Medical Education Activities for Clinicians Since …Physicians’ Desk Reference (PDR). Nezam H. Afdhal, MD, has received grant/research support from Bristol-Myers Squibb, Coley Pharmaceutical

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Program Information ..................................................................................................................................................2About This Program .....................................................................................................................................................5Faculty Biographies .....................................................................................................................................................6Drugs or Investigational Agents Mentioned in This Presentation ...........................................................8

AgendaIntroduction .................................................................................................................................................................9 Eugene R. Schiff, MD

The Handwriting on the Wall: The Increasing Challenge of HCV Disease Burden ...............�� Hashem B. El-Serag, MD, MPH

Reality Check: Assessing the Present to Anticipate the Future .................................................... �6 Nezam H. Afdhal, MD

Finding Our Way in the Maze: Changing Direction Toward More Effective Treatment................................................................................................................................................ 22 Mark S. Sulkowski, MD

Q & A Faculty Panel

Conclusion ................................................................................................................................................................... 29 Eugene R. Schiff, MD

Table of Contents

Who Moved My PEG?� The Changing Future of Anti-HCV Therapy

Medical Education Activities for Clinicians Since 1980

TM

This independent CME activity is supported by an educational grant from Vertex Pharmaceuticals Incorporated.

Copyright © 2007. Projects In Knowledge, Inc. All rights reserved.Projects In Knowledge, Overlook at Great Notch, �50 Clove Road, Little Falls, NJ 07424www.projectsinknowledge.com

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Program Information

Target Audience

This CME activity is designed for gastroenterologists and other clinicians who treat patients with HCV infection.

Activity Goal

The goal of Who Moved My PEG? The Changing Future of Anti-HCV Therapy is to provide state-of-the-art, clinically relevant information that will provide clinicians with new insights into HCV epidemiology and disease burden imposed by chronic HCV; role of HCV in the development of HCC; goals for treatment success; methods for minimizing resistance in HCV as compared with HIV and HBV; current and emerging approaches to anti-HCV therapy, including STAT-C (protease and polymerase inhibitors), and the potential role that these agents may play in the future.

Learning Objectives

• Integrate knowledge of disease burden imposed by chronic HCV to determine the importance of intervention that minimizes the sequelae, including HCC, of chronic HCV.

• Utilizing an understanding of the parameters for anti-HCV treatment success, assess viral load, liver function tests, and liver fibrosis/inflammation in considering treatment strategies that may improve outcomes.

• Differentiate potential efficacy and safety considerations of protease and polymerase inhibitors, based on preliminary data, as therapeutic options in the treatment of patients with HCV infection in the future.

CME Information: PhysiciansStatement of Accreditation

Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

Projects In Knowledge designates this educational activity for a maximum of �.5 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Disclosure Information

The Disclosure Policy of Projects In Knowledge requires that presenters comply with the Standards for Commercial Support. All faculty are required to disclose any personal interest or relationship they or their spouse/partner have with the supporters of this activity or any commercial interest that is discussed in their presentation. Any discussions of unlabeled/unapproved uses of drugs or devices will also be disclosed.

For complete prescribing information on the products discussed during this CME activity, please see your current Physicians’ Desk Reference (PDR).

Nezam H. Afdhal, MD, has received grant/research support from Bristol-Myers Squibb, Coley Pharmaceutical Group, EchoSens, Gilead Sciences, Inc, GlaxoSmithKline, Idenix Pharmaceuticals, Idun Pharmaceuticals, Inc, InterMune Inc, Isis Pharmaceuticals, Inc, Novartis Pharmaceuticals Corporation, Ortho Biotech Products, LP, Prometheus Laboratories, Inc, Quest Pharmaceutical Services, Salix Pharmaceuticals, Inc, Schering-Plough Corporation, United Therapeutics, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated; is a consultant for Arrow Pharmaceuticals, Atlas Pharmaceuticals, BioCryst Pharmaceuticals, Inc, Biogen Idec, EchoSens, Gilead Sciences, Inc, GlaxoSmithKline, Idenix Pharmaceuticals, Idera Pharmaceuticals, Inc, InterMune Inc, Isis Pharmaceuticals, Inc, Novartis Pharmaceuticals Corporation, Ortho Biotech Products, LP, Prometheus Laboratories, Inc, Salix Pharmaceuticals, Inc, Schering-Plough Corporation, Sirtris Pharmaceuticals, Stromedix, Inc, Valeant Pharmaceuticals International, Vertex Pharmaceuticals Incorporated, ViroPharma Incorporated, Wyeth Pharmaceuticals, and XTL Biopharmaceuticals Ltd; and is on the speakers bureaus of Bristol-Myers Squibb, Gilead Sciences, Inc, Idenix Pharmaceuticals, Novartis Pharmaceuticals Corporation, and Schering-Plough Corporation. Dr. Afdhal has disclosed that he will reference unlabeled/unapproved uses of consensus interferon and colchicine in nonresponders, PEG-IFN as maintenance therapy, and ribavirin in higher than approved doses.

