In 2007, the standard care of treatment for chronic infection with hepatitis C virus (HCV) consists of the concomitant administration of pegylated interferon alfa (PEG-interferon alfa) and ribavirin. PEG-interferon alfa is an interferon alfa that has been modified chemically by addition of polyethylene glycol, a large inert molecule. When compared to thrice-weekly administration of standard interferon, pegylation prolongs the half-life of interferon-alfa and increases the rate of sustained virological response (SVR) among patients with chronic HCV infection. However, despite this improvement, the rate of SVR remains relatively low in patients with chronic hepatitis C (CHC), particularly when the infection is linked to viral genotypes 1 and 4 [1-3]. Moreover, co-administration of PEG-interferon alfa and ribavirin is associated with numerous side effects and is contraindicated in several clinical situations. Under these conditions, the need for new treatments for this serious global health problem is obvious and pressing.
Because the efficacy of combined PEG-interferon alfa and ribavirin is at least partly based on the immunomodulatory properties of these molecules , it seems evident that the development of new molecules able to improve this effect and act as immunomodulators is likely to be useful.
Among these new molecules of potential interest, distinctions must be made between those that are interferons (IFNs); those which specifically modulate T cells or act on Toll-like receptors; the therapeutic vaccines; and the cyclophilin inhibitors.
Before discussing all of these molecules, it must be emphasized that the role of the immune system in CHC is contentious. It is, however, widely accepted that various modifications of the humoral and cellular immune responses are observed in hepatitis C. Moreover, it is also widely accepted that the mechanism of action of (PEG)-interferon is at least partly linked to activation of the innate immune response through stimulation of intracellular signal-transduction pathways . Among these pathways, the retinoic acid-inducible gene pathway, the Toll- like receptor pathway, and the Jak-STAT pathway have been identified [5,6,7,8]. IFN is also able to interact with the adaptive immune system by inducing cytotoxic lymphocytes, promoting T-cell proliferation and blocking T-cell apoptosis .
Presently, many clinical studies are devoted to examining the impact of shorter or longer durations of treatment combining PEG-interferon alfa and ribavirin in relation to different viral genotypes, and also to the kinetics of viral decline following initiation of antiviral therapy [10-12].
Despite these immune effects and the existence of a direct inhibitory effect on HCV replication, the efficacy of (PEG)-interferon remains limited; however, its concomitant administration with ribavirin greatly improves its efficacy. Among all potential mechanisms of action of ribavirin, it has also been suggested that this drug may modulate the immune system by increasing the Th1 cellular immune response .
Among the newer agents, new forms of interferons are at different clinical phases of development (Table 1).
| ||TABLE 1. Interferons in development |
Consensus interferon alfa (InfergenTM) (Valeant Pharmaceuticals International) is a bio-optimized, selective type 1 interferon alfa originally developed by Amgen which differs from interferon alfa-2a and interferon alfa-2b by 19 and 18 amino acids, respectively, located in 2 of the protein's 3 domains. It is available in different countries for the treatment of CHC but is seldom used because it requires frequent administration. It has been mainly studied in comparison with standard interferon alfa without demonstrating a statistically significant superiority. Its side effects are similar to those observed with (PEG)-interferon alfa. The results of two studies, however, suggest that patients with CHC who are refractory to PEG-interferon alfa plus ribavirin or who relapse may benefit from additional therapy with consensus interferon alfa and ribavirin [14-16]. A phase 3 multicenter trial (the DIRECT trial) evaluating daily subcutaneous administration of consensus interferon alfa plus ribavirin versus no treatment in CHC patients who did not respond to previous combination therapy with PEG-interferon alfa plus ribavirin, is ongoing. The results of this trial should be available at the end of 2007. Based on the first results of the DIRECT trial-notably that a shorter washout duration after PEG-interferon alfa and ribavirin administration seems to give better results-a new multicenter, randomized US study is enrolling patients who received initial treatment with PEG-interferon alfa and ribavirin and achieved a greater than 2log10 decline in HCV RNA at week 12 but still have detectable virus. The patients will be immediately randomized to receive consensus interferon alfa plus ribavirin for 36 or 48 weeks or continue on their PEG-interferon alfa and ribavirin for an additional 36 weeks of therapy. A pegylated version of InfergenTM has been used only in a phase 1 clinical trial but at present there is no evidence for superiority of this pegylated form over other pegylated ones.
