Future therapies for hepatitis C: where do we go from here?

Samuel Sigal and Ira Jacobson*  About the authors

Chronic hepatitis C affects over three million people in the US, is associated with the development of cirrhosis and hepatocellular carcinoma, and represents the most common indication for liver transplantation. Although treatment has improved, nearly 50% of patients fail to achieve a sustained virologic response (SVR). Nonresponse to treatment is particularly prevalent in patients infected with HCV genotype 1 (the predominant HCV genotype in the US), those with cirrhosis or with HIV coinfection, and African Americans.

Research in HCV therapy focuses on refining existing drugs and on developing compounds with novel mechanisms of action. Taribavirin (Valeant, Costa Mesa, CA) is a prodrug that is converted to ribavirin and concentrated in the liver. In two phase III trials that compared treatment with either pegylated interferon (PEG-IFN)-2b, or PEG-IFN-2a in combination with taribavirin versus ribavirin alone, taribavirin failed to meet noninferiority criteria for efficacy although superior hematologic safety was demonstrated.¹ (See supplementary information for the full list of abstracts). Further studies with taribavirin dosage based on body weight are expected. Eltrombopag (GlaxoSmithKline, Middlesex, UK) is a novel small molecule that functions as a potent thrombopoietin. A phase II study has shown eltrombopag to raise platelet counts effectively to levels >200 10⁹/l which enables the use of standard HCV therapy in 71–91% of patients.² The capacity to treat patients with cirrhosis and HCV might, therefore, be facilitated by the use of this agent in conjunction with interferon-based therapy.

A novel recombinant protein that consists of interferon- fused to human albumin—albumin interferon—is under development. This agent has an exceptionally long plasma half-life, which allows its administration every 2–4 weeks. Albumin interferon treatment has been associated with a 21% SVR rate in patients who have previously failed to respond to treatment with PEG-IFN plus ribavirin.² In a study with treatment-naive patients, the 24-week response rate with albumin interferon (dose 900 g or 1200 g every 2 weeks) compared favorably with that of PEG-IFN-2a treatment.² Large phase III trials are expected to be initiated shortly. Other potential advances in interferon therapy include the development of novel interferons (gene-shuffled interferons) such as locteron (OctoPlus, Leiden, The Netherlands) and a new administration route that involves implantation of a subcutaneous device that releases interferon- over several months.¹

The greatest potential advance in HCV therapy lies in orally available small molecules that provide specifically targeted antiviral therapies for HCV (STAT-C), such as HCV protease and polymerase inhibitors. Telaprevir (Vertex Pharmaceuticals Inc., Cambridge, MA) forms a covalently but reversibly bound complex with HCV protease. A 4.4 log₁₀ median reduction in viral load at day 14 of treatment has been shown in patients given 750 mg telaprevir every 8 h, and an additional logarithmic reduction has been shown for telaprevir in combination with PEG-IFN.^{3, 4} A decline in HCV RNA to undetectable levels by day 28 of treatment has been shown in 12 of 12 patients on telaprevir combined with PEG-IFN-2a and ribavirin. Encouraging follow-up data have begun to emerge on the patients included in these early trials.² Two large trials in treatment-naive patients are in progress and further trials are anticipated.⁵ Treatment-resistant viral mutations have been detected in patients on telaprevir monotherapy,^{1, 6} but the addition of PEG-IFN seems to repress the emergence of these resistant strains.^{2, 6} Other HCV protease inhibitors that are under development include SCH503034 (Schering-Plough, Kenilworth, NJ), ITMN-191 (Intermune, Brisbane, CA), and GS9132 (Gilead Sciences, Foster City, CA).⁴ SCH503034 has been shown to induce a mean 2-log reduction in HCV RNA with 14 days of treatment, and, when combined with PEG IFN-2b, 4 of 10 prior nonresponders became HCV-RNA-negative.⁴ This drug is the focus of a large, international, phase II study in patients who previously did not respond to therapy; further trials are anticipated.

Valopicitabine (Idenix Pharmaceuticals Inc., Cambridge, MA) is a nucleoside (cytidine) analog that inhibits viral RNA polymerase and has been shown to possess antiviral activity in early trials. Compared with PEG-IFN and ribavirin, combination therapy with valopicitabine and PEG-IFN in nonresponders was associated with a greater mean decline in HCV RNA levels.² PEG-IFN and valopicitabine combination therapy in treatment-naive patients has shown promising antiviral activity with an early virologic response exhibited in 82–92% of patients, and HCV-RNA negativity in up to 68% of patients by week 24 of treatment.² Other nucleoside inhibitors (R1626; Roche, Basel, Switzerland) and non-nucleoside, allosteric inhibitors of polymerase activity (HCV-796; Wyeth, Madison, NJ), have shown evidence of antiviral activity and are under development.¹ The antiviral activity of nonimmunosuppressive cyclosporin analogs (NIM811 [Novartis, Basel Switzerland]; DEBIO-025 [Debiopharm, Lausanne, Switzerland]) is also being investigated. These molecules disturb interaction of the replicase with cyclophilin B, a functional regulator of the HCV RNA-dependent RNA polymerase that is independent of the calcineurin–nuclear factor of activated T cells pathway involved in immunosuppression.^{4, 7} N-glycosylation of viral glycoproteins is important in viral morphogenesis, and inhibition of -glucosidase 1 activity adversely affects viral maturation.⁸ In preclinical studies, celgosivir, an -glucosidase 1 inhibitor (Migenix Inc., Vancouver, BC and Schering-Plough, Kenilworth, NJ), has shown synergy with interferon- and ribavirin, and a phase II study is in progress.⁹

Immunomodulatory approaches that are being studied include agonists of Toll-like receptors(TLR), which activate pathways of innate, cellular and humoral immunity. CpG oligonucleotides, which contain motifs resembling bacterial DNA, activate TLR-9 expressed in plasmacytoid dendritic cells and B cells. CpG 10101 (Coley Pharmaceuticals, Wellesley, MA) is a CpG oligonucleotide product that has shown antiviral activity in early trials and enhanced responses when combined with PEG IFN and ribavirin in prior relapsers.² Possible therapeutic vaccines are also under investigation, such as one derived from the HCV envelope protein E1.¹⁰ Heat-killed Saccharmomyces cerevisiae expressing HCV nonstructural protein 3 and core antigen (GlobeImmune, Louisville, CO) elicits HCV-specific T-cell responses in mice and in peripheral blood mononuclear cells derived from HCV-infected patients; an early clinical report showed enhanced acquired immunity to HCV antigens and possible antiviral activity.²

The introduction of targeted antiviral therapies for HCV and other new agents has the potential to lead to rapid viral clearance, increased SVR rates, and reduced duration of therapy. Earlier protease and polymerase inhibitors, and nucleic-based technology, have failed because of insufficient antiviral activity, safety, or delivery issues. Eventually one or more of the agents discussed here, or other promising approaches that are undergoing preclinical tests (p7 protein inhibitors, internal ribosome entry-site inhibitors, small interfering RNAs), will prove to be safe and effective. We predict that as testing evolves, new rules for tailored HCV therapy will be established, facilitating highly individualized treatments that involve combinations of agents. There is much work to do but a sense of excitement and optimism prevails.

Competing interests

I Jacobson declared he has associations with the following companies: Bristol-Myers Squibb, Celera, Coley, Gilead, GlaxoSmithKline, Globimmune, Human Genome Sciences, Idenix, Intarcia, Intermune, Merck, Novartis, Pfizer, Schering, TAP, Valeant, Vertex and XTL.
S Sigal declared he has associations with the following company: GlaxoSmithKline.

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