Hashem B. El-Serag, MD, MPH, has received grant/research support from Schering-Plough Corporation and is a consultant for Vertex Pharmaceuticals Incorporated. Dr. El-Serag will not reference unlabeled/unapproved use of drugs or devices.

Eugene R. Schiff, MD, has received grant/research support from Abbott Laboratories, Bayer Pharmaceuticals Corporation, Bristol-Myers Squibb, Coley Pharmaceutical Group, Gilead Sciences, Inc, GlaxoSmithKline, Idenix Pharmaceuticals Inc, Ortho Biotech Products, LP, Prometheus Laboratories Inc, Roche Diagnostics, Roche Molecular, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, and Vertex Pharmaceuticals Incorporated; is a consultant for Abbott Laboratories, Achillion Pharmaceuticals, Bayer

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Pharmaceuticals Corporation, Bristol-Myers Squibb, Cadence Pharmaceuticals, Gilead Sciences, Inc, GlaxoSmithKline, GlobeImmune, Inc, Idenix Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Ortho Biotech Products, LP, Pfizer Inc, Pharmasset, Inc, Prometheus Laboratories Inc, Roche Molecular, Salix Pharmaceuticals, Inc, Schering-Plough Corporation, and SciClone Pharmaceuticals; and is on the speakers bureau of Gilead Sciences, Inc, Ortho Biotech Products, LP, and Schering-Plough Corporation.

Mark S. Sulkowski, MD, has received grant/research support from Bristol-Myers Squibb, Human Genome Sciences, Idenix Pharmaceuticals, Roche Laboratories, Schering-Plough Corporation, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Incorporated; and is on the scientific advisory boards of Bristol-Myers Squibb, Human Genome Sciences, Idenix Pharmaceuticals, Merck & Co, Inc, Roche Laboratories, Schering-Plough Corporation and Vertex Pharmaceuticals Incorporated. Dr Sulkowski has disclosed that he will reference uses of currently marketed agents: ritonavir, and

investigational agents: boceprevir, HCV-796, R�626, telaprevir, and valopicitabine.

Peer Reviewer has disclosed no significant relationships.

Projects In Knowledge’s staff members have no significant relationships to disclose.

Conflicts of interest are thoroughly vetted by the Executive Committee of Projects In Knowledge. All conflicts are resolved prior to the beginning of the activity by the Trust In Knowledge peer review process.

The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge.

This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the clinician caring for the patient.

This independent CME activity is sponsored and coordinated by Projects In Knowledge and supported by an educational grant from Vertex Pharmaceuticals Incorporated.

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The story of anti-hepatitis C virus (HCV) therapy began in �997 when interferon alfa-2a and -2b were approved for the treatment of HCV. The next year, Spencer Johnson, MD, published his parable about change, Who Moved My Cheese? The book’s timing was fortuitous because change, as both a directive and a descriptor, would apply to the next �0 or more years of anti-HCV therapy. In �998, the combination of ribavirin and interferon was approved. In 200� and 2002, standard interferon gave way to newly approved peginterferon alfa-2b and -2a, respectively, as the approved standard of care in combination with ribavirin.

Since that time, researchers, not willing to lay aside the quest for greater efficacy, have continued to study adjustments of constituent doses, alternative interferons, alternative ribavirins, predictors of success, and strategies to manage toxicity. Abstract books from national and international liver meetings pour forth evidence of changing hypotheses, new data, and more finely nuanced conclusions. Novel therapies now emerging under the banner of change include specifically targeted antiviral therapy for HCV (STAT-C). STAT-C agents in phase II testing—SCH 50�0�4, telaprevir, and valopicitabine—represent a bold contrast to the immunomodulatory action of current interferon-based therapies.

Join us as we learn to embrace change and explore new horizons in anti-HCV therapy.

About This Program

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Nezam H. Afdhal, MD, is chief of hepatology and director of the Liver Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts. He is also an associate professor of medicine at Harvard Medical School. Dr. Afdhal received his MD degree in 1981 from the Royal College of Surgeons in

Ireland and did fellowship training at University College Dublin and at Boston University School of Medicine.

Dr. Afdhal’s clinical expertise focuses on the management of the complications of liver disease, including cirrhosis and portal hypertension. He is the director of a clinical trials group focusing on novel treatments of hepatitis B and C. In addition, he is the principal investigator of the national Colchicine versus PEG-INTRON Long-Term (COPILOT) study focusing on the prevention of cirrhosis and liver cancer from hepatitis C. Additional research interests include basic research in gallstone disease and in liver fibrosis.

