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Future trends in managing hepatitis C John G. McHutchison, MD*, Anouk T. Dev, MD, PhD Division of Gastroenterology and GI/Hepatology Research, Duke Clinical Research Institute, Duke University Medical Center, P.O. Box 17969, Durham, NC 27710, USA
Current standard therapy with pegylated interferon (PEG-IFN) plus ribavirin (RBV) produces a sustained virologic response (SVR) in more than 50% of patients who have chronic hepatitis C [1–3], but such therapy is associated with certain limitations including high cost, morbidity from side effects, and the requirement for prolonged (6–12 months) treatment. In addition, a substantial proportion of patients do not achieve an adequate response and might therefore require further therapy, and patients who have advanced liver disease or contraindications to current therapy have limited treatment options. Further, the growing number of patients who have chronic hepatitis C who are undergoing treatment will contribute to the need for new agents and innovative treatment strategies for those who do not respond to currently available therapy. The search for new therapies will focus on the development of agents that have improved efficacy or tolerability. Desired features of agents for the treatment of hepatitis C virus (HCV) infection include oral bioavailability, a high degree of antiviral efficacy, greater tolerability, minimal or no development of resistance, cost effectiveness, and broad application for most patients [4]. To date, such therapy is not available, and current standard regimens of PEG-IFN plus RBV are likely to remain the mainstay of
Dr. McHutchison has received grants and research support from or has acted as an advisor for Akros Pharma, Amgen, Biomedicines, Bristol-Myers Squibb, Fujisawa, Gilead Sciences, IDUN, Isis Pharmaceuticals, Prometheus Laboratories, Ribozyme Pharmaceuticals, Roche Pharmaceuticals, Sciclone, and Schering-Plough Corporation, and he has consulted for Anadys Pharmaceuticals, Centocor, GlaxoSmithKline, Intermune Pharmaceuticals, Isis Pharmaceuticals, National Genetics Institute, Prometheus Laboratories, Ribozyme Pharmaceuticals, and Schering-Plough Corporation. He is also a member of Speaker’s Bureaus for Intermune Pharmaceuticals, Roche Pharmaceuticals, and Schering-Plough Corporation. * Corresponding author. E-mail address:
[email protected] (J.G. McHutchison). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2003.12.001
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Box 1. Anti-hepatitis C virus therapeutics under development Modified interferons (IFNs)/new delivery methods Disposable infusion pumps Controlled-release injectables Oral delivery systems Liposome-based systems Ribavirin analogs Levovirin Viramadine Other immunomodulatory agents Inosine 59-monophosphate dehydrogenase (IMPDH) inhibitors Histamine dihydrochloride Thymosin-a1 Amantadine Molecular-based therapies HCV enzyme inhibitors Antisense oligonucleotides Ribozymes Short interfering RNAs Antifibrotic agents c interferon Vaccines
anti-HCV therapy for the next decade. Many new agents and treatment strategies are currently under intense investigation (Box 1). Enhancement of current therapies Adherence and viral testing Response rates to current treatment regimens might be improved by promoting adherence to anti-HCV therapy. A retrospective analysis of three randomized clinical trials evaluating standard IFNa-2b plus RBV or PEGIFNa-2b plus RBV demonstrated that patients who were maintained on greater than or equal to 80% of their total IFN and RBV doses for greater than or equal to 80% of the expected duration of therapy (80/80/80 adherence) had higher SVR rates compared with patients who received reduced doses (\ 80% of one or both drugs for 80% of the expected duration of therapy) [5]. The benefit was particularly evident among patients who had HCV genotype 1 infection. Among patients who had genotype 1 who
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received PEG-IFNa-2b 1.5 lg/kg weekly plus RBV 800 mg/day for 48 weeks, 51% of patients who had 80/80/80 adherence achieved SVR compared with 34% of patients who received reduced doses (P = 0.011). Statistical modeling demonstrated a progressive positive correlation between SVR rates and adherence. The most frequent reason for nonadherence was treatment-related side effects ([75% of patients) followed by failure to attend scheduled appointments, withdrawal of consent, and nonadherence in the absence of apparent side effects. Strategies to improve adherence to therapy may involve interventions directed at the patient and the support staff, modifications to the treatment regimen, and management of side effects. Potential strategies include the use of medication diaries, electronic monitoring devices, and directly observed therapy for selected patients at high risk of nonadherence [5]. Follow-up telephone calls from support