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JOURNAL OPTIONS COLLECTION

Hepatitis Journal Options – Volume 3, Issue 2

PROGRAM DIRECTOR FACULTY
Raymond T. Chung, MD Jasmohan Bajaj, MD
Associate Professor of Medicine Assistant Professor of Medicine
Department of Medicine Division of Gastroenterology, Hepatology
Harvard Medical School and Nutrition
Director of Hepatology Virginia Commonwealth University and
Medical Director, Liver Transplant Program McGuire VA Medical Center
Massachusetts General Hospital Richmond, Virginia
Boston, Massachusetts
Wissam Bleibel, MD
Robert G. Gish, MD Hepatology Fellow
Medical Director Beth Israel Deaconess Medical Center
Liver Transplant Program Harvard Medical School
California Pacific Medical Center Boston, Massachusetts
San Francisco, California
Steven Flamm, MD
Stephen A. Harrison, MD, LTC, MC Associate Professor of Medicine
Chief of Hepatology Medical Director, Liver Transplantation
Brooke Army Medical Center Feinberg School of Medicine
Associate Professor of Medicine Northwestern University
University of Texas Health Science Center Chicago, Illinois
San Antonio, Texas

Jointly sponsored by Postgraduate Institute for
Medicine and Clinical Care Options, LLC

This activity is supported by educational grants from:

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 1

Ira M. Jacobson, MD
Vincent Astor Professor of Clinical Medicine
Chief, Division of Gastroenterology and Hepatology
Department of Medicine
Weill Cornell Medical College
Attending Physician
Division of Gastroenterology and Hepatology
Department of Medicine
NewYork-Presbyterian Hospital
New York, New York

Daryl T-Y Lau, MD, MSc, MPH
Associate Professor
Harvard Medical School
Director, Translational Liver Research
Beth Israel Deaconess Medical Center
Boston, Massachusetts

Kevin Mullen, MD
Professor of Medicine
Case Western Reserve University
Cleveland, Ohio

David R. Nelson, MD
Professor of Medicine
Division of Gastroenterology, Hepatology, and Nutrition
Director of Hepatology and Liver Transplantation
University of Florida College of Medicine
Gainesville, Florida

Nancy Reau, MD
Assistant Professor of Medicine
Center for Liver Disease
University of Chicago
Chicago, Illinois

Richard K. Sterling, MD, MSc, FACP, FACG
Professor of Medicine
Associate Chair of Education and Training
Division of Gastroenterology, Hepatology, and Nutrition
Virginia Commonwealth University
Richmond, Virginia

Mark S. Sulkowski, MD
Associate Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland

STAFF
Edward King, MA
Vice President, Editorial
Clinical Care Options, LLC

Taryn O’Loughlin Gross, PhD
Associate Managing Editor
Clinical Care Options, LLC

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 2

Kara Nyberg, PhD
Editorial Contributor

DISCLOSURES
Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners,
managers and other individuals who are in a position to control the content of CME activities. All relevant
conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of
studies utilized in this activity, and patient care recommendations. PIM is committed to providing its
learners with high quality CME activities and related materials that promote improvements or quality in
healthcare and not a specific proprietary business interest of a commercial interest.

The faculty and CCO staff reported the following financial relationships or relationships to products or
devices they or their spouse/life partner have with commercial interests related to the content of this CME
activity.

Raymond T. Chung, MD, has disclosed that he has received grants or research support from Gilead
Sciences, GlaxoSmithKline, Roche, Romark, Schering-Plough, and Vertex; has served as a consultant for
Gilead Sciences, Merck, Pfizer, and Roche; and has received fees for non-CME services from Roche.

Robert G. Gish, MD, has disclosed that he has received grant or research support from Bayer-Onyx,
Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Hoffmann-La Roche, Idenix/Novartis, Merck,
Nucleonics, Pfizer, Schering-Plough, SciClone Pharmaceuticals, and Valeant; has served as a consultant
for Anadys Pharmaceuticals, Bayer AG, Bristol-Myers Squibb, Hoffmann, Gilead Sciences,
GlaxoSmithKline, GlobeImmune, Hepahope, Hoffman-LaRoche, Human Genome Sciences, Idenix,
Innogenetics, Merck, Metabasis Therapeutics, Nucleonics, Pharmasset, Schering-Plough, SciClone
Pharmaceuticals, Valeant Pharmaceuticals, and Zymogenetics; and has served on speaker bureaus for
Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman-LaRoche, Ortho Biotech, Salix,
Schering-Plough, and Three Rivers.