Dr. Afdhal is on the editorial board of Gastroenterology and Hepatology, as well as the advisory board of the American Liver Foundation and the Massachusetts State Advisory Board for HCV. He has published more than 100 papers in journals such as Gastroenterology, Hepatology, Gut, and Journal of Hepatology, as well as 30 book chapters and 2 books. He has spoken nationally and internationally on chronic liver disease and received many awards, including the American Liver Foundation Award for Excellence and the Mitchell Lectureship of the Royal College of Physicians. In 2003, Dr. Afdhal became a Fulbright Scholar to direct a joint US/Egyp-tian program in hepatitis C. He is a member of the American Gastroenterological Association, the American Association for the Study of Liver Diseases, and the European Association for the Study of the Liver.

Faculty Biographies

Eugene R. Schiff, md

Chief, Division of Hepatology Director, Center for Liver Diseases University of Miami School of Medicine Miami, Florida

Nezam H. Afdhal, md

Chief of Hepatology Director, Liver Center Beth Israel Deaconess Medical Center Boston, Massachusetts

Eugene R. Schiff, MD, is the Leonard Miller Professor of Medicine, chief of the Division of Hepatology, and director of the Center for Liver Diseases at the University of Miami School of Medicine in Miami, Florida. Dr. Schiff earned his BA at the University of Michigan in Ann Arbor, and his MD at Columbia

University College of Physicians and Surgeons in New York City. After graduating, he completed his internship at Cincin-nati General Hospital in Cincinnati, Ohio, and his residen-cies in internal medicine at Cincinnati General Hospital and Parkland Memorial Hospital in Dallas, Texas. His fellowship in gastroenterology was conducted at the University of Texas Southwestern Medical School in Dallas.

Dr. Schiff is the co-editor of Schiff ’s Diseases of the Liver, now in its tenth edition, and has authored and co-authored more than 200 articles, books, and book chapters concerning liver diseases and related topics. His articles have been published in the Journal of the American Medical Association, Journal of Clinical Investigation, Hepatology, Journal of Hepatology, Liver Transplantation, New England Journal of Medicine, Annals of Internal Medicine, and Gastroenterology.

A respected leader in his field, Dr. Schiff is the past president of the American Association for the Study of Liver Diseases and past chairman of the Biliary Section of the American Gastroenterological Association. Dr. Schiff is a Master of the American College of Gastroenterology, a Master of the Ameri-can College of Physicians, a Fellow of the Royal College of Physicians, and a Fellow of the American Gastroenterological Association. In addition, he was a member of the Gastroenter-ology Subspecialty Board of the American Board of Internal Medicine and former chair of the Food and Drug Administra-tion’s Gastrointestinal Drugs Advisory Committee. Dr. Schiff is the recipient of numerous honors and awards, including the Florida Laureate Award presented by the American College of Physicians and the Distinguished Service award of the Ameri-can Association for the Study of Liver Diseases.

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Mark S. Sulkowski, MD, is an associate professor of medicine in the Department of Medicine at Johns Hopkins University School of Medicine, in Baltimore, Maryland. He received his MD in 1992 from Temple University School of Medicine, Philadelphia, Pennsylvania, and completed his fellowship in infectious diseases in

1998 at Johns Hopkins University School of Medicine.

Dr. Sulkowski has been the principal investigator for numer-ous clinical trials related to the management of hepatitis in persons with and without HIV coinfection and is a co-investigator for the Johns Hopkins University Adult AIDS Clinical Trials Unit and a member of the unit’s Liver Diseases subcommittee. In addition, he currently serves as vice presi-dent and director of clinical research at the Hepatitis Resource Network in Tacoma, Washington. Dr. Sulkowski is a member of many professional societies, including the American Association for the Study of Liver Diseases, Infectious Diseases Society of America, and International AIDS Society-USA, in which he has been a member of the Core Faculty since 1999. Dr. Sulkowski has been an invited speaker to numerous national and international conferences on hepatitis.

A leading contributor to the professional literature, Dr. Sulkowski is author or co-author of peer-reviewed scientific articles in journals such as Clinical Infectious Diseases, Journal of the American Medical Association, American Journal of Gastroenterology, and The New England Journal of Medicine. He is on the editorial board of Hepatitis: Index and Reviews, is the section editor of “Liver Infections” in Current Treatment Opinions in Infectious Diseases, and is also editor of HCV/HIV Coinfection Monthly.

Hashem B. El-Serag, MD, MPH, obtained his medical degree from Al-Arab Medical University in Libya, completed his internship and residency in internal medicine (1995) at Greenwich Hospital, Yale University, Connecticut, and completed a fellowship in clinical gastroenterology (1997) at the University of New Mexico in

Albuquerque, where he also earned a masters degree in public health (1998). In 1999, Dr. El-Serag joined the Michael E. DeBakey VA Medical Center and Baylor College of Medicine in Houston, where, in 2004, he was promoted to an associate professor of medicine. He is currently the associate director for the Houston Center for Quality of Care and Utilization Studies and chief of the center’s Division of Clinical Epidemi-ology and Outcomes.

