combination with one another. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, define the best regimens, and determine treatment strategies that produce the best outcomes. Several DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. We review the clinical pharmacology, trial results, and remaining challenges of DAAs for the treatment of HCV.

Figure 1

Schematic diagram of the HCV life cycle. The life cycle of HCV is similar to that of other members of the Flaviviridae family. Extracellular HCV virions interact with receptor molecules at the cell surface (a) and undergo receptor-mediated endocytosis (b) into a low-pH vesicle. Following HCV glycoprotein-mediated membrane fusion, the viral RNA is released into the cytoplasm (c). The genomic RNA is translated to generate a single large polyprotein that is processed into the 10 mature HCV proteins in association with a virus-derived ER-like membrane structure termed the membranous web (d). The mature HCV proteins replicate the RNA genome via a minus-strand replicative intermediate to produce progeny RNA. A portion of this newly synthesized RNA is packaged into nucleocapsids and associated with the HCV glycoproteins, leading to budding into the ER (f). Virions follow the cellular secretory pathway (g), and, during this transit, maturation of particles occurs (g). Mature virions are released from the cell, completing the life cycle (h). +, positive-sense genomic RNA; +/−, minus-strand replicative intermediate associated with positive-strand genomic RNA. Reproduced from Reference 11 with permission from the American Society for Microbiology.

Figure 2

(a) Treatment algorithm for peginterferon and ribavirin (PR) and telaprevir (TPV). All patients receive 12 weeks of TPV with PR, after which time the TPV is discontinued and the duration of continued PR treatment is dictated by virologic response at week 4, prior treatment history, and perhaps presence of cirrhosis upon liver biopsy. (b) Treatment algorithm for PR and boceprevir (BOC). All patients receive a 4-week lead-in period with just PR before BOC is added. BOC is used with PR for 24 and 32 weeks in those who are treatment naive and treatment experienced, respectively. The need for continued PR treatment is then determined by virologic response during the 4-week PR lead-in, virologic response at week 8, prior treatment history, and presence or absence of cirrhosis upon liver biopsy. Other abbreviations: HCV, hepatitis C virus; IU, international units.