Albumin-interferon alfa (AlbuferonTM) (Human Genome Sciences) is an 85.7-kD protein consisting of recombinant human interferon alfa-2b genetically fused to recombinant serum albumin. AlbuferonTM has a prolonged elimination half-life and provides greater exposure relative to interferon alfa. In phase 2 studies, it has been shown that AlbuferonTM is well tolerated at doses up to 1200 μg, exerts an efficacy which seems at least comparable to that observed with PEG-interferon alfa, and induces side effects similar to those induced by PEG-interferon alfa. Pharmacokinetic data indicate that AlbuferonTM has a half-life of about 6 days . Recent results have demonstrated that AlbuferonTM given every two weeks and every four weeks (Q4w) may achieve similar results in interferon alfa-naïve subjects with genotype-2 or -3 CHC  or with genotype 1 . Phase 3 clinical studies have now been started. However, it is a concern that the only advantage of AlbuferonTM in comparison to PEG-interferon alfa could be a reduction in dosing frequency. In contrast, it is tempting to suggest that if the results obtained with Q4w administration of AlbuferonTM in conjunction with ribavirin are not inferior to those obtained with PEG-interferon alfa and ribavirin, then an advantage will exist in favor of AlbuferonTM.
Development of other interferon formulations remains at an early stage.
Omega interferon (Intarcia Therapeutics, Inc.) is a naturally occurring human type 1 IFN that is 60% homologous to IFN-alfa and 30% homologous to IFN-beta. The results of phase 2 studies comparing omega interferon alone versus the combination of omega interferon and ribavirin in genotype-1 CHC patients have recently been presented. They suggest a higher efficacy of the combination treatment, with a 36% SVR rate observed in the combination arm .
LocteronTM (Biolex Therapeutics) is a combination of recombinant interferon alfa and an advanced controlled release drug-delivery technology. Initial pharmacokinetic and pharmacodynamic data favor administration of the drug every two weeks , and a phase 2a clinical study combining LocteronTM and ribavirin is now ongoing.
MultiferonTM ( Viragen, Inc.) is a highly purified, multisubtype, natural human IFN-alfa derived from human white blood cells. It is marketed in different countries mainly for the adjuvant treatment of malignant melanoma. Data regarding this compound in CHC patients are scarce .
Pegylated MAXY-alfa (R7025) (developed by Maxygen in partnership with Roche) has started a phase 1b clinical trial. This product has improved antiviral and immunomodularity activities compared to PEG-interferon alfa-2a . In vitro it has been claimed to be 50 times more potent than PEG-interferon alfa. However, development of this drug has been halted.
Interferon alfa-2b-XL (Flamel Technologies) is a new sustained-release formulation of interferon alfa, which has been shown in a phase 1-2 clinical trial to provoke a prolonged release of interferon alfa over 7 days and with a similar antiviral response to that obtained with interferon alfa . Trials are currently under way comparing this novel interferon to PEG-interferon alfa.
Since all three forms of interferon (IFN-alfa, IFN-beta and IFN-gamma) have been shown to be effective inhibitors of HCV replication in human cell lines carrying HCV replicons, combination therapies using different interferons could also be an intriguing therapeutic possibility [25-27].
Based on their potential immunostimulatory properties, several interleukins (IL) have been administered in the context of CHC patients. Among these, interleukin-10, interleukin-12, and interleukin-2 have been administered in clinical trials without any significant efficacy but have elicited numerous side effects [28-30].
Thymosin alpha 1 (thymalfasin, ZadaxinTM) (SciClone Pharmaceuticals) is a synthetic 28-amino acid peptide, derived from human thymus gland extracts, that modulates immune responses . Among its effects, thymalfasin stimulates expression of MHC class I receptors, reduces the level of apoptosis, and promotes expansion of the Th1 subset of T cells by increasing the production of IFN gamma and IL-2. It requires twice-weekly injections. Phase 2 clinical studies show a slight advantage for the triple therapy thymalfasin, PEG-interferon alfa and ribavirin in comparison to PEG-interferon alfa and ribavirin in genotype-1 CHC nonresponder patients . A phase 3 clinical study is currently underway with a similar design involving nonresponders.