Dr. El-Serag’s research focuses on the clinical epidemiology and outcomes of several liver disorders, particularly hepatocel-lular carcinoma (HCC) and hepatitis C. Dr. El-Serag has more than 130 articles published or in press. His studies appear in notable journals such as the New England Journal of Medicine, Annals of Internal Medicine, Archives of Internal Medicine, Gastroenterology, Hepatology, and Gut. Importantly, his work constitutes most of the published literature on the modern epidemiology of HCC in the United States. His seminal paper on HCC, “Rising Incidence of Hepatocellular Carcinoma in the United States,” was published in 1999 in the New England Journal of Medicine and has been cited approximately 900 times and featured on several media outlets. Regarded as a renowned expert, Dr. El-Serag has been an invited speaker to multiple National Institutes of Health (NIH) workshops and consensus conferences on HCC.

Dr. El-Serag has assumed several leadership roles in national organizations, such as the American Gastroenterological Association, the American College of Gastroenterology, and the American Association for the Study of Liver Diseases, and is the associate editor for Gastroenterology, a leading specialty journal.

Hashem B. El-Serag, md, mph

Associate Professor of Medicine Department of Medicine Michael E. DeBakey VA Medical Center and Baylor College of Medicine Houston, Texas

Mark S. Sulkowski, md

Associate Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins University School of Medicine Division of Infectious Disease Baltimore, Maryland

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Drugs or Investigational Agents Mentioned in This Presentation

Generic Trade Names

Albumin interferon Albuferon

ANA 245 —

BILB 1941 —

BILN 2061 —

Boceprevir (SCH 503034) —

Colchicine Colchicine

CPG 10101 —

E2 vaccine —

HCV-796 —

IC41 vaccine —

Interferon alfa-2a Roferon A*

Interferon alfa-2b Intron A*

Interferon alfacon-1, consensus interferon Infergen*

Interferon gamma Actimmune

Interferon omega —

Isatoribine —

Peginterferon alfa-2a PEGASYS*

Peginterferon alfa-2b PEG-Intron*

R1626 —

Ribavirin Rebetol*, Copegus*

Ritonavir Norvir

Thymalfasin (thymosin alpha 1) Zadaxin

Viramidine (taribavirin) —

Telaprevir (VX-950) —

Valopicitabine (NM-283) —

* Approved for the treatment of hepatitis C infection by Food and Drug Administration.

Projects In Knowledge requires that faculty disclose any reference(s) to unlabeled or unapproved uses of drugs or devices as part of their presentations. The audience is advised that this CME activity will contain such discussion.

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Within the field of antiviral therapy for hepatitis C virus (HCV) disease, the first wave of change began in 1997, with the approval of interferon alfa-2a. The evolution of therapy between then and now confirms the inevitability of change. Spencer Johnson, MD’s book, Who Moved My Cheese?, pro-vides a framework for navigating change. Among his prin-ciples are the imperatives to anticipate change, adapt, and be prepared to change again in the future.

As clinicians who care for patients with HCV disease, we catch the signals of a second wave of change on the near horizon. Despite the availability of approved anti-HCV therapies, the burden of HCV disease continues to increase at alarming rates. Peginterferon in combination with ribavirin is no longer the primary focus of anti-HCV clinical trials. Specifically targeted antiviral therapy for HCV (STAT-C) is gaining attention not

only of researchers, but also of clinicians looking toward more effective therapies. Already, HCV-796, R1626, SCH 503034, telaprevir, and valopicitabine are advancing in phase II trials and with promising results.

Parameters of success and treatment durations will likely be altered as these agents continue to prove their efficacy. Pegin-terferon may take on a new role as a synergistic component of new treatment regimens including STAT-C agents. Clini-cians will need to cultivate the mindset of a virologist in order to maximize targeted therapies and manage issues of drug resistance. How we will respond to the growing disease burden in our patient population depends upon how we adapt to the new mindset and skills that these emerging novel therapies will require of us.

IntroductionEugene R. Schiff, MD

Suggested ReadingsCornberg M, Manns MP. New approaches and therapeutic modalities for the treatment of patients with chronic hepatitis C. Ann Hepatol. 2005;4:144-150.

Johnson, S. Who Moved My Cheese? New York: G. P. Putnam’s Sons, 1998.

Pawlotsky J-M. Current and future concepts in hepatitis C therapy. Semin Liver Dis. 2005;25:72-83.