staff and patient education designed to provide feedback regarding viral loads, management of treatment-related side effects [6], and the need for lifestyle changes are likely to be beneficial [5]. Support groups and frequent follow-up clinic visits might also be important. The introduction of PEG-IFNs, with the decreased number of injections compared with standard IFN (weekly versus three times per week), is also likely to be associated with improved adherence [5]. Viral testing early in the course of therapy can be used to predict patients who are more likely to achieve a response and, more accurately, patients who are unlikely to respond. Among patients receiving weekly PEG-IFNa2b 1.5 lg/kg weekly plus RBV 800 mg/day, a greater than or equal to 2-log10 decrease in HCV RNA after 12 weeks of therapy had a negative predictive value of 100%; none of the patients who failed to achieve a greater than or equal to 2-log10 decrease in HCV RNA after 12 weeks subsequently achieved SVR [7]. The effect was evident primarily among patients who had HCV genotype 1; patients who have genotypes 2 and 3 have such a high rate of response that early testing is unlikely to be necessary in most patients. The clinical decision to continue therapy beyond 12 weeks, however, must take into consideration a number of other factors (eg, patient tolerance and possible stabilization of fibrosis progression in patients who have advanced histology). Novel interferons/cytokines and interferon delivery methods Beyond PEG-IFNs there are several novel parenteral IFN and cytokines in early development [4], including PEG-IFNa-con-1; omega IFN; albumin-bound IFN; interleukins (IL)-28A, -28B, and -29; and engineered, second-generation IFNs. Oral agents that can stimulate the production of IFN (eg, ANA245) are also under development. There are also a number of new delivery systems under investigation designed to produce sustained IFN release into the systemic circulation, including disposable infusion pumps, controlled-release injectables (using a polymer matrix) for
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intramuscular or subcutaneous administration, oral delivery systems (eg, polyaminoacid-based systems), and the encapsulation of IFN in liposomes [8]. Ribavirin analogs Although the addition of RBV to IFN-based regimens improves SVR rates, the drug is associated with side effects (particularly anemia) that often require dosage reduction or discontinuation of treatment [1,4,6]. RBV-induced anemia is believed to be caused by the accumulation of the phosphorylated form of RBV in red blood cells (RBCs) [9,10]. RBCs lack the phosphatase activity responsible for converting phosphorylated RBV back to the parent compound, the only form capable of being transported out of the cell [9]. RBV analogs such as levovirin and viramidine, which are designed to produce the efficacy of RBV while avoiding its RBC toxicity, are under investigation [9,10]. Levovirin, the L-enantiomer of RBV, undergoes a different metabolic pathway than the parent compound [9,10]. Levovirin retains the immunomodulatory properties of RBV but, unlike RBV, levovirin is not phosphorylated and does not accumulate in RBCs [9,10], the likely reason for its potentially improved safety profile. In preclinical studies, levovirin was not associated with anemia or genotoxicity [11,12]. In a phase I study in humans, levovirin was safe and well tolerated at the single doses tested (200–1200 mg) with no anemia [13]. Viramidine is a prodrug of RBV that retains the antiviral and immunomodulatory properties of the parent drug but lacks its uptake and toxicity characteristics [10]. Because viramidine does not use the same nucleoside transporter as RBV, it accumulates in RBCs to a much lower degree than RBV [10,14]. Viramidine also is taken up into hepatocytes by a mechanism distinct from that of RBV, with greater affinity for the liver [9]. The difference between the agents in hepatic and RBC uptake results in a much higher liver-to-RBC ratio for viramidine compared with RBV [14]. The liver-targeting properties of viramidine appear to be responsible for the decreased propensity of the drug to cause anemia. In Cynomolgus monkeys there were no observable effects limits for viramidine at doses of greater than 300 mg/kg daily administered for 14 days [14]. In contrast, RBV 100 mg/kg daily for 14 days produced significant decreases in RBC, hematocrit, and hemoglobin counts. Phase II and Phase III studies of viramidine in combination with IFN are ongoing [4]. Inosine 59-monophosphate dehydrogenase inhibitors IMPDH is the rate-limiting enzyme involved in the biosynthesis of guanine [4]. Drugs that inhibit IMPDH have antiproliferative, antiviral, and immunomodulatory effects [8]. Selective IMPDH inhibitors include RBV, mycophenolate, and the investigational agent VX-497. VX-497 is an orally