Stephen A. Harrison, MD, LTC, MC, has disclosed that he has served as a consultant for Roche and
has received fees for non-CME services from Bristol-Myers Squibb and Roche.

Jasmohan Bajaj, MD, has disclosed that he has received grants or research support from and served a
consultant for Salix Pharmaceuticals.

Wissam Bleibel, MD, has no significant financial relationships to disclose.

Steven L. Flamm, MD, has disclosed that he has received fees for non-CME services from Gilead
Sciences; consulting fees from Gilead Sciences and Salix Pharmaceuticals; and grants or research
support from Gilead Sciences, Salix Pharmaceuticals, and Vertex.

Ira M. Jacobson, MD, has disclosed that he has received grants or research support from Anadys,
Boehringer Ingelheim, Gilead Sciences, GlobeImmune, Human Genome Sciences, Idenix, Intarcia,
Merck, Novartis, Pharmasset, Roche, Schering-Plough, Valeant, and Vertex; has served as a consultant
for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlobeImmune, Human Genome
Sciences, Idenix, Intermune, Merck, Novartis, Pfizer, Pharmasset, Roche, Sanofi-Aventis, Schering-
Plough, Virochem, Vertex, and Zymogenetics; and has served on speaker bureaus for Bristol-Myers
Squibb, Gilead Sciences, Novartis, and Schering-Plough.

Daryl T-Y Lau, MD, MSc, MPH, FRCP(C), has disclosed that she has received consulting fees and fees
from non-CME services from Bristol-Myers Squibb and Gilead Sciences and grants or research support
from Bristol-Myers Squibb, Pharmasset, and Roche.

Kevin Mullen, MD, has disclosed that he has served as a consultant for Hyperion Therapeutics, Ocera
Pharmaceuticals, and Salix Pharmaceuticals.

David R. Nelson, MD, has disclosed that he has received grants or research support and has served as
a consultant for Vertex.

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 3

and warnings. BA. MSN. LEARNING OBJECTIVES ƒ Recall data on the efficacy of telaprevir in combination with peginterferon/ribavirin in treatment- naive. Sterling. Any procedures. or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use. MD. 4 . PhD. Trace Hutchison. Schering-Plough. has disclosed that he has received grants or research support from Bayer-Onyx. Richard K. DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Roche. Kara Nyberg. Bristol-Myers Squibb. BSN and Jan Schultz. Vertex. BSN. Julia Kirkwood.Nancy Reau. MA. MA. Schering-Plough. and has received fees for non-CME services from GlaxoSmithKline. and Wako. LLC. has served as a consultant for Roche. has disclosed that he has received grants or research support and has served as a consultant for Gilead Sciences and Vertex. genotype 1 patients ƒ Discuss the efficacy and safety of tenofovir vs adefovir for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B patients ƒ Describe the results of long-term maintenance peginterferon alfa-2a therapy in HCV-infected patients with previous nonresponse ƒ Summarize the efficacy of rifaximin for the treatment of hepatic encephalopathy Copyright © 2009 Clinical Care Options. Postgraduate Institute of Medicine (PIM) and Clinical Care Options. hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interests related to the content of this CME activity of any amount during the past 12 months. TARGET AUDIENCE This activity is intended for physicians and other healthcare professionals involved in the clinical management of patients with viral hepatitis. RN. PharmD. BSN. has no significant financial relationships to disclose. PhD. and Wako. FACG. and Roche. RN. MSc. All rights reserved. CCMEP. Taryn O’Loughlin Gross. RN. review of any applicable manufacturer’s product information. GOAL The goal of this activity is for participants to acquire knowledge on recent clinical findings regarding the clinical management of patients with viral hepatitis and understanding of their implications for clinical practice. MD. has disclosed that she has served as a consultant for Gilead Sciences and has received fees for non-CME services from Bristol-Myers Squibb. Linda Graham. Mark S. medications. The following PIM clinical content reviewers. Edward King. Sulkowski. The information presented in this activity is not meant to serve as a guideline for patient management. Jan Hixon. FACP. has no significant financial relationships to disclose. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. has no significant financial relationships to disclose. contraindications. LLC. LLC do not recommend the use of any agent outside of the labeled indications. RN. Please refer to the official prescribing information for each product for discussion of approved indication. and comparison with recommendations of other authorities. MD. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM and Clinical Care Options.