Histamine dihydrochloride (CepleneTM) (EpiCept Corporation) is an immune modulator that prevents oxidative stress, which theoretically should protect immune cells and thereby liver cells. It also enhances IFN activation of T- and natural killer cells. In a phase 2 clinical study, 120 naïve patients received a combination of interferon alfa-2b (thrice weekly) and histamine dihydrochloride to determine the safety and potential efficacy of histamine in combination therapy. An SVR was obtained in 38% of genotype-1 patients and 29% of patients with a high viral load. Histamine was well tolerated but the absence of a control arm does not allow for correct interpretation of the results of this trial . The clinical development of histamine as an HCV therapeutic has been discontinued.
Among the intracellular pathways influenced by exogenous interferon administration, activation of Toll- like receptors (TLR) has been clearly identified. Activation of these receptors (mainly TLR3, TLR7 and TLR9) by specific agonists (often called immune response modifiers or IRMs) has been associated with activation of the innate immune system leading to host IFN production. The production of other cytokines such as IL-12 or IFN-gamma is also enhanced. In addition to cytokine induction, IRMs induce functional maturation of dendritic cells resulting in their migration to lymph nodes and subsequent T-cell activation.
Isatoribine (Anadys Pharmaceuticals, Inc.) is a guanosine nucleoside analogue which was first identified as an IFN inducer  and then as a TLR7 agonist. In preclinical studies, isatoribine does not exert direct antiviral activity. In the first clinical study in patients with CHC, it was demonstrated that intravenous administration of this molecule is able to reduce plasma HCV RNA. This reduction in viral load was correlated with induction of cellular markers of a heightened immune antiviral state . Side effects were limited. Since pharmaceutical development of isatoribine is limited due to its poor bioavailability, a prodrug of isatoribine (ANA975) has been developed. However, in June 2006, development of ANA975 was suspended due to significant side effects observed in preclinical 13-week toxicological studies in animals. These side effects appear to be related to the intense immune stimulation observed in these animals.
CPG 10101 (ActilonTM) (Coley Pharmaceutical Group, Inc.) is a TLR9 agonist . In preliminary clinical trials, a dose-dependent antiviral response was observed in CHC patients. Recently, data obtained in a study of 74 HCV genotype-1-infected, treatment-refractory, relapsed patients who had previously received at least 24 weeks of PEG-interferon alfa plus ribavirin have been presented. This group of patients was treated for up to 48 weeks if a 2 log10 reduction in viral load was observed at week 12. The patients were randomized and treated initially for 12 weeks using different combined treatments with PEGinterferon alfa and ribavirin. At 24 weeks on therapy with ActilonTM, 7 out of 14 patients were HCV RNA-negative.
These 7 patients completed 48 weeks of therapy but only 2 of them were still HCV RNA-negative in the first weeks following cessation of treatment [37,38]. Moreover, in another clinical trial including null responders and also using different combined treatments with PEG-interferon alfa and ribavirin, no meaningful differences in viral load reduction were observed in any of the treatment arms.
In January 2007, and based on the results obtained in these two clinical trials, it was announced that development of ActilonTM was to be suspended. It must be emphasized that this drug has not been evaluated in combination with PEG-interferon alfa and ribavirin in the treatment of a naïve population, nor has it been investigated as a replacement therapy for PEG-interferon alfa.
Resiquimod, a TLR7 and TLR8 agonist (3M Pharmaceuticals), has been administered to CHC patients but did not demonstrate antiviral effects, potentially related to tolerability difficulties that constrained the dose level and frequency .
To date, it is evident that drugs directed at TLRs in the context of CHC patients have been relatively disappointing.
Therapeutic vaccines are another option, even if their conceptualization is particularly difficult (Table 2). Indeed, the target of the vaccine, the immune response to be obtained, and the importance of a specific HCV cellular immune response are still undetermined.
| ||TABLE 2. Therapeutic vaccines in development |
Among potential candidates, HCV/MF59 vaccine (Chiron) consists of the E1E2 heterodimeric glycoprotein. In healthy volunteers, it was able to induce antibodies that bound to E1E2 and CD81, the putative HCV receptor .
