The first wave: HCV NS3 protease inhibitors telaprevir and boceprevir
Boceprevir and telaprevir are peptidomimetic serine protease inhibitors that have been recently approved for the treatment of HCV chronic infection. The addition of these drugs to the prior standard of care, pegylated interferon and ribavirin, improves sustained virological response rates for treatment-naive and treatment-experienced patients and shortens the duration of treatment for over half of treatment-naive patients. This review describes the clinical data supporting the approval and use
... f telaprevir and boceprevir, the algorithm for the use of these drugs, their adverse effects, as well as their important drug-drug interactions. Although agents targeting several sites in the HCV viral life cycle are in development, to date, only telaprevir and boceprevir (drugs that inhibit the NS3/4a serine protease) have been FDA-approved for treatment of chronic hepatitis C. The year 2011 witnessed a dramatic development in the field of therapy for chronic HCV infection with the approval of two protease inhibitors (PIs), telaprevir and boceprevir. These drugs represent the first of an anticipated wave of direct-acting antiviral agents (DAAs) representing several mechanisms of action undergoing ongoing study. Both of the available PIs must be used in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) and are approved, at this time, only for genotype 1 infection. Pivotal clinical trials demonstrated two important benefits from the addition of these drugs to PEG-IFN and RBV: improved rates of sustained virological response (SVR) and shortened duration of treatment for a substantial proportion of patients with the use of response-guided therapy (RGT). This review describes the clinical trial data supporting the approval and use of telaprevir and boceprevir for patients with chronic HCV infection, including important findings from early phase studies, results of the pivotal Phase III studies (Tables 1 and 2) , and available data related to treatment of historically difficult to cure patients. In addition, this review compares the similarities and differences between the two drugs (Table 3) and provides an algorithm for their use in clinical practice (Figure 1) based on their FDA-approved indications and the latest American Association for the Study of Liver Diseases (AASLD) guidelines for the treatment of HCV . Lastly, the review characterizes the adverse event and drug-drug interaction profiles (Table 4 ) to help guide safe and appropriate use of these medications. Overview of serine protease inhibitors telaprevir and boceprevir Mechanism and spectrum of action Both boceprevir and telaprevir are peptidomimetic inhibitors that bind reversibly to the active site of the NS3/4a serine protease enzyme active site [2, 3] . They prevent the cleavage of the portion of the genomederived polypeptide required for the generation of the individual non-structural proteins essential to the HCV viral life cycle. Exposure to either drug results in potent inhibition of viral replication in vitro and in vivo. However, monotherapy results in the rapid emergence of resistant variants (further described in Resistance), resulting in the need for concomitant administration of PEG-IFN and RBV. Although approved only for treatment of HCV genotype 1 and clearly not pangenotypic in their spectrum of activity, variable degrees of suppression of other genotypes may occur, as demonstrated for telaprevir in a recent study in patients with HCV genotype 2 but not genotype 3  .