not those of Clinical Care Options. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. 3. 2009 through June 9. 2010: 1. Readers should verify all information and data before treating patients or using any therapies described in these materials. you may access your online certificate by selecting the certificate link on the posttest confirmation page. LLC. participants must follow these steps during the period from June 10. Submit answers to the posttest questions and evaluation questions online. After submitting the evaluation. Study the educational activity online or printed out. INSTRUCTIONS FOR CREDIT Participation in this self-study activity should be completed in approximately 1 hour. 5 . Copyright © 2009 Clinical Care Options. learning objectives. DISCLAIMER The materials published on the Clinical Care Options Web site reflect the views of the reviewers or authors of the CCO material. or the companies providing educational grants. All rights reserved. Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. There are no costs/fees for this activity. A qualified health care professional should be consulted before using any therapeutic product discussed. the CME provider. Register online at http://clinicaloptions. LLC. To successfully complete this activity and receive credit. Records of all CME activities completed can be found on the "My CME" page. Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. and faculty disclosures.com 2. You must receive a test score of at least 70% and respond to all evaluation questions to receive a certificate. Read the target audience. LLC. 4.PHYSICIAN CONTINUING MEDICAL EDUCATION Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine and Clinical Care Options.

...............................................................Hepatitis Journal Options – Volume 3........ 15 Lok-Gastroenterol-2009: HCC in hepatitis C–related advanced liver disease .................................. 66 Copyright © 2009 Clinical Care Options....................................................................................................................................... 7 Di Bisceglie-NEJM-2008: Maintenance HCV therapy with low-dose peginterferon ......................................................................................................................................................... Issue 2 CONTENTS McHutchinson-NEJM-2009: Telaprevir for chronic HCV genotype 1 infection .............. 6 ........................................................................ 21 Bacon-Hepatology-2008: Consensus interferon/ribavirin retreatment for peginterferon/ribavirin nonresponders ......... LLC.. 35 Marcellin-NEJM-2008: Tenofovir for chronic hepatitis B........... 28 Rossignol-Hepatology-2008: Improved response rates in chronic hepatitis C with nitazoxanide ........... 54 Bajaj-AJG-2009: Effect of fatigue on driving skills in hepatic encephalopathy patients ... 41 Moucari-Hepatology-2009: Early serum HBsAg drop and SVR in HBeAg-negative patients ............................. 61 Posttest ... All rights reserved........................... 49 Maclayton-Ann_Pharmacother-2009: Rifaximin for hepatic encephalopathy.............................

PROVE 1: Combination of Telaprevir With Peginterferon/Ribavirin Significantly
Increases SVR in Treatment-Naive Patients With HCV Genotype 1

„ PROVE 1: multicenter, randomized, double-blind, placebo-controlled, phase IIb trial
conducted in United States[1]

Summary of Key Conclusions
„ Coadministration of a 12-week course of telaprevir (TVR) with 24 or 48 weeks of
peginterferon alfa-2a (pegIFN)/ribavirin (RBV) significantly increased sustained virologic
response (SVR) rates in treatment-naive patients infected with genotype 1 HCV compared
with 48 weeks of peginterferon/ribavirin alone
„ Coadministration of TVR also resulted in higher rate of rapid virologic response (RVR) and
lower relapse rate compared with pegIFN/RBV
„ TVR coadministration increased rate of treatment discontinuation due to adverse effects,
predominantly rash
„ Small subset of TVR-treated patients experienced virologic breakthrough in association with
protease resistance mutations

Background
„ SVR occurs in < 50% of chronic genotype 1 HCV–infected patients receiving pegIFN/RBV
therapy
● Response rates even lower in select subpopulations (eg, blacks)
„ Telaprevir a novel investigational inhibitor of HCV NS3-4A protease
● Monotherapy previously demonstrated to lead to viral breakthrough due to
emergence of resistance mutations[2]
● Coadministration with pegIFN/RBV hypothesized to reduce risk of emergence of
resistance mutations while enhancing antiviral potency of standard of care therapy
„ Current study assessed efficacy and safety of combining TVR with pegIFN/RBV in treatment-
naive patients infected with genotype 1 HCV
● Ability of combination to shorten duration of therapy also assessed