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bioavailable, small molecule with demonstrated broad in vitro activity against a wide variety of viruses [4]. VX-497 also has inhibitory activity in the HCV replicon system as a single agent and additive activity to that of IFN [15] or IFN/RBV. Fifty-three previously untreated patients who had HCV genotype 1 were randomized to receive IFNa-2b plus VX-497 100 mg or 300 mg orally or placebo orally three times daily for 4 weeks [15]. VX-497 was well tolerated, with no anemia and no additional hematologic toxicity over that seen with IFNa-2b monotherapy. There was a trend toward greater reductions in HCV RNA among patients in the VX-497 100 mg group compared with the placebo group, although the difference did not reach statistical significance. Longer-term studies are currently underway to better determine the anti-HCV efficacy of VX-497/IFNa combinations. Mycophenolate mofetil is also under evaluation in combination with PEGIFNa-2a in patients who relapsed or did not respond to IFN/RBV therapy [16]. A number of other, more potent IMPDH inhibitors are also currently under development.
Other adjuvant immunomodulatory agents Histamine dihydrochloride exhibits various immunomodulatory effects by way of T-cells and natural killer (NK) cells and inhibits phagocyte-derived oxidative stress and inflammation [17]. A randomized trial compared four dosage regimens of histamine dihydrochloride in combination with IFNa-2b in treatment-na€ıve patients [18]. Patients received a fixed 1 mg dose of histamine dihydrochloride in one of four schedules: (1) once a day, three times a week; (2) once a day, five times a week; (3) twice a day, three times a week; or (4) twice a day, five times a week. The SVR rate at the end of the follow-up period (week 72) ranged from 31% to 38% across the dosage groups [18]. Although this was not a placebo-controlled trial, these SVR rates were higher than those typically achieved with standard IFNa monotherapy. Larger phase II studies evaluating histamine dihydrochloride in combination with standard agents (ie, PEG-IFN, RBV) are currently underway. Thymosin-a1 is a synthetic 28-amino acid nonglycosylated peptide derivative of a purified thymosin extract from the thymus gland and other cells. The compound has immunoregulatory activity that includes the promotion of T-cell maturation, increased NK cell activity, and the increased production of IFNc, IL-2, and IL-3 [19]. Small pilot studies evaluating the safety and efficacy of thymosin-a1 in combination with IFNa have suggested that the drug is more effective than IFN monotherapy [20–22] and that the compound might have a role in combination with IFN in patients who do not respond to first-line IFN monotherapy [8]; however, deficiencies in the design of these studies preclude a valid conclusion regarding the efficacy of thymosin-a1. Currently there are two double-blind, multicenter trials underway assessing the efficacy of thymosin-a1 plus PEG-IFNa-2a
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in cirrhotic and noncirrhotic patients who have not responded to IFN monotherapy or IFN/RBV combination therapy [8]. Amantadine is an antiviral agent that has activity against a wide range of viruses, including influenza A [23]. Amantadine appears to interfere with the early stages of viral replication or the uncoating or primary transcription of viral RNA; however, the drug has shown little or no direct inhibition of HCV replication in vitro [4,23]. In patients who had previously untreated chronic hepatitis C, the results of some, but not all, randomized trials evaluating the addition of amantadine to standard IFNa have suggested that the combination therapy modestly improves SVR rates [24]. A metaanalysis of five trials involving 924 treatment-na€ıve patients showed that standard IFNa plus amantadine was associated with a significantly higher SVR rate compared with standard IFNa monotherapy (22.4% versus 16.6%; P \ 0.03) [4]. Data evaluating the efficacy of amantadine in tripletherapy regimens in combination with standard IFNa and RBV are also equivocal. Among 400 patients who had previously untreated disease, amantadine/IFNa/RBV produced SVR in 52% of patients compared with 43% of patients receiving IFNa/RBV, although the difference did not quite reach statistical significance (P = 0.055); no significant difference in response rates between treatment regimens in patients infected with HCV genotype 1 was observed [25]. Because PEG-IFN/RBV therapy produces higher SVR rates, the value of adding amantadine to such regimens in previously untreated patients needs evaluation, and additional randomized trials of triple therapy using PEG-IFN are ongoing [4]. The role of amantadine in combination with IFN and RBV among patients who have failed prior IFN monotherapy or standard IFN/RBV combination therapy has not been clearly established, and further evaluation might be warranted, particularly in combination with PEG-IFN and RBV [24].