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Despite the decreasing incidence of new HCV infection, the burden of HCV-related disease continues to grow at an alarming rate. The age-adjusted hepatocellular carcinoma (HCC) incidence rates increased more than two-fold in the last two decades. Currently, the annual, age-adjusted rate of HCC is between 3.5 and 4.5 cases per 100,000 persons in the population. The largest proportional increases occurred among whites (Hispanics and non-Hispanics), while the lowest proportional increases occurred among Asians. During recent years, as incidence rates increased, the age-distribution of HCC patients has shifted towards relatively younger ages, with greatest proportional increases between ages 45 and 65 years.

Four published studies examined temporal changes in HCC risk factors in the United States. Two studies were from large, single referral centers where viral risk factor ascertainment was based on serology findings, while the other two studies were from national databases in which risk factors were ascertained from ICD-9 codes in billing or discharge records. In all four studies, the greatest proportional increases occurred in HCV-related HCC, while HBV-related HCC had the lowest rates, remaining stable in most studies.

Chronic HCV infection is a major risk factor for development of HCC. Markers of HCV infection are found in 27% to 52% of HCC cases in the United States, 44% to 66% of HCC cases in Italy, 27% to 58% of cases in France, 60% to 75% in Spain, and 80% to 90% in Japan. In a meta-analysis

of 21 case-control studies, HCC risk was increased 17-fold in HCV-infected patients compared with HCV-negative controls (95% confidence intervals [CI]: 14 - 22).

HCV increases HCC risk by promoting fibrosis and eventually cirrhosis. Once HCV-related cirrhosis is established, HCC develops at an annual rate of 1% to 4%. Factors that predispose to development of HCC include advanced age, older age at the time of acquisition of infection, male gender, heavy alcohol intake (>50 g/day), diabetes, obesity, and coinfection with HIV or HBV. There is no strong evidence that HCV viral factors like genotype, load or quasispecies are important in determining the risk of progression to cirrhosis or HCC.

Successful antiviral therapy in patients with HCV-related cirrhosis may reduce future risk of HCC, but the evidence is weak and comes mostly from non-randomized trials. The lack of randomization may exaggerate treatment benefits as it is likely healthier patients tend to get treated more frequently than those with advanced liver disease and are known to be more likely to develop HCC.

There are several obstacles that need to be overcome in order to translate the efficacy of HCV antiviral therapy into effectiveness in reducing HCC incidence. These obstacles include under-diagnosis of HCV, the limited proportion of eligible candidates, the considerable drop out due to side effects, and the relative low response rate in patients with cirrhosis.

The Handwriting on the Wall: The Increasing Challenge of HCV Disease BurdenHashem B. El-Serag, MD, MPH

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Suggested Readings Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. J Hepatol. 2001;34:593-602.

Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology. 2004;127:1372-1380.

Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer. 1998;75:347-354.

El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology. 2002;36(5 Suppl 1):S74-S83.

El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127(5 Suppl 1):S27-S34.

El-Serag HB. Translational research: the study of community effectiveness in digestive and liver disorders. Gastroenterology. 2007;132:8-10.

El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817-823.

El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med. 2000;160:3227-3230.

Hassan MM, Frome A, Patt YZ, El-Serag HB. Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States. J Clin Gastroenterol. 2002;35:266-269.

Kulkarni K, Barcak E, El-Serag H, Goodgame R. The impact of immigration on the increasing incidence of hepatocellular carcinoma in the United States. Aliment Pharmacol Ther. 2004;20:445-450.

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The Handwriting on the Wall: The Increasing Challenge of HCV Disease Burden Hashem B. El-Serag, MD, MPH

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The Handwriting on the Wall: The Increasing Challenge of HCV Disease Burden Hashem B. El-Serag, MD, MPH

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The past two decades have seen sustained virologic response (SVR) rates to anti-HCV therapy increase from <10% with standard inter-feron for 24 weeks to >50% with peginterferon plus ribavirin for 48 weeks. Response rates remain nonequivalent across patient popula-tions, however. Viral factors such as genotype, viral load, and coinfec-tion status, and patient factors such as race, age, body weight, and presence of cirrhosis, continue to affect treatment outcomes, despite the overall advances made. For example, African Americans respond to peginterferon/ribavirin therapy at about half the rate as Caucasian Americans. HCV-infected patients who are coinfected with human im-munodeficiency virus (HIV) also have a response rate of about half that of monoinfected patients.

Recent clinical trials have sought to identify treatment strategies that can be tailored to the individual patient. Duration of therapy, tailored according to rapidity of viral clearance, has been a key treatment vari-able since Davis et al first demonstrated the absence of early virologic response at week 12 as a negative predictor of SVR. Since publication of that study in 2003, the possibility of predicting response has moved up to as early as week 4. Rapidity of response may now be considered along with genotype and baseline viral load, in an algorithmic fashion, to arrive at the optimal duration of treatment for an individual patient. While some patients benefit from a shorter duration of therapy, other patients—particularly late responders with genotype 1 infection—may benefit from extended durations of therapy. The prolonged therapy offers an increased likelihood of response, as well as a decreased likeli-hood of relapse. Some patient groups may benefit from alternative dosing of peginterferon or ribavirin. The Weight-Based Dosing of PEG-INTRON and REBETOL (WIN-R) study has studied the effect of weight-based dosing of ribavirin, in combination with peginterferon alfa-2b, on SVR rates in selected patient groups, including African Americans and patients with cirrhosis. In both of these groups, weight-based dosing of ribavirin offered a significant advantage over standard ribavirin dosing.