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 1

Schematic of Study Design

Eligibility
„ Inclusion criteria
● 18-65 years of age
● Chronic genotype 1 HCV infection
● Treatment naive
● Adequate hematologic function
„ Exclusion criteria
● Decompensated liver disease
● Liver biopsy indicating cirrhosis within 2 years of study enrollment
● Hepatocellular carcinoma
● Another cause of clinically significant liver disease
● Coinfection with HBV, HIV-1, or HIV-2

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 2

Baseline Characteristics
„ Baseline characteristics well balanced across treatment groups

12-Wk TVR + 24- 12-Wk TVR + 48-
12-Wk TVR + PegIFN/RBV
Wk PegIFN/RBV Wk PegIFN/RBV
Characteristic PegIFN/RBV Arm Control Arm
Arm Arm
(n = 17) (n = 75)
(n = 79) (n = 79)
Median age, yrs (range) 49 (34-63) 49 (21-61) 50 (26-61) 49 (24-59)
Male, % 71 68 61 57
Race, %
• White 76 76 76 79
• Black 18 9 10 12
• Hispanic 6 11 9 8
• Other 0 4 5 1
Median BMI 28.6 26.9 25.8 26.9
Genotype 1 HCV subtype, %
• 1a 53 67 61 67
• 1b 35 22 34 27
• Indeterminate 12 11 5 7
Mean HCV RNA, log10 IU/mL 6.57 6.54 6.47 6.68
Fibrosis, %
• None/minimal 24 30 43 25
• Portal 53 52 39 49
• Bridging 24 18 18 25
Mean ALT, IU/mL 80 73 72 68
BMI, body mass index.

Description of Current Analysis
„ Patients enrolled at 37 centers in United States June - September 2006
„ Primary endpoint
● SVR, defined as undetectable HCV RNA (< 30 IU/mL) 24 weeks after end of therapy
„ Secondary endpoints
● Other response rates
● Virologic breakthrough
● Safety, toxicity
„ Chemical, hematologic, and virologic assessments performed at screening, Days 1 and 4,
and Weeks 2-4, 6, 8, 10, 12, 16, 20, 24, 28, 36, and 48
„ Patients who experienced virologic breakthrough during first 12 weeks discontinued TVR or
placebo but remained on pegIFN/RBV for up to 48 weeks
● Virologic breakthrough defined as HCV RNA increase of ≥ 1 log10 IU/mL from nadir or
HCV RNA > 100 IU/mL in patients with previous undetectable HCV RNA
● Blood samples with HCV RNA > 1000 IU/mL subjected to population sequencing of
NS3-4A region to detect for resistance mutations
„ Intent-to-treat analysis

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 3

4 . All rights reserved.Main Findings „ Coadministration of 12 weeks of TVR with 24 or 48 total weeks of pegIFN/RBV significantly increased SVR rate over standard treatment with pegIFN/RBV ● 61% to 67% SVR rate with TVR plus 24 or 48 weeks of pegIFN/RBV vs 41% with pegIFN/RBV alone ● Rates of SVR in small subset of black patients markedly higher with TVR plus pegIFN/RBV vs pegIFN/RBV alone (44% vs 11%. LLC. respectively) „ Rates of rapid virologic response significantly higher for all TVR arms vs control arm ● 81% RVR rate with TVR plus 24 or 48 weeks of pegIFN/RBV vs 11% with pegIFN/RBV alone „ Relapse rates lower with TVR plus 24 or 48 weeks of pegIFN/RBV vs pegIFN/RBV alone „ Rate of ALT normalization similar between TVR arms and control arm at end of treatment (76% vs 75%) „ Viral breakthrough occurred in 12 of 175 patients (7%) receiving TVR ● Most breakthrough events (75%) occurred during Weeks 1-4 ● 10 of 12 patients (83%) experienced breakthrough before HCV RNA became undetectable ● Breakthrough associated with differing pattern of resistance mutations according to genotypic subtype ƒ 10 patients with genotype 1a had V36M and R155K mutations ƒ 1 patient with genotype 1b had A156T mutation ƒ Remaining patient had predominantly wild-type HCV „ Treatment discontinuation due to adverse events more frequent in TVR arms vs control arm (21% vs 11%) ● Rash most common reason for discontinuation Copyright © 2009 Clinical Care Options.