Molecular-based therapies Hepatitis C virus enzyme inhibitors HCV is a positive-stranded RNA virus 9.6 kb in length that belongs to the flaviviridae family of viruses [26,27]. The genome is flanked by 59 and 39 untranslated regions, which are required for translation and replication of the viral RNA [4]. The genome encodes a polyprotein of approximately 3000 amino acid residues that is processed posttranslationally by host and viral proteases into 10 structural (core, E1, E2, p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins [4,26,27]. The nonstructural proteins encode several enzymes required for protein processing and replication (eg, proteases, helicases, polymerases), thus providing novel targets for the development of antiviral therapies [26]. Proteins that are potential therapeutic targets for inhibition include NS3 protease, NS3 helicase, NS3 bifunctional protease/helicase, and the NS5B RNA-dependent RNA polymerase,
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whose three-dimensional structures have been determined recently [27]. Because of their specificity many of these enzymes are promising targets for drug therapy. A number of potential inhibitors have been described and some are in the early stages of preclinical and clinical development [4]; however, there are a number of barriers to the development of HCV enzyme inhibitors, including the need to have activity against a broad range of genotypes (6) and subtypes (90) and the potential for the development of viral resistance. It will likely be several years before the clinical potential of any specific HCV enzyme inhibitor is known. Antisense oligonucleotides Antisense oligonucleotides are unmodified or chemically modified single-stranded DNA or RNA molecules designed to prevent the translation of viral RNA [28]. The antisense oligonucleotide specifically binds to a target mRNA, resulting in a hybrid mRNA that is subsequently degraded by the cellular enzyme RNAase H [4,28]. ISIS-14803 is a 20-base antisense oligonucleotide currently under development that is complementary to a highly conserved region of the HCV internal ribosomal entry site (IRES) [29]. ISIS-14803 has been demonstrated to have dose-dependent anti-HCV activity in a number of in vitro and in vivo models [29]. In a phase I/II trial, 28 patients infected with HCV (primarily including patients who had not responded to prior IFN-based therapy) received escalating doses of intravenous or subcutaneous ISIS-14803 [30]. Treatment was generally well tolerated and associated with HCV RNA reductions greater than 1.0 log10; however, some of the responding patients experienced transient and asymptomatic increases in serum alanine aminotransferase (ALT) levels. Current and planned studies are designed to evaluate the long-term efficacy and safety of this agent in a variety of patient populations and combination treatment regimens [29]. Ribozymes Ribozymes are catalytic RNA molecules that act by binding to and cleaving specific sequences of RNA. Although unmodified ribozymes are subject to rapid host nuclease degradation, chemical modifications produce improved stability. Animal studies of a ribozyme targeted at the 59 untranslated region of HCV (RPI.13919) have demonstrated that this agent is distributed to the liver in sufficient amounts to inhibit HCV-IRESluciferase expression after intravenous administration [31]. RPI.13919 has also been shown to produce dose-dependent inhibition of viral replication in vitro, and the effect is potentiated by IFN [4]. Short interfering RNAs Short interfering RNAs are the byproducts of the cleaving of doublestranded RNA, an intermediate in the replication of many viruses. Short
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interfering RNA molecules associate with the RNA-induced silencing complex, a multiprotein complex. Thus, homologous mRNA is targeted for degradation, leading to the selective destruction of nonself double-stranded RNA. HCV-specific short interfering RNAs have recently been demonstrated to block HCV replication and protein expression in vitro by a mechanism that is independent of IFN [32], which suggests that the induction of RNA interference has a potential role as a therapeutic modality in patients who have chronic HCV infection.