Several options are available for patients who are nonresponders to peginterferon/ribavirin therapy. Current treatment may be modified in the hopes of yet achieving SVR. Such modification may include treat-ment with the alternative interferon, interferon alfacon-1 (consensus interferon, or CIFN). The DIRECT (Daily-Dose Consensus Interfer-on and Ribavirin: Efficacy of Combined Therapy) trial has demonstrat-ed viral clearance with CIFN in prior nonresponders to peginterferon alfa-2a or 2b plus ribavirin in a dose-dependent manner. Maintenance therapy, using low-dose peginterferon monotherapy, is a strategy that may help to suppress viral load and to achieve histologic benefit in nonresponders, thereby potentially preventing fibrosis progression. The effect of maintenance therapy is being studied in three long-term studies: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis), COPILOT (Colchicine versus PegIntron Long-Term), and EPIC-3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis). Final and complete results from these trials are pending. Neverthe-less, controlled trials have already documented several benefits of maintenance therapy, such as reduced hepatic inflammatory score and reduced risk of bleeding from portal hypertension. Key anticipated findings from these studies will be whether or not prevention of fibrosis progression will, in turn, prevent the development of hepatocellular carcinoma.

The most exciting option for nonresponders and other hard-to-treat patient groups is the development of new potent antivirals that have the potential to produce rapid viral clearance through a mechanism exclusive of interferon gene activation. Without dependence on host-specific responses, specifically targeted antiviral therapy for HCV (STAT-C) may reduce the variability in response currently seen with immune-modifying interferon therapy. Early findings from targeted antivirals currently in clinical development suggest that we may opti-mistically anticipate the future and the treatment strategies it will hold for multiple patient groups.

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Reality Check: Assessing the Present to Anticipate the FutureNezam H. Afdhal, MD

Suggested ReadingsAfdhal N, Freilich B, Levine R, et al. Colchicine versus PEG-INTRON Long Term (COPILOT) Trial: interim analysis of clinical outcomes at year 2. Hepatology. 2004;40:239A.

Afdhal N, Jacobson I, Brown R, et al. The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C: results from the WIN-R trial. Abstract 655. Presented at: Digestive Disease Week 2006; May 20–25, 2006; Los Angeles, Calif.

Bacon B, Regev A, Ghalib R, et al. Use of daily interferon alfacon-1 (Infergen®, CIFN) plus ribavirin (RBV) in patients infected with hepatitis C (HCV) who are nonresponders to previous pegylated interferon plus RBV therapy: 24-week data from the DIRECT trial. Hepatology. 2006;44:698A.

Berg T, von Wagner M, Hinrichsen H, et al. Reduction of the relative relapse rate by prolongation of the duration of a therapy with peginterferon alfa-2a plus ribavirin in patients with genotype 1 infection up to 72 weeks. Hepatology. 2004;40:238A.

Buti M, Valdes A, Sanchez-Avila F, Esteban R, Lurie Y. Extending combination therapy with peginterferon alfa-2b plus ribavirin for genotype 1 chronic hepatitis C late responders: a report of 9 cases. Hepatology. 2003;37:1226-1227.

Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.

Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451-459.

Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477.

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Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.

Ferenci P, Fried MW, Shiffman ML, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol. 2005;43:425-433.

Katze MG, He Y, Gale M Jr. Viruses and interferon: a fight for supremacy. Nat Rev Immunol. 2002;2:675-687.

Laguno M, Murillas J, Blanco JL, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS. 2004;18:F27-F36.

Sanchez-Tapias JM, Diago M, Escartin P, et al. Longer treatment duration with peginterferon alfa-2a (40 KD) (PEGASYS ) and ribavirin (COPEGUS) in naive patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomized multicenter TERAVIC-4 study. Hepatology. 2004;40:218A.

Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147-1171.

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004; 351:438-450.

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Reality Check: Assessing the Present to Anticipate the Future Nezam H. Afdhal, MD

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Since the discovery of the hepatitis C virus in 1989, the identi-fication and screening of HCV-targeted drugs have been ham-pered by the lack of small animal models and the inability to infect cultured cells. However, the development of an in vitro replication system, the HCV replicon, was a major advance in the evaluation of candidate antiviral agents in cell culture. The development of targeted antivirals is based on the identifica-tion and selection of molecules with a high affinity to bind to a functional site of an HCV target structure, resulting in inter-ruption of the virus life cycle. The development and selection of these molecules are based on detailed understanding of the three-dimensional structure of the HCV target.