and diarrhea ● Rash typically maculopapular and resolved following treatment discontinuation ● Decrease in hemoglobin levels more common in TVR arms vs control 12-Wk TVR + 24. LLC. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. including rash. All rights reserved. Gordon SC.360:1827-1838.132:1767-1777. N Engl J Med. Gastroenterology. Kieffer TL. pruritus. Everson GT. 2009. Sarrazin C. McHutchison JG. „ Most common adverse events were those typically associated with interferon-based treatment ● Certain of these adverse events occurred more often in TVR-treated arms. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. % (n = 17) (n = 79) (n = 79) Fatigue 82 70 73 76 Nausea 65 56 48 29 Influenza-like illness 35 49 38 43 Pruritus 24 48 40 23 Headache 53 47 43 60 Insomnia 35 44 34 39 Diarrhea 24 42 34 28 Anemia 35 37 29 27 Rash 53 60 61 41 • Mild 47 33 39 32 • Moderate 0 18 17 8 • Severe 6 9 5 1 Erythema at injection site 35 28 32 24 References 1. et al. Bartels D. Copyright © 2009 Clinical Care Options. nausea. 2007. 12-Wk TVR + 48- Adverse Events Occurring 12-Wk TVR + Wk PegIFN/RBV Wk PegIFN/RBV Control Arm in ≥ 30% of Patients in Any PegIFN/RBV Arm Arm Arm (n = 75) Treatment Group. 5 . 2. et al.

Another important observation was that adverse events such as rash. Consistent with this observation. 2) telaprevir plus peginterferon/ribavirin for 12 weeks. a shorter treatment duration of 24 weeks with telaprevir-containing regimens may be possible compared with the current 48 weeks with peginterferon/ribavirin in the genotype 1 HCV– infected treatment-naive population. The findings from the PROVE studies have dramatic implications. all of the PROVE studies suggest that future regimens containing STAT-C drugs will lead to higher SVR rates for both treatment-naive and treatment-experienced genotype 1 HCV–infected patients (20% to 30% above the rate achieved with standard peginterferon/ribavirin). Those arms that did not contain ribavirin had much lower SVR rates because of higher rates of breakthrough or relapse. nausea. durations of telaprevir induction. n = 75). as well as lower relapse rates in the telaprevir arms. some arms in PROVE 2 and PROVE 3 did not. MD Use of standard therapy of peginterferon and ribavirin produces a sustained virologic response (SVR) in fewer than one half of all individuals infected with genotype 1 hepatitis C virus (HCV). 3) telaprevir plus peginterferon/ribavirin for 12 weeks (exploratory group. and diarrhea occurred more frequently in the telaprevir arms vs the control arm. Nelson. One promising approach involves the use of specifically targeted antiviral therapy for HCV (STAT-C) agents that directly inhibit critical enzymes in the viral replication cycle (ie. a higher proportion of telaprevir-treated patients discontinued treatment because of adverse events vs the control arm (21% vs 11%.[1] The rationale for the study was that the addition of this protease inhibitor to the current standard of care might constitute a more effective antiviral regimen that leads to more rapid virologic suppression. which included many of the same treatment arms as in PROVE 1 but with slightly different treatment combinations. ribavirin will remain a critical component of HCV therapy for this STAT-C regimen. respectively). given the very low relapse rate. end-of-treatment response. 250 patients were randomly assigned to one of 4 groups: 1) telaprevir plus peginterferon/ribavirin for 12 weeks. In addition. Numerous strategies have been undertaken to try to improve response rates in this population of patients. and patient populations (eg. In addition. a treatment duration of only 12 weeks is inferior to 24 weeks due to higher relapse rates. and SVR were observed among telaprevir-treated patients who received either 24 or 48 total weeks of therapy compared with patients in the control arm (SVR: 61% to 67% vs 41%. Twelve patients (7%) receiving telaprevir experienced virologic breakthrough during treatment. polymerase or protease regions). The current PROVE 1 study assessed one such STAT-C agent—telaprevir—in combination with peginterferon/ribavirin in treatment-naive patients infected with genotype 1 HCV (Hep JO McHutchison_NEJM_2009_CS). Although these regimens will provide greater HCV antiviral activity. followed by peginterferon/ribavirin alone for 12 weeks (n = 79). Telaprevir-containing therapy lasting 24 weeks appears to be appropriate for patients with a rapid virologic response. obesity. Combined data from the PROVE studies also suggest that the addition of STAT-C agents to standard therapy may overcome negative host factors. The PROVE 1 results[1] are important to consider in conjunction with the findings from the PROVE 2[2] and PROVE 3 (Capsule Summary)[3] companion studies. these data suggest that. The differing genetic barrier for the development of resistance and breakthrough according to HCV subtype (1a vs 1b) is a new concept that will require genotypic subtyping in future clinical care. or 4) standard peginterferon/ribavirin for 48 weeks (control arm. followed by peginterferon/ribavirin alone for 36 weeks (n = 79). such as race. as these are the first extensive phase II data to suggest that a new treatment paradigm is at hand for HCV infection. Breakthrough was more common in patients infected with genotype 1a vs 1b HCV (10 vs 1 individual) and was characterized by an increase in on-treatment HBV DNA of ≥ 1 log10 copies/mL. which was primarily attributed to the development of resistance to the protease inhibitor. Therefore. . resulting in a higher SVR rate and a shorter duration of therapy.Use of Telaprevir in Combination With Peginterferon/Ribavirin in Genotype 1 HCV David R. various issues pertaining to resistance will need to be incorporated into future practice. overall. n = 17). and cirrhosis. To test this assumption. nonresponders). Higher rates of rapid virologic response. pruritus. the new therapies will be accompanied by additional adverse events that will make therapy more challenging. Therefore. such as education around compliance and adherence. However. respectively). Whereas all treatment arms in PROVE 1 contained ribavirin.

