New agents for the treatment of hepatitis C – focus on telaprevir

New agents for the treatment of hepatitis C virus – focus on telaprevir

Authors: Thompson AJ, Patel K

Published Date November 2012
Volume 2012:4 Pages 75 - 84
DOI: http://dx.doi.org/10.2147/VAAT.S12707

AJ Thompson,^1–3 K Patel³¹Department of Gastroenterology, St Vincent's Hospital, University of Melbourne, ²Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia; ³Duke Clinical Research Institute and Department of Gastroenterology, Duke University Medical Center, Durham, NC, USA

Source

Abstract:
Antiviral therapy for hepatitis C virus (HCV) is rapidly evolving with the advent of direct-acting antiviral agents. Telaprevir is a first-generation linear ketoamide inhibitor of HCV NS3 protease. Approved in 2011 as standard-of-care for the treatment of patients chronically infected with HCV genotype 1, telaprevir represents a major therapeutic advance. Used in combination with PEGylated interferon-alfa and ribavirin, telaprevir-based regimens cured > 75% of treatment-naïve patients in the Phase III registration studies. Telaprevir is also effective for patients who have previously failed interferon-based therapy. Telaprevir presents a number of new challenges for clinicians, including a more demanding dosing schedule, telaprevir-specific adverse events, potential for drug–drug interactions, and selection of drug-resistant HCV variants.

Keywords: telaprevir, HCV, NS3, protease inhibitor, resistance

Introduction

There are up to 170 million individuals chronically infected with hepatitis C virus (HCV) worldwide, all of whom are at risk of the long-term complications of cirrhosis, liver failure, and hepatocellular carcinoma.

1 Chronic HCV infection is currently the leading indication for liver transplantation in the Western world. Furthermore, without intervention, the burden of disease secondary to HCV infection is projected to increase over the coming decades as the HCV population ages. The complications of chronic HCV may be prevented by viral eradication.

The standard-of-care treatment for the past decade has been the combination of PEGylated interferon-α (pegIFN) and ribavirin. Unfortunately this treatment will only cure at best 50% of individuals infected with HCV genotype 1, which is the most prevalent HCV genotype in the US and Europe. Furthermore, pegIFN and ribavirin therapy is poorly tolerated by many patients and must be taken for 12 months.

The past decade has seen great investment in the development of direct-acting antiviral agents, culminating in the regulatory approval in 2011 of telaprevir and boceprevir, the first anti-HCV protease inhibitors. This review summarizes the evidence supporting the use of telaprevir for the treatment of chronic HCV....

Highlights

Pharmacology of telaprevir
The pharmacokinetic properties of telaprevir have been evaluated in healthy adult subjects as well as in subjects with chronic HCV genotype 1. In treatment-naïve subjects with chronic HCV treated with multiple doses of telaprevir (750 mg every 8 hours) in combination with pegIFN and ribavirin, the mean ± standard deviation peak plasma concentration was.....

Telaprevir for treatment of HCV genotype 1
Telaprevir was developed using experimental models of HCV genotype 1, and the antiviral effect of telaprevir is consequently relatively specific for HCV genotype 1 both in vitro and in vivo. Telaprevir does have activity in vitro against HCV genotype 6.

Telaprevir has intermediate activity against HCV genotypes 2 and 3 in vitro (activity for genotype 2 . genotype 3). In a small Phase IIa study, telaprevir was shown to have antiviral activity for HCV genotype 2 in patients, but not for genotype 3.
However, telaprevir is not currently indicated for HCV genotype 2 because the virological cure rate with dual pegIFN and ribavirin therapy is greater than 70%. HCV genotypes 4 and 5.......

Viral resistance
Monotherapy with all HCV protease inhibitors in clinical development has been complicated by the rapid emergence of resistant variants. The high replication rate of HCV, and the error-prone nature of the replication cycle, allow resistant...

Safety and tolerability of telaprevir in practice
The introduction of telaprevir represents a major therapeutic advance. Unfortunately, the drug is associated with adverse events that are additive to the toxicity of pegIFN and ribavirin. The major adverse events of telaprevir include pruritus, rash, anemia, and gastrointestinal upset (nausea, diarrhea, perianal discomfort/pruritus, hemorrhoids).
In the Phase II/III studies, rash of all grades was reported in 56% of patients receiving telaprevir compared .....

Drug–drug interactions
Common drugs that should not be coadministered with telaprevir include atorvastatin, lovastatin, and simvastatin (HMG CoA reductase inhibitors), clarithromycin and erythromycin (macrolide antibiotics), ketoconazole and itraconazole (antifungals), and the herbal product Hypericum perforatum (St John’s wort).....

Future perspectives
It should be noted that multiple HCV NS3/4a protease inhibitors have now entered Phase III development (eg, TMC435).
A number of these promising agents are likely to offer similar or increased efficacy, with improved tolerability and single-daily dosing schedules. Therefore, telaprevir is likely to be replaced as a first-line protease inhibitor in the relatively near future. In fact, the treatment landscape for HCV is changing dramatically and at a rapid rate. Direct inhibitors of multiple steps in the viral lifecycle are in the advanced stages of clinical development, with potent inhibitors of HCV NS5B polymerase (nucleo(s/t)ide, non-nucleoside inhibitors), and HCV_NS5A already in Phase II/III development. It is conceivable that, within the decade, clinicians will be able to choose between one of a number of interferon-free combination regimes with pan-genotypic activity........

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