Hepatitis C Therapy in Non-genotype 1 Patients

The Near Future

C. Wartelle-Bladou; G. Le Folgoc; M. Bourlière; L. Lecomte

Disclosures

J Viral Hepat. 2012;19(8):525-536. 

In This Article

Abstract and Introduction

Abstract

Summary. Worldwide, 50–70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.

Introduction

There are approximately 170–200 million people chronically infected with hepatitis C virus (HCV) worldwide. Chronic hepatitis C can lead to cirrhosis and its subsequent complications such as hepatocellular carcinoma with more than 350 000 people dying each year from hepatitis C–related liver disease. Clearance of the virus is associated with improved histological outcomes, morbidity and mortality. The therapeutic goal is therefore to achieve a sustained virological response (SVR) defined as undetectable HCV RNA 6 months after cessation of therapy. Among the six identified HCV genotypes, genotype 1 (GT-1) is the most prevalent and was, until the approval in 2011 of two-first-generation NS3/4A protease inhibitors (PIs) in combination with pegylated interferon (PEG-INF)-α and ribavirin, the most difficult to cure. The launch in 2011 of boceprevir and telaprevir was a major landmark in the management of GT-1-infected patients. In association with PEG-INF and ribavirin, these two drugs increase the chances of cure by 30% with SVR rates in the range of 66–75% in naïve patients.[1–3] The benefit appears to be even more important in treatment-experienced patients in whom the chances of cure increase by 50–60% in relapsers, 40–45% in partial responders and 25% in null responders.[4,5]

However, this major advance benefits only GT-1 patients while there remains worldwide 50–70 million subjects infected with an HCV genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin (PR) remains the currently approved standard-of-care treatment (SOC). HCV genotypes present specific geographical distribution (Fig. 1), leading to a quasi-mono-genotypic HCV infection in some parts of the world such as Egypt, where the HCV infection prevalence reaches 15% in the general population with an almost exclusive GT-4 distribution. In such a country, chronic hepatitis C will exert an increasing substantial disease burden without more effective treatments.

Figure 1.

Hepatitis C virus (HCV) genotype distribution worldwide (courtesy of S. Locarnini).

The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A PIs, nucleos(t)ide (NIs) and non-nucleoside inhibitors (NNIs) of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-proteins-directed antiviral agents are cyclophilin inhibitors and silibinin. Several drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds.

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