Antifibrotic agents The development of hepatic fibrosis is initiated by an injurious stimulus (eg, HCV infection) resulting in a cascade of events that are mediated by a variety of cytokines. Therapeutic approaches aimed at reducing liver inflammation and preventing the development of fibrosis in the absence of viral clearance are important objectives in patients who have chronic hepatitis C, especially patients who are unresponsive to antiviral therapy or who have contraindications to current therapies. Potential antifibrotic therapies include cytokine manipulation and antifibrotic agents. Although several antifibrotic compounds are under development, for the most part these agents have not progressed beyond preclinical evaluation. IFNc has a number of properties (antimicrobial, antiproliferative, and antifibrotic) that suggest that it might have a role in preventing the progression of liver fibrosis. In subgenomic HCV replicon constructs IFNc inhibits protein synthesis and RNA replication [33]. IFNc has also been shown to downregulate transforming growth factor-b and to decrease hepatic stellate cell activation and proliferation [4]. In patients who have idiopathic pulmonary fibrosis who are not responsive to glucocorticoids alone, the combination of IFNc and prednisolone improves markers of pulmonary function [34]. A randomized, double-blind, multicenter phase II trial is currently evaluating the ability of IFNc-1b to improve histologic fibrosis in 450 patients infected with HCV who have severe liver fibrosis or compensated cirrhosis who have failed IFNa therapy [4].
Vaccines The development of a vaccine against HCV has been slow because of substantial barriers including the lack of a small animal model, the high degree of HCV genomic variability, and difficulties with producing high quantities of HCV in tissue culture [35]. Targets for HCV DNA vaccines include envelope glycoproteins (E1 or E2), core antigen, and nonstructural proteins (NS3, NS4, NS5) [36,37]. The development of a novel HCV replicon system might allow for faster progress in HCV vaccine development [35]; however, a clinically available vaccine remains many years away.
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Summary The treatment of chronic hepatitis C remains less than ideal for all patients. Despite the availability of new treatment regimens such as PEG-IFNs plus RBV, which produce significant improvements in SVR rates, there remains a substantial proportion of patients who do not achieve sustained viral clearance. This situation is particularly true for difficult-totreat populations (eg, patients who have HCV genotype 1 infection or cirrhosis). These regimens are also associated with substantial side effects that can lead to nonadherence, dosage reductions, and treatment discontinuation [6]; however, these regimens will continue to be the primary treatments for the next decade. A number of new therapeutic agents and strategies are under development that have the potential to further improve SVR rates. The goal of the new agents and strategies is to increase SVR rates significantly over current therapy and to improve tolerability. It is likely that new regimens will involve the use of multiple-drug combinations to produce improved SVR rates and to diminish or reduce the emergence of viral resistance; however, the addition of new agents to the current anti-HCV regimen will also increase the complexity of treatment. When a third drug is added numerous potential treatment sequences need to be explored to determine the schedule that will produce optimal results. Treatment regimens for chronic hepatitis C will continue to evolve and improve. Expanding knowledge of the molecular biology of HCV has provided the basis for developing a number of novel therapeutic targets. Promising initial results have been demonstrated with several new therapies; however, most of these agents and strategies require considerable further investigation before their potential role in the treatment of chronic hepatitis C can be determined.
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