Another vaccine, called E1 (Innogenetics NV), is a purified 135-amino acid E1 recombinant protein consisting of a C-terminally truncated consensus-sequence form of the natural E1 protein derived from viral isolates from a patient infected with HCV genotype 1b. In a first study performed on chronic hepatitis C patients, HCV E1-vaccination was well tolerated and induced both E1-specific cellular and humoral responses . These effects were correlated with a reduction in liver inflammation and fibrosis, suggesting a potential antifibrotic effect. No modification in viral load was observed. More recently , however, a phase 2 study comparing this vaccine with a placebo was not able to demonstrate superiority of the vaccine in preventing fibrosis progression after 15 months. The latter study confirmed that this E1 vaccine is able to induce cellular and humoral responses. However, development of this drug has been halted.
The peptide vaccine IC41 (Intercell AG) consists of five synthetic peptides harboring HCV CD4 and CD8 T- cell epitopes and the synthetic adjuvant poly-L-arginine. It has been designed to induce HCV-specific CD4 and CD8 T- cell responses . Amulticenter phase 2 study of this vaccine suggests that it might have some effects by stimulating these immune responses without inducing important side effects. The authors have demonstrated a correlation between individual RNA responses and immune responses . Moreover, a study combining IC41 with PEG-interferon alfa and ribavirin in a limited number of CHC patients has shown that there is no interference between interferon alfa / ribavirin administration and the immune response. A phase 2 efficacy study is now in progress.
TG4040 is another therapeutic vaccine developed by Transgene. It is a recombinant modified virus Ankara ( MVA) vaccinia virus containing nucleotide sequences encoding nonstructural NS3, NS4 and NS5 proteins of HCV. It aims at inducing a cellular immune response against NS3, NS4 and NS5b. A phase 1 study enrolling CHC patients has just begun.
A therapeutic vaccine based on the combination of virosome-formulated peptides developed by Pevion Biotech is currently under investigation in 30 healthy volunteers in Switzerland. It has been suggested that this vaccine would be able to induce specific cytotoxic T lymphocyte (CTL) responses associated with a supportive T-cell response.
GI-5005 (GlobeImmune, Inc.) is a therapeutic vaccine which expresses an NS3-core fusion protein based on a proprietary, immunotherapeutic platform utilizing whole, heat-killed recombinant Saccharomyces cerevisae yeast genetically modified to express HCV-specific protein targets. The proteins used in this technology are believed to be essential for HCV replication and are highly conserved among HCV genotypes 1a and 1b. An interim analysis was presented at the American Association for the Study of Liver Diseases meeting in 2006, showing that this vaccine induced a cellular immune response in 12 out of 29 CHC patients with a reduction in serum alanineaminotransferase (ALT) levels and a 1 log10 viral load decrease in 3 patients .
The use of immunotherapeutic DNA vaccine is another potential HCV treatment option: the therapeutic vaccine ChronVac-CTM (Tripep AB) is one of these possibilities.
Other theoretical possibilities involving new vaccines are also under investigation. Among them, the potential of self-adjuvant epitope-based constructs , or the concomitant use of adjuvants able to induce broad B- and T-cell responses  have been described.
Different cyclophilin inhibitors (cyclosporine, mycophenolic acid) have demonstrated an ability to suppress HCV replication in cell culture. This effect seems to be due to the inhibition of a cellular replication cofactor, cyclophilin (CyP) B. This inhibiting effect is related to the ability of cyclophilins to enhance RNA binding of the NS5b polymerase and is not associated with an immune phenomenon. For this reason, different new compounds with limited or devoted immunosuppressive activity such as NIM811 (Novartis) or DEBIO-025 (Debiopharm SA) are now in development [46,47]. This topic is further developed in another chapter of this issue.
In conclusion, numerous agents able to induce an immune response to HCV are under development and represent a promising therapeutic approach owing to their avoidance of drug resistance. However, much work remains to be done before the clinical utility of most of these agents has been demonstrated. More importantly, our knowledge of the immune system needs to be greatly improved to be able to identify better future compounds.
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