Several specific small-molecule inhibitors are undergoing test-ing in the preclinical phase and some have advanced to phase I and II clinical trials in humans. The three most common targets include IRES, which is integral to polyprotein transla-tion; NS3 serine protease, a major catalyst in posttranslational polyprotein processing; and NS5B RNA-dependent RNA polymerase, the enzyme that is crucial for RNA replication. An NS3 protease inhibitor, telaprevir (VX-950), has demonstrated highly potent antiviral activity in several preclinical models. In addition, several other NS3 protease inhibitors are undergoing preclinical evaluation. HCV RNA-dependent RNA polymerase is also a promising potential target for specific HCV inhibi-tors. The polymerase activity can be inhibited by nucleoside or nucleotide analogs, such as valopicitabine (NM-283), that bind with high affinity to the catalytic site.

Valopicitabine, a nucleoside analog, has demonstrated signifi-cant antiviral efficacy against HCV, both in vitro and in the Bovine Diarrhea Virus (BDV) system (and in animal model, ie, infected chimpanzees). Phase I and II clinical trials have demonstrated that monotherapy with valopicitabine is associ-ated with consistent anti-HCV activity in patients infected with HCV genotype 1 independent of prior interferon therapy. Valopicitabine alone is associated with reduction of HCV RNA of approximately 0.7 to 1 log

10; however, in combination with

peginterferon, synergistic antiviral activity has been observed with reduction of HCV RNA of ~ 2.5 to 3 log

10. Recent find-

ings from a phase II study showed that 48 weeks of valopici-tabine plus peginterferon produced end-of-treatment viral clearance in about 50% of treatment-naive patients. No data on the rate of viral relapse have been reported, however. In an-other phase II study, 16% of nonresponders and 42% of partial responders achieved HCV RNA negativity by the end of the 48-week study period. Unfortunately, no subject achieved an SVR, reflecting a 100% relapse rate. Further studies are needed

to determine if the addition of ribavirin would boost response rates by reducing viral relapse.

Other polymerase inhibitors in clinical trials include HCV-796, a nonnucleoside inhibitor that has demonstrated potent antiviral activity alone and in combination with peginterferon alfa-2b, and R1626, a nucleoside inhibitor that led to a >3-log

10 reduction in serum HCV RNA levels when given alone

for 14 days. Further research is under way to define the efficacy and safety of these agents.

Three NS3 protease inhibitors have undergone phase I testing in HCV genotype 1-infected patients. The first such molecule, BILN 2061, demonstrated potent anti-HCV activity with an approximate 3-log

10 reduction in HCV RNA after only 48

hours of therapy; however, no further studies are planned due to animal toxicity. In phase Ib testing, patients taking telaprevir alone at 750 mg thrice daily by mouth experienced a mean HCV RNA reduction of about 4.4 log

10 after 2 weeks of dos-

ing. In combination with peginterferon alfa-2a and ribavirin, telaprevir led to full suppression of HCV RNA in 12 of 12 HCV genotype-1 infected persons treated for 28 days. Recent 12-week data from PROVE 1, a phase II trial of telaprevir plus peginterferon and ribavirin, demonstrated a high rate of rapid virologic response and maintenance of the response posttreat-ment in patients with HCV genotype-1 infection. The clinical implication of these findings is the potential for shorter treat-ment duration in this population. Rash, gastrointestinal events, and anemia were the most common adverse events.

Finally, phase I studies of another protease inhibitor, boceprevir (SCH 503034), with and without peginterferon alfa-2b, in patients infected with HCV genotype 1 have been presented. Boceprevir monotherapy was associated with a reduction of HCV RNA of 2 to 3 log

10, and combination therapy with pe-

ginterferon alfa-2b demonstrated synergistic anti-HCV activity. Phase II studies are under way to evaluate boceprevir with peginterferon alfa-2b, with or without ribavirin, in patients with chronic hepatitis C, genotype 1, who did not respond to previous treatment with peginterferon alfa plus ribavirin and those who are naive to anti-HCV therapy. In vitro studies suggest that the barrier to viral resistance may be increased when boceprevir is combined with either HCV-796 or NM107 (the active moiety of valopicitabine), a nucleoside polymerase inhibitor.

While research on these potent targeted antivirals is exciting, the drawback of developing specific small-molecule inhibitors is their potential to select for resistant HCV mutants during

Finding Our Way in the Maze: Changing Direction Toward More Effective TreatmentMark S. Sulkowski, MD

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therapy. Indeed, early studies suggest that resistance mutations may emerge in vitro and in vivo following therapy with HCV protease inhibitors. Accordingly, many experts believe that combination therapy with peginterferon alfa or other long-acting interferons, with or without ribavirin, will be the most

effective approach. In addition, the combination of several classes of antiviral agents, such as polymerase and protease inhibitors, is also promising. Further research will define the role of these and other agents in future anti-HCV treatment regimens.

