Review Article: Specifically Targeted Anti-viral Therapy for Hepatitis C – A New Era in Therapy

C. M. Lange; C. Sarrazin; S. Zeuzem

Disclosures

Aliment Pharmacol Ther. 2010;32(1):14-28. 

In This Article

Abstract and Introduction

Abstract

Background Novel, directly acting anti-viral agents, also named 'specifically targeted anti-viral therapy for hepatitis C' (STAT-C) compounds, are currently under development.
Aim To review the potential of STAT-C agents which are currently under clinical development, with a focus on agents that target HCV proteins.
Methods Studies evaluating STAT-C compounds were identified by systematic literature search using PubMed as well as databases of abstracts presented in English at recent liver and gastroenterology congresses.
Results Numerous directly-acting anti-viral agents are currently under clinical phase I–III evaluation. Final results of phase II clinical trials evaluating the most advanced compounds telaprevir and boceprevir indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alfa and ribavirin strongly improves the chance to achieve a SVR in treatment-naive HCV genotype 1 patient as well as in prior nonresponders and relapsers to standard therapy. Monotherapy with directly acting anti-virals is not suitable. NS5B polymerase inhibitors in general have a lower anti-viral efficacy than protease inhibitors.
Conclusions STAT-C compounds in addition to pegylated interferon-alfa and ribavirin can improve SVR rates at least in HCV genotype 1 patients. Future research needs to evaluate whether a SVR can be achieved by combination therapies of STAT-C compounds in interferon-free regimens.

Introduction

With the current standard of care, a combination therapy of pegylated interferon-alfa plus weight based ribavirin for 24 to 72 weeks, only half of all patients with chronic hepatitis C can be cured.[1–4] The chance to achieve a sustained virologic reponse (SVR) by such regimens differs significantly between HCV genotypes with SVR rates of 40–50% in patients infected with genotype 1, contrasted by SVR rates of approximately 80% in those infected with genotypes 2 or 3.[1–5] In addition, treatment with pegylated interferon-alfa and ribavirin is long (up to 72 weeks) and associated with numerous side effects like anaemia, flu-like symptoms or depression. In view of these facts, there is an urgent need for improved treatment strategies. The exploding knowledge of the HCV life cycle and of structural features of the HCV proteins has supported the development of many promising directly acting anti-viral agents, also named 'specifically targeted anti-viral therapy for hepatitis C' (STAT-C) compounds.[6–13] Figure 1 summarizes the HCV life cycle and potential targets for STAT-C.[11,12] Many of these direct anti-virals are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir that are both inhibitors of the HCV NS3 protease and that have been shown to significantly enhance SVR rates in HCV genotype 1 patients, when applied in addition to pegylated interferon-alfa and ribavirin.[14–16] These and other STAT-C compounds will be described in this review with a focus on agents that were already evaluated in clinical trials (Table 1). Anti-virals targeting host proteins which are mandatory for HCV replication (e.g. nitazoxanide, celgosivir or DEBIO-025) are reviewed elsewhere.[17–21]

Figure 1.

The HCV replication complex. After clathrin-mediated endocytosis, fusion of HCV with cellular membranes, and uncoating the viral nucleocapsid, the single-stranded positive-sense RNA genome of the virus of approximately 9600 nucleotides is released into the cytoplasm to serve as a messenger RNA for the HCV polyprotein precursor. The HCV genome contains a single large open reading frame encoding for a polyprotein of approximately 3100 amino acids. The translated section of the HCV genome is flanked by the strongly conserved HCV 3′ and 5′ untranslated regions (UTR). The 5′ UTR is comprised of four highly structured domains forming the internal ribosome entry site (IRES), which is a virus-specific structure to initiate HCV mRNA translation. From the initially translated polyprotein, the structural HCV protein core (C) and envelope 1 and 2 (E1, E2); p7; and the six nonstructural HCV proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, are processed by both viral and host proteases. The core protein forms the viral nucleocapsid carrying E1 and E2, which are receptors for viral attachment and host cell entry. The tetraspanin protein CD81, claudin-1, occludine, scavenger receptor class B type 1 (SR-B1), the low-density lipoprotein (LDL) receptor, glycosaminoglycans and the dendritic cell-/lymph node-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN/L-SIGN) have been identified as putative ligands for E1 and E2.[83–86] The nonstructural proteins are mainly enzymes essential for the HCV life cycle. P7 is a small hydrophobic protein that oligomerises into a circular hexamer, most probably serving as an ion channel through the viral lipid membrane.[7,87–91] NS2 and NS3 are viral proteases required for the procession of the HCV polyprotein. NS2 is a metalloproteinase that cleaves itself from the NS2/NS3 protein, leading to its own loss of function and to the release of the NS3 protein.[7,90,91] NS3 provides a serine protease activity and a helicase/NTPase activity. The serine protease domain comprises two β-barrels and four α-helices. The serine protease catalytic triad – histidine 57, asparagine 81 and serine 139 – is located in a small groove between the two β-barrels. NS3 forms a tight, noncovalent complex with its obligatory cofactor and enhancer NS4A, which is essential for proper protein folding. The NS3/4A protease cleaves the junctions between NS3/NS4A, NS4A/NS4B, NS4B/NS5A and NS5A/NS5B. Besides its essential role in protein processing, NS3 is integrated into the HCV RNA replication complex, supporting the unwinding of viral RNA by its helicase activity. NS4B and NS5B are involved in the organization of the HCV replication complex by interactions with lipid membranes, which lead to the formation of the so called membranous web.[11,12,69,92] The membranous web comprises of rearranged intracellular lipid membranes derived from the endoplasmic reticulum. It provides the basis for the highly structured association of viral proteins and RNA, and of cellular proteins and cofactors within the replication complex. In addition, NS4B and NS5B are involved in transport of viral RNA within the replication complex.[11,12,69,92] NS5B is an RNA-dependent RNA-polymerase which catalyses the synthesis of a complementary negative-strand RNA by using the positive-strand RNA genome as a template.[11,12,69] From this newly synthesized negative-strand RNA, numerous RNA strands of positive polarity are produced by NS5B activity which serve as templates for further replication and polyprotein translation. As a result of its poor fidelity leading to a high rate of errors in its RNA sequencing, numerous different isolates are generated during HCV replication in a given patient, termed HCV quasispecies. It is thought that as a result of the lack of proof-reading of the NS5B polymerase together with the high replication rate of HCV every possible mutation will be generated each day. Thus, NS5B is one key factor in the development of viral resistance during STAT-C therapies.

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