Jay H. Hoofnagle

New therapies for hepatitis C

No challenge in clinical hepatology is as great today as the management of patients with chronic hepatitis C who have failed to respond to an adequate course of antiviral therapy. At present, the optimal regimen is a combination of peginterferon and ribavirin.1 When given for 24 or 48 weeks, this combination results in a sustained eradication of hepatitis C virus (HCV) and a long-term remission of the disease in at least 75% of patients with genotype 2 or 3 HCV infection and in 40%-50% of those with genotype 1.2,3 Although impressive, these sustained virological response (SVR) rates leave as many as half of patients without benefit and with no means of ameliorating the subsequent course of the disease. Despite the importance of chronic hepatitis C (the leading cause of end-stage liver disease and need for liver transplantation in the Western world) and the intensity of the research on this viral infection, there have been no further improvements in response rates to therapy in many years. When will this change? In this issue of HEPATOLOGY, two original articles provide exciting new results on a novel orally available antiviral agent that has potent effects against HCV in vitro and in vivo.4,5 VX-950, now known as telaprevir, is a peptide-mimetic drug that was developed with structurebased drug design.6 Telaprevir is a specific, reversible inhibitor of the HCV genotype 1 serine protease encoded by the nonstructural 3 and 4A region of the viral genome. This protease is essential for HCV replication,7 and its inhibition in cell culture systems results in marked suppression of viral replication.6,7 In humans, telaprevir is orally available and causes a rapid and marked decrease in serum HCV RNA levels.8 In phase Ia studies using various doses and schedules, a dose of 750 mg of telaprevir given every 8 hours resulted in rapid 3-5 log10 decreases in serum HCV RNA levels in virtually all patients. Stopping therapy at 2 weeks led to a rapid return of HCV RNA to the pretreatment levels. These results suggest that longer term therapy might lead to the eradication of the virus in a high proportion of patients. However, even before the application of VX-950 to humans, the specter of antiviral drug resistance was raised. In replicon cell culture systems, the application of VX950 was found to select for HCV variants with drug resistance.9 Similar kinetics for the development of antiviral resistance were found for other inhibitors of the nonstructural 3 protease, although these variants had different specific mutations and mechanisms of resistance. These findings indicated that the long-term use of HCV protease inhibitors would probably require a combination therapy with other protease inhibitors, HCV polymerase inhibitors, or perhaps peginterferon with or without ribavirin. It was the last combination that was eventually pursued. In this issue of HEPATOLOGY, Forestier and her coinvestigators4 from Saarland University Hospital, the University of Amsterdam, and Vertex Pharmaceutics describe the preliminary clinical results of a small phase Ib trial of telaprevir.4 The report provides information on HCV RNA and alanine aminotransferase levels in 8 patients who received telaprevir alone, 8 who received telaprevir with peginterferon, and 4 who served as controls and received peginterferon alone for 2 weeks. Telaprevir was then stopped, but the patients were offered a continuation of treatment with a combination of peginterferon and ribavirin until 48 weeks and thus were provided the standard of care for chronic hepatitis C, genotype 1. Telaprevir led to a rapid decline in HCV RNA levels within 1-4 days. The combination of peginterferon with telaprevir resulted in a similar early decline in viral levels, but importantly, the combination therapy was associated with an additional, continuing decline after the first 4 days of treatment. At 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.10 The basis for the synergy between peginterferon and telaprevir is suggested by the second article in this issue on telaprevir by Kieffer and coworkers5 from Vertex Pharmaceuticals and the Johann Wolfgang von Goethe University Hospital at Frankfurt, who investigated variations in Abbreviations: HCV, hepatitis C virus; SVR, sustained virological response. Supported in part by the Intramural Division of the National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health). Apurva A. Modi and Jay H. Hoofnagle are employees of the National Institutes of Health (US Public Health Service, US Department of Health and Human Services). Address reprint requests to: Jay H. Hoofnagle, M.D., Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 31, Room 9A27, 31 Center Drive, Bethesda, MD 20892. E-mail: hoofnaglej@extra.niddk.nih.gov; fax: 301-480-7926. Copyright

Milk thistle and chronic liver disease.