Suggested ReadingsAfdhal N, Obrien C, Godofsky E, et al. Valopicitabine (NM283), alone or with PEG-interferon, compared to PEG interferon/ribavirin (PEGIFN/RBV) retreatment in patients with HCV-1 infection and prior non-response to PEGIFN/RBV: one-year results [abstract 6]. Presented at: 42nd Annual Meeting of the European Association for the Study of the Liver; April 11-15, 2007; Barcelona, Spain.

Afdhal N, Rodriguez-Torres M, Lawitz E, et al. Enhanced antiviral efficacy for valopicitabine (NM283) plus peg-interferon in hepatitis C patients with HCV genotype-1 infection: Results of a phase lla multicenter trial. J Hepatol. 2005;42:39-40.

Godofsky E, Afdhal N, Rustgi V, Shick L, Duncan L, Zhou XJ, et al. A phase I/II dose escalation trial assessing tolerance, pharmacokinetics, and antiviral activity of NM283, a novel antiviral treatment for hepatitis C. Gastroenterology. 2004;126:A681.

Lamarre D, Anderson PC, Bailey M, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature. 2003;426:186-189.

Lawitz E, Nguyen T, Younes Z, et al. Clearance of HCV RNA with valopicitabine (NM283) plus peg-interferon in treatment-naive patients with HCV-1 infection: results at 24 and 48 weeks [abstract 14]. Presented at: 42nd Annual Meeting of the European Association for the Study of the Liver; April 11-15, 2007; Barcelona, Spain.

Lawitz EJ, Rodriguez-Torres M, Muir A, et al. 28 days of the hepatitis C protease inhibitor VX-950, in combination with PEG-interferon-ALFA-2a and ribavirin, is well-tolerated and demonstrates robust antiviral effects. Gastroenterology. 2006;131:950-951.

McHutchison JG, Everson GT, Gordon S, et al. Results of an interim analysis of a phase 2 study of telaprevir (VX-950) with peginterferon a-2a and ribavirin in previously untreated subjects with hepatitis C [abstract 786]. Presented at: 42nd Annual Meeting of the European Association for the Study of the Liver; April 11-15, 2007; Barcelona, Spain.

Reesink HW, Forestier N, Weegink CJ, et al. Initial results of a 14-day study of the hepatitis C virus inhibitor protease VX-950, in combination with peginterferon-alfa-2a. J Hepatol. 2006;44:S272.

Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. In press.

Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology. 2007;132:1270-1278.

Finding Our Way in the Maze: Changing Direction Toward More Effective TreatmentMark S. Sulkowski, MD

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Finding Our Way in the Maze: Changing Direction Toward More Effective Treatment Mark S. Sulkowski, MD

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ConclusionEugene R. Schiff, MD

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Despite the advances in antiviral therapy for chronic HCV infection over the past two decades, the burden of disease continues to increase. The age-adjusted incidence of hepatocel-lular carcinoma increased more than two-fold in the last two decades, with HCV responsible for a large proportion of the increase. It now has the fastest growing mortality rate among cancers in the United States.

These epidemiologic data reflect a reality, which suggests that future anti-HCV therapy must improve upon the past in terms of efficacy, safety, and availability to HCV-infected individuals. Current standard-of-care therapy offers limited hope of cure to HCV-monoinfected patients, nearly 50% of whom will not respond. That hope is diminished among patients with a factor associated with suboptimal response, such as HIV-coinfection or African-American race, and absent among those with a contraindication to or intolerance of either peginterferon or ribavirin.

Findings from early clinical trials of STAT-C agents point to a future in which viral loads in our patients may be suppressed

very rapidly. Adding these agents to our current standard-of-care peginterferon/ribavirin protocol would allow the immune-modifying and antiviral effects of interferon and ribavirin to continue, for now. In addition, the combination would be prevention against the development of STAT-C resistance. Further into the future, however, peginterferon and ribavirin may be removed, replaced instead with one or more additional STAT-C agents. Multiple targeted agents, such as a protease inhibitor combined with one or two polymerase inhibitors, may offer the most potent suppression, as well as increased protection from resistance mutations.

As always, change at the research bench leads to change in how we practice. This coming wave of change will perhaps require more adaptation on our part than any HCV-related change of the last two decades. However, as we adapt to, and even enjoy, the coming change, our patients’ hopes for a positive outcome—including cure and lessening of disease burden—may have significant reason to grow.

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Medical Education Activities for Clinicians Since …Physicians’ Desk Reference (PDR). Nezam H. Afdhal, MD, has received grant/research support from Bristol-Myers Squibb, Coley Pharmaceutical