Paul Glue, MD
Director, Clinical Pharmacology
Schering-Plough Research Institute
Kenilworth, New Jersey
Key Learning Objective
At the end of the session the participants will be able to:
· review the near-term and longer-tem treatment prospects for chronic hepatitis C, based on recent research findings
In the late 1980s, interferon-alfa monotherapy was approved as a treatment for chronic hepatitis C (CHC). The development of HCV-RNA assays in the early 1990s showed the efficacy of interferon monotherapy to be modest at best. Other therapies, including oral ribavirin as monotherapy, were ineffective (Bodenheimer, et al. 1997). In the mid-1990s, the combination of interferon-a2b (Intron A) and ribavirin was shown to be more efficacious than Intron A alone (Reichard, et al. 1998). This was confirmed in several large controlled studies in interferon-naïve patients (McHutchison, et al. 1998; Poynard, et al. 1998) and in interferon-relapse patients (Davis, et al. 1998). However, response rates in some patient groups (e.g., patients infected with genotype 1) are modest, and tolerability problems with this combination can lead to dose reduction and/or treatment discontinuation. Thus, investigation of new treatments for chronic hepatitis C continues.
Near Term New Treatments
Clinical trials with pegylated interferon-a2b (PEG-Intron) as monotherapy have been completed, and a large clinical trial of PEG-Intron plus ribavirin is underway. PEG-Intron is a 1:1 conjugate of interferon-a2b and a 12,000 dalton polyethylene glycol molecule. Pegylation reduces the clearance of interferon-a2b. It has pharmacokinetic characteristics consistent with once weekly administration. In clinical studies, once weekly PEG-Intron had identical pharmacodynamic characteristics to Intron-A administered 3x/week, with equivalent or superior anti-HCV activity (Glue, et al. 1999a). Combination studies with PEG-Intron and ribavirin demonstrated increased activity of the combination compared with PEG-Intron alone (Glue, et al. 1999b; see Table 1).
Table 1: Proportion of Patients with Undetectable Serum HCV-RNA* after 24 Weeks Treatment with PEG-Intron Alone or Combined with Ribavirin: End of Treatment and 4 Week Follow-up Data.
Week 24 (end of treatment) PEG dose PEG mono PEG + ribavirin 0.35 3/6; 50% 7/12; 58% 0.7 5/8; 63% 11/16; 69% 1.4 4/8; 50% 13/16; 81% Week 28 (4 weeks post-treatment) PEG mono PEG + ribavirin 0/6; 0% 3/12; 0% 4/9; 44% 8/15; 53% 4/7; 57% 11/15; 73%
* qPCR assay; LOQ: 100 copies/mL Longer Term Treatment Prospects
There are a number of novel treatment strategies for CHC in development. Work in this area is hampered by the lack of availability of HCV tissue culture methods, or convenient small animal CHC models. Indeed, many aspects of HCV’s lifecycle are still poorly understood. However, recent developments with HCV surrogate viral assays (Lai, et al. 1999), and the recent description of a cloned hepatoma cell line culture system capable of producing certain HCV proteins (Lohmann, et al. 1999), may assist in the more rapid development of novel and rational therapies.
The most closely anticipated novel treatment strategy involves inhibiting viral replication/ assembly through inhibition of HCV translational and postranslational processing (NS3 protease), or by inhibiting processing of nonstructural proteins (NS5b polymerase, helicase). While none of these compounds have yet entered clinical testing, recently ribavirin has been shown to have modest inhibitory effects against polymerase (Hong, et al. 1999). It is anticipated that when available, these newer compounds will be used as part of a combination treatment regimen rather than as monotherapy. The internal ribosomal entry site (IRES) is a critical step in the translation of the HCV genome, and may be another target for development of anti-HCV agents.
Previous attempts to confer immunity to HCV by vaccination have been unsuccessful, reflecting the highly polymorphic nature of this virus. Nonspecific immune stimulating strategies (e.g., IL-2, IL-12, GM-CSF) have not been successful, and are limited by these compounds’ toxicities. Immune modulating strategies, to prevent inflammatory activity producing hepatocyte damage or to reverse fibrosis, are presently being explored, and appear promising. For example, interleukin 10 (IL-10), a TH2 cytokine, was recently shown to reverse biopsy fibrosis scores in a Phase II trial, in the absence of any antiviral activity (Nelson, et al. 1999). This finding requires confirmation in a larger study. Other novel strategies might include techniques to block hepatocyte infection/viral entry (e.g., by inhibition of CD81; Pileri, et al. 1999).
In addition to new therapies, clinical strategies will have to be developed to determine optimal treat-ment strategies (choice of treatment, dose and duration) based on patients’ clinical characteristics (genotype, viral load, etc.). The role of induction therapy needs to be clarified. CHC treatment of patients with renal or liver dysfunction, transplant patients, patients with hemoglobino-pathies, HIV/HCV co-infected patients and children will also need to be explored.
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2. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Intervention Therapy Group. New Engl J Med 1998;339:1493-9.
3. Glue P, Fang JW, Sabo R, Rouzier-Panis R, Raffanel C, Gupta SK, et al. Peg-Interferon-a2B: Pharmacokinetics, pharmacodynamics, safety and preliminary efficiency data. Hepatology 1999;30:189A.
4. Glue P, Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Jacobs S, et al. A dose-ranging study of peg-intron and ribavirin in chronic hepitatis C – safety, efficacy and virologic rationale. Hepatology 1999b;30:303A.
5. Hong Z, Ferrari E, Wright-Minogue J, Skelton A, Glue P, Zhong W, et al. Direct antiviral activity of ribavirin: hepatitis C virus NSSB polymerase incorporates ribavirin triphosphate into nascent RNA products. Hepatology 1999;30:354A.
6. Lai VCH, Hong Z, Zhong W, Skeleton A, Donis R, Lau J. Generation of a hepatitis C virus NS3 protease-dependent chimeric pestivirus – a cell-based antiviral assay. Hepatology 1999;30:617A.
7. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenchlger R. Replication of subgenomic hepatitis C virus RNAs in a hematoma cell line. Science 1999;285:110-3.
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9. Nelson DR, Lauwers GY, Lau JY, Davis GL. A pilot study of recombinant human interleukin 10 (tenovilTM) in patients with chronic hepatitis C who failed interferon-based therapy. Hepatology 1999;30:189A.
10. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, et al. Binding of hepatitis C virus to CD81 Science 1999;282:938-41.
11. Poynard T, Marcellin P, Lee SS, Niederau C, Minuk GS, Ideo G, et al. Randomised trial of interferon alpha 2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426-32.
12. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg, Weiland O. Randomized, double-blind, placebo-controlled trial of interferon alpha2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 1998;351:83-7.