Milk thistle has been used for centuries to treat acute and chronic liver diseases and, even today, is one of the most widely used herbal medications. Its active ingredients appear to be several closely related flavinoids, collectively known as silymarin. Most silymarin preparations have at least a dozen molecular components and their isomers, including silybin, isosilybin, cis-silybin, silydianin, and silychristine. It is not clear whether one, several, or all of these components are the active ingredient(s), and most commercial preparations represent rough extracts of the milk thistle plant (Silybum Marianum) rather than a purified subcomponent. Results of studies in experimental animal models suggest that silymarin has a broad spectrum of hepatoprotective effects. Thus, silymarin can protect experimental animals against injury from several toxins, including amanita phalloides, carbon tetrachloride, ethanol, and galactosamine. Silymarin is partially protective even when given after exposure. The basis for this hepatoprotective activity may be the antioxidant qualities of the several flavinoids, but antifibrotic, antiinflammatory and immune modulatory actions of silymarin may also be important. A safe and effective, broad-spectrum hepatoprotective agent would likely be very useful in the management of liver disease. Yet, despite its clear effects in experimental animal models, silymarin has yet to be proven effective in ameliorating human liver disease. Part of the problem is that silymarin has never been adequately evaluated using objective and clinically meaningful endpoints in well-characterized cohorts of patients with welldefined forms of liver disease. Because of its safety, lack of side effects, activity in animal models, and centuries-long traditional use in liver disease, milk thistle has been introduced and is widely used as an herbal preparation in the United States. It is available in most health food stores and in many conventional grocery stores where it is advertised as beneficial for the liver or for “liver wellness.” Food and Drug Administration (FDA) rules prohibit the advertisement of any agent as a specific therapy for liver disease, unless it has been proven to be safe and effective, in which case it would be regulated as a drug rather than an herbal preparation. In surveys conducted in liver disease clinics, between 10% and 15% of patients report taking milk thistle, almost entirely on the basis of advice from friends, magazine articles, or the Internet rather than on advice of a physician. Clearly, proof of the efficacy of milk thistle preparations (or lack thereof) and further documentation of its safety are critical needs in improving management of liver disease. In the recently published Action Plan for Liver Disease Research (http://liverplan.niddk.nih.gov), evaluation of nonspecific hepatoprotective agents such as silymarin was listed as an unmet and important research goal. To address these issues, the National Center for Complementary and Alternative Medicine (NCCAM) in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) held a research workshop entitled “Silymarin for Chronic Liver Disease” (http://www.niddk.nih. gov/federal/ddicc/meetings.htm). In this workshop, two critical first steps for development of silymarin as a therapy for liver disease were defined: (1) to identify a standard, reliable silymarin product that could be used in clinical investigation and (2) to initiate phase I/II trials of this product in liver disease. Disease conditions that were considered most appropriate for evaluation were nonalcoholic steatohepatitis (NASH) and chronic hepatitis C, with particular focus on patients who were nonresponders to conventional therapy. The goals for pilot, phase I/II studies were to define the optimal dose and dosing regimen for silymarin and to identify the appropriate patient cohorts and surrogate markers for assessment of efficacy and safety. These elements were considered critical, before expensive, definitive trials of silymarin therapy were initiated that might depend upon more long-term therapy and more critical clinical endpoints. Accordingly, in March 2005, NCCAM published an announcement of availability of an industry collaboration for the development and evaluation of a commercial form of silymarin (http://nccam.nih.gov/research/announcements/active.htm). This announcement requested a partnership with a commercial entity that could provide a well-characterized, standard formulation of silymarin that could be evaluated in humans under an FDA-approved Investigational New Drug (IND) Application. Finally, in June 2005, NCCAM and NIDDK published a Request for Applications for a Silymarin Clinical Research Consortium. The Consortium will consist of approximately four Clinical Centers and a single Data Coordinating Center, which would be charged with the design and conduct of phase I/II clinical trials of silymarin in NASH and chronic hepatitis C. Each applicant for a Clinical Center is asked to document their experience in participating in multi-center clinical trials, experience in evaluation and follow-up of patients with liver disease, and insight and knowledge about design and conduct of phase I/II clinical trials. Applicants for the Data Coordinating Center are asked to document experience with managing multi-center clinical trials and data acquisition, management and analysis. A letter of intent is requested by August 15, 2005 and final applications by September 12, 2005. Applicants are limited to the United States. Details of the RFA are available at: http://grants.nih.gov/ grants/guide/rfa-files/RFA-AT-05-006.html.