The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.

Disclosures

Semin Liver Dis. 2011;31(4):399-409. 

In This Article

Abstract and Introduction

Abstract

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.

Introduction

In May 2011, telaprevir and boceprevir were approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic hepatitis C virus (HCV) genotype 1. Dual therapy with pegylated interferon (pegIFN) and ribavirin (RBV) is no longer the standard of care for genotype 1 HCV. The new treatment paradigm includes one direct-acting antiviral (DAA), a protease inhibitor (PI), in combination with pegIFN and RBV. The addition of a DAA to pegIFN/RBV nearly doubles the chances of response to treatment at the cost of increased toxicity. This is only the first wave of DAA use since many agents with different mechanisms of action and improved safety profiles are in phase I, II, and III of clinical development (Table 1 and Table 2). The use of three agents to treat HCV mirrors human immunodeficiency virus (HIV) triple combination treatment in many ways. Combination treatment seems inevitable to prevent emergence of resistance in HCV. Clinical trials are ongoing to identify the ideal regimen which would be potent, well tolerated, with minimal drug-drug interactions, once daily, all oral, and for as short a duration as possible (Table 3). Two major differences between HIV and the treatment of HCV are that treatment of HCV is for a definite duration and that HCV is curable. In this article, we examine new concepts of treatment of HCV with DAAs in general and review investigational compounds that have entered phase II of clinical development.

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