Review Article: Novel Therapeutic Options for Chronic Hepatitis C

Evangelos Cholongitas; George V. Papatheodoridis


Aliment Pharmacol Ther. 2008;27(10):866-884. 

In This Article

Abstract and Introduction

Background: The efficacy of treatment against hepatitis C virus has improved, but it is still far from ideal. Thus, new antihepatitis C virus therapies are required.
Aim: To evaluate the data on antihepatitis C virus approaches beyond the current standard combination of pegylated interferon-alpha and ribavirin.
Method: We reviewed the available literature regarding novel antihepatitis C virus options, given alone or in combination with existing agents.
Results: New interferons and ribavirin alternatives have been tried aiming to improve the efficacy and the safety/tolerability profile of standard agents. The hepatitis C virus polymerase and NS3/4A protease have been rather popular targets for new antihepatitis C virus agents. The combination of such inhibitors with pegylated interferon-alpha and ribavirin seems to act synergistically and to prevent viral resistance, compared to monotherapies. Several novel immunomodulators are currently evaluated and may be useful in combination therapies. Alternative strategies (inhibition of hepatitis C virus protein translation, assembly/release or binding) or agents with different modes of action (statins, S-adenosylmethionine and herbs) need further evaluation.
Conclusions: Many novel promising antihepatitis C virus agents are being developed, offering hope for future therapies that may target multiple points of the viral life cycle and/or host immune response. Newer approaches should ideally provide safe, effective and more tolerable therapy to all chronic hepatitis C virus patients.

The management of chronic hepatitis C virus (HCV) infection is extremely important, as approximately 500 000 patients die every year because of complications of HCV-related end-stage liver disease.[1] The efficacy of therapy has improved over the last decade, but still more than 40% of chronic hepatitis C (CHC) patients do not eventually respond to the combination of pegylated interferon-alpha (PEG-IFNα) and ribavirin (RBV), which is the current standard of care.[2] In particular, sustained virological response (SVR), which is the desirable therapeutic end-point, is achieved in 45-55% of nave patients infected with genotype 1 or 4 and 80% of those infected with genotypes 2 or 3.[2,3] As patients with genotype 1 or 4 represent the majority of CHC cases in most parts of the world, it is evident that current treatment is far from ideal. Moreover, in the increasing numbers of nonresponders to a previous standard course, the current combination of PEG-IFNα and RBV offers rather poor SVR rates and is therefore not currently recommended. Finally, the current combination therapy is associated with frequent and potentially severe side effects and cannot be given to all patients, particularly to those with advanced liver disease who mostly require therapeutic intervention. From all these, it is evident that novel and more efficacious anti-HCV therapies are urgently needed.

The availability of new culture systems has created opportunities not only for the better understanding of HCV infection biology, but also for the identification of new methods that could lead to the discovery of novel anti-viral therapies.[4,5] In particular, the development of HCV subgenomic replicons, which are able to replicate autonomously in cell culture, and a system derived from a genotype 2a genome isolated from a Japanese patient with fulminant hepatitis, which produces infectious virus particles, have reinforced this field.[4,5] On the basis of new insights into virology of HCV (attachment, entry into cells, replication and release; Figure 1) and host cellular immune response, the effort to find new agents has focused on targeting specific steps of the viral life cycle, including inhibitors of HCV enzymes, nucleoside analogues targeting viral RNA and immunomodulators.[6] Although many new anti-viral compounds have been synthesized and several of them shown promising anti-viral efficacy in preclinical and early clinical trials, their safety and clinical efficacy have to be proved in the long term.[7]

Schematic picture of the replicative cycle of hepatitis C virus in hepatocytes. Each step represents a potential site of therapeutic intervention.

This review focuses on the therapeutic approaches, beyond the standard combination of PEG-IFNα and RBV, which are currently being evaluated for the treatment against HCV ( Table 1 ).


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