Telaprevir: a hepatitis C NS3/4A protease inhibitor.

BACKGROUND: Telaprevir is a hepatitis C NS3/4A protease inhibitor approved by the US Food and Drug Administration as part of combination therapy for the management of chronic hepatitis C virus (HCV) genotype 1 infection.
OBJECTIVE: The article reviews published literature on telaprevir, including its chemistry, mechanism of action, resistance, pharmacodynamic and pharmacokinetic properties, drug interactions, therapeutic efficacy, HIV/HCV coinfection, pharmacogenomics, adverse events, pharmacoeconomics, and dosing and administration.
METHODS: English-language literature was included. Searches of MEDLINE and BIOSIS databases from 1975 through January 2012 were performed. Emphasis was placed on reference citations involving clinical trials, randomized controlled trials, and research in humans. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from recent scientific meetings. Search terms included, but were not limited to, telaprevir, VX-950, hepatitis C virus genotype 1, resistance, pharmacology, pharmacokinetics, pharmacodynamics, drug interactions, pharmacogenomics, adverse events, and therapeutic use.
RESULTS: Review of the databases revealed 471 publications/abstracts on this subject. Of these, 85 were chosen based on the review criteria. Two Phase III studies investigated the efficacy and tolerability of telaprevir administered for 12 weeks (T12) when used with peginterferon alfa and ribavirin (PR) in treatment-naive subjects. The ADVANCE study reported that patients who had an extended rapid virologic response (eRVR; an undetectable HCV RNA level at both 4 and 12 weeks of treatment) with triple therapy could be treated with PR for a total of 24 weeks (T12PR24 group) versus standard PR treatment for 48 weeks (PR48 group [control]). The proportions of patients who achieved sustained virologic response (SVR; undetectable HCV RNA concentration at 24 weeks after the completion of therapy) in the T12PR24 and PR48 groups were 89% and 44%, respectively. The ILLUMINATE study reported T12PR24 was noninferior to T12PR48 in patients with an eRVR to combination therapy. In the REALIZE study, patients with a history of relapse responded well to T12PR48 compared with PR48 (SVR, 83% vs 24%). Telaprevir is a substrate/inhibitor of cytochrome P450 (CYP3A4) and a substrate/inhibitor of P-glycoprotein and poses an important risk for drug interactions. Adverse drug events (ADEs) reported most commonly with triple therapy compared with the T or PR regimen alone were rash, pruritus, nausea, diarrhea, and anemia. The serious AEs most commonly reported during T + PR therapy were anemia, rash, and pruritus. Two reports concluded that T combined with PR was not cost-effective due to the high cost of telaprevir. One study reported that the combination of T + PR would be cost-effective if the treatment rate of HCV genotype 1 infected patients reached 50%.
CONCLUSION: Including telaprevir as part of triple therapy for the management of chronic HCV genotype 1 infection significantly increases the likelihood of achieving an SVR over standard dual drug therapy (PR) in both treatment-naive and -experienced patients. However, due to the high cost, the use of triple therapy with telaprevir will likely be limited to patient groups known to respond poorly to dual therapy.