An Oral Protease Inhibitor for Hepatitis C Virus Infection

Jenny J. Kim; Colleen M; Culley; Rima A. Mohammad


Am J Health Syst Pharm. 2012;69(1):19-33. 

In This Article

Abstract and Introduction


Purpose The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, viral drug resistance, dosage and administration, and place in therapy of telaprevir are reviewed.
Summary Telaprevir is an oral NS3/4A protease inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in adult patients with compensated liver disease, including cirrhosis. In Phase II clinical trials, triple therapy (telaprevir with peginterferon alfa and ribavirin) demonstrated 20–39% higher rates of sustained virological response (SVR) versus standard therapy (peginterferon alfa and ribavirin) in patients with chronic HCV genotype 1. Higher SVR rates were observed in treatment-naive patients or patients who did not respond to prior therapy (did not achieve SVR). Phase III studies also found improved SVR rates in patients treated with triple therapy. Telaprevir is recommended in combination with peginterferon alfa-2a and ribavirin for treatment-naive patients and patients who did not previously respond to peginterferon alfa-2a and ribavirin therapy. Telaprevir is a substrate and inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein. Drugs that induce or inhibit CYP3A4 may affect concentrations of telaprevir, resulting in reduced efficacy or increased concentrations of telaprevir (and an increased risk for adverse reactions). The most common adverse events reported with telaprevir monotherapy versus placebo were diarrhea, nausea, fatigue, and dry skin.
Conclusion Telaprevir, an HCV NS3/4A protease inhibitor, has been shown to be effective in increasing SVR rates when used with peginterferon alfa and ribavirin in patients with chronic HCV genotype 1 infection, regardless of treatment history


Hepatitis C virus (HCV) affects roughly 170 million people worldwide and is a leading cause of chronic liver disease and liver transplantation.[1–3] There are two distinct phases of HCV: acute infection and chronic infection. Of patients with acute HCV infection, approximately 75–85% will develop chronic HCV, and 60–70% will develop chronic liver disease.[2] An estimated 3.2 million people in the United States have chronic HCV infection, and the mortality rate of patients who develop hepatocellular carcinoma (HCC) or cirrhosis as a consequence of chronic HCV infection is 1–5%.[2] The acute and chronic phases of HCV infection are distinguished by clinical symptoms (e.g., jaundice), history and duration of elevated alanine transaminase (ALT) levels, and the results of serum laboratory testing for anti-HCV antibody and the presence of HCV RNA.[4] HCV RNA can be detected as early as 2 weeks after an acute exposure, though anti-HCV antibodies may not be detectable before 8–12 weeks. During the first four to six months after exposure, anti-HCV antibody and HCV RNA levels should be retested to confirm the resolution of HCV infection. For patients who develop chronic HCV infection, the HCV genotype should be identified to determine the appropriate treatment and duration of therapy. HCV genotypes (1–6) are geographically specific; in the United States, the most common HCV genotype is 1 (subtypes 1a and 1b), followed by genotypes 2 and 3.[4,5] A U.S. population study of 265 individuals with HCV infection found that 75.3% of patients had HCV genotype 1, 16.3% had HCV genotype 2, and 8.5% had HCV genotype 3.[5]

The goal of therapy is the prevention of HCV-related complications (e.g., cirrhosis, HCC) and mortality.[4] Treatment is initiated for chronic HCV infection based on several factors, such as the severity of liver disease, risk:benefit ratio of therapy, and presence of bridging fibrosis or compensated liver.[4] Due to the slow progression of chronic HCV, treatment response is determined by surrogate virological measurements rather than clinical endpoints. The goal of treatment response is virological cure or sustained virological response (SVR) of undetectable HCV RNA levels 24 weeks after completion of therapy (defined as a lower limit of detection [LLOD] of <50 IU/mL). Other virological responses may help to predict the likelihood of SVR, such as rapid virological response (RVR), defined as an undetectable HCV RNA level at week 4 of treatment.[4]

Practice guidelines of the American Association for the Study of Liver Diseases (AASLD) currently recommend the combination of peginterferon alfa-2a or alfa-2b and ribavirin, which nonspecifically targets HCV, for the treatment of chronic HCV infection.[4] The treatment regimen for chronic HCV infection, treatment duration, and treatment response rate (defined by SVR) depend on the HCV genotype. With standard therapy, the SVR rate of patients with HCV genotype 1 is 42–52% and it is 76–84% for patients with HCV genotype 2 or 3.[6–8] Since patients with HCV genotype 1 are less likely to respond to treatment, they require a longer duration of therapy (48–72 weeks) compared with patients with HCV genotype 2 or 3 (24 weeks).[4,8,9] The duration of therapy may be extended to 72 weeks in patients with HCV genotype 1 who have a delayed clearance of HCV RNA between weeks 12 and 24.[4,9]

There are several limitations to combination therapy with peginterferon alfa-2a or alfa-2b and ribavirin, including significant dose-limiting safety issues (e.g., depression, flulike symptoms, thrombocytopenia), treatment discontinuation rates of 5–15% due to adverse events, and clinical considerations (e.g., coinfection with human immunodeficiency virus [HIV], decompensated liver disease, retreatment).[6–8] These limitations prompted the development of new antiviral agents to improve the efficacy and safety of treatment in patients with chronic HCV infection. Direct-acting antivirals (DAA) target important viral enzymes specific to HCV (e.g., NS3/4A serine protease, NS5B polymerase).[10] NS3/4A serine protease processes HCV polyproteins into nonstructural proteins, which are essential to the HCV replication cycle.[11]

There are two types of protease inhibitors based on the type of bond formed with NS3/4A protease: non-covalent product-based inhibitors (e.g., ciluprevir) and covalent reversible inhibitors (e.g., telaprevir, boceprevir).[11] The development of ciluprevir was discontinued after it was found to cause cardiotoxicity in experimental animal studies. Boceprevir (Victrelis, Schering, Whitehouse Station, NJ), approved by the Food and Drug Administration (FDA) on May 13, 2011, was shown to improve SVR rates in HCV treatment-naive patients and patients with chronic HCV genotype 1 infection who previously had a partial response to or relapsed after treatment with peginterferon alfa and ribavirin.[12,13] On May 23, 2011, telaprevir (Incivek, Vertex, Cambridge, MA) was approved for the treatment of chronic HCV genotype 1 infection in adult patients with compensated liver disease, including cirrhosis, who have not been previously treated with, have not responded to, have partially responded to, or have relapsed after interferon-based treatment.[14] This article reviews the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, viral drug resistance, dosage and administration, and place in therapy of telaprevir.


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