Elsevier

Current Opinion in Virology

Volume 1, Issue 6, December 2011, Pages 599-606
Current Opinion in Virology

Resistance to anti-HCV protease inhibitors

https://doi.org/10.1016/j.coviro.2011.10.001Get rights and content

The era of direct acting antiviral therapy for HCV infection has dawned with the recent approval of the NS3 protease inhibitors telaprevir and boceprevir. The development of DAA therapy is an exciting advance for clinicians and patients, but it will also bring new challenges. For the first time, drug resistance has become an issue to consider in the management of HCV. This brief review summarizes the current literature concerning resistance to the HCV NS3 protease inhibitors, both experimental and clinical, and identifies the key questions facing the field.

Highlights

► The NS3 protease inhibitors telaprevir (TVR) and boceprevir (BOC) are now approved for the treatment of genotype 1 HCV in North America and Europe. ► Resistance variants are selected rapidly with monotherapy. ► Key resistance residues for TVR and BOC include R155, A156, V36 and T54. ► TVR and BOC are therefore used in combination with peginterferon-α and ribavirin (RBV). ► Interferon-free treatment regimens are in development.

Introduction

Chronic infection with the hepatitis C virus (HCV) is estimated to affect 130–170 million individuals worldwide [1]. Chronic hepatitis C causes liver failure and liver cancer, and is the leading cause of liver transplantation in the Western world. These complications may be prevented by curative antiviral therapy. Unfortunately the standard-of-care treatment for the past decade, peginterferon-α (pegIFN) and ribavirin (RBV), cures only 40–50% of patients with genotype 1 HCV, the most common genotype in North America and Europe. More effective therapy has been a clinical priority.

Great effort has been invested in developing novel therapies that directly target the HCV lifecycle, collectively termed direct acting antiviral agents (DAAs). These candidates now include direct inhibitors of the HCV non-structural (NS) 3/4a protease, the NS5B polymerase and the NS5a phosphoprotein. The most advanced class are the NS3 protease inhibitors (PIs), and the first two agents, telaprevir [2, 3] and boceprevir [4, 5], were approved as first line agents for the treatment of chronic genotype 1 HCV in 2011.

The development of telaprevir and boceprevir has been instructive. As for the treatment of HIV, monotherapy is complicated by the rapid emergence of resistant variants. This occurs as a result of the high replication rate of HCV, the error-prone nature of the replication cycle, and the lack of a viral proof-reading mechanism. In fact, most single-mutations and double-mutations are likely to occur spontaneously before treatment, existing as minor populations within the viral quasispecies. Treatment with NS3 inhibitors therefore remains reliant on combination with an effective pegIFN and RBV backbone. Not all individuals are responsive to pegIFN and RBV therapy however, placing them at high risk for DAA treatment failure owing to functional monotherapy. The clinical significance of the HCV resistance-associated variants that emerge in this setting is not yet known. It is therefore timely to review the current literature concerning resistance to HCV protease inhibitors, and to consider the important issues confronting the field.

Section snippets

The HCV replication strategy promotes the emergence of resistant variants

The rapid emergence of drug resistance occurs as a consequence of the HCV replication strategy. The virus replicates at a rapid rate to produce 1012 virion particles/day (approximately 100-fold more than HIV) [6]. The RNA polymerase has poor fidelity and lacks an exonucleolytic proof-reading mechanism. Replication is inherently error-prone and is estimated to have an error-rate of in the order of 10−3 to 10−5 mutations per nucleotide per genomic replication (corresponding to a natural

The HCV NS3/4a protease

The HCV NS3 protein is a multifunctional protein that plays an essential role in the HCV life cycle. The NS3 protein possesses two major activities. Within the N-terminal third (approximately 180 amino acids) of the protein resides a serine-type protease that mediates the cis-cleavage of the NS3/4A site and subsequent cleavage of NS4A/4B, NS4B/5A and NS5A/5B junctions to liberate the HCV non-structural (NS) proteins for the assembly of the HCV replication complex. Approximately 440 amino acids

Development of NS3 protease inhibitors

The essential role of the HCV NS3/4a protease in the HCV life cycle, and its enzymatic activity, made it a prime target for the development of antiviral drugs. The crystal structure of the NS3 helicase domain was resolved in the late 1990s [15, 16, 17, 18, 19]. The enzyme has an unusually shallow substrate-binding pocket, located on the surface of the protein. The shallow catalytic site made the development of inhibitors a difficult task, and the traditional approach of screening libraries of

Resistance to NS3 protease inhibitors

The shallow catalytic site of the HCV NS3 protease allows minor structural modifications to interfere with substrate binding, promoting resistance. Single amino acid changes have been identified for all protease inhibitors that are associated with reduced drug sensitivity in vitro. Therefore, protease inhibitors have a low genetic barrier to resistance.

Clinical significance of protease inhibitor resistance associated variants

The development of telaprevir and boceprevir has already meant a number of important lessons concerning drug resistance have been learnt.

Protease inhibitor monotherapy is clearly ineffective, owing to the rapid and universal selection of resistance associated variants within days [31]. The rapidity with which resistant variants are selected suggests that resistance associated variants are present before treatment is started. Indeed, mathematical modeling predicts that all possible single and

Conclusion

HCV NS3 protease inhibitors have now been approved for the treatment of genotype 1 HCV. They have a low genetic barrier to resistance and must be used in combination with pegIFN and RBV. Indeed, the IFN responsiveness of a patient, and the ability of the pegIFN and RBV backbone to suppress pre-existing resistance associated variants determine the efficacy of telaprevir/boceprevir regimens. In patients who fail treatment, reversion to wild-type HCV is observed over time, and there is not yet

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

We are grateful to Dr. Jason Roberts of the Victorian Infectious Diseases Reference Laboratory, for assistance provided during the preparation of this manuscript.

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