as well as peginterferon/ribavirin consolidation. in addition to the potential utility of a “lead-in” phase of peginterferon/ribavirin. These are clearly encouraging times for patients with HCV. the long-term effects of the selection and persistence of resistance to telaprevir in nonresponders remains to be established. .Phase III studies of telaprevir in combination with peginterferon/ribavirin are ongoing and will refine the concepts reported in the PROVE trials. In addition. and the landscape is rapidly changing in their favor. These studies should help to define the optimal duration of triple therapy.

Dusheiko G. viral breakthrough or relapse to peginterferon-alfa2a/b and ribavirin therapy: SVR results of the PROVE3 study. Program and abstracts of the 44th Annual Meeting of the European Association for the Study of the Liver. Manns M. Telaprevir in hepatitis C genotype-1-infected patients with prior non-response. 2009. Gordon SC. April 22-26. N Engl J Med.REFERENCES 1.360:1839-1850. Copenhagen. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. et al. 2009. Everson GT. Abstract 1044. N Engl J Med.360:1827-1838. . et al. Adda N. Denmark. Forestier N. Hézode C. 2. et al. McHutchison JG. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. 2009. 3. Muir A.

hepatocellular carcinoma (HCC). ALT.HALT-C: Long-term Maintenance Peginterferon alfa-2a Not Associated With Reduced Disease Progression Rates in Prior Nonresponders With Advanced Chronic HCV Infection „ HALT-C: prospective. significantly more of those receiving low-dose peginterferon alfa-2a died vs those untreated „ High discontinuation rate with 41% of patients not able to maintain original peginterferon 90- µg/week starting dose through 3. controlled trial[1] Summary of Key Conclusions „ Patients with chronic hepatitis C and advanced fibrosis who did not achieve sustained virologic response (SVR) to previous peginterferon/ribavirin did not receive clinical benefit from maintenance therapy with low-dose peginterferon alfa-2a ● Significant decreases in HCV RNA.5 years comparable to that observed in patients who received no HCV treatment „ Rates of serious adverse events similar between patients treated with peginterferon and those who received no treatment ● Among patients with noncirrhotic fibrosis at baseline. and ultimately death in those without SVR „ Long-term maintenance antiviral therapy hypothesized to have histologic benefit and therefore prevent liver disease progression in patients without SVR to initial treatment ● Suggested by retrospective analyses[2.3] but not yet demonstrated in prospective studies „ Current study prospectively evaluated liver disease progression following long-term peginterferon maintenance therapy in patients with advanced chronic hepatitis C who did not achieve SVR to previous interferon-based therapy Schematic of Study Design Copyright © 2009 Clinical Care Options. All rights reserved.5 years Background „ Antiviral therapy yields SVR in approximately one half of all treated patients with chronic HCV infection ● Disease can progress to cirrhosis. 1 . randomized. LLC. and histologic necroinflammatory scores observed with peginterferon treatment ● However. liver failure. rate of clinical and histologic disease progression over 3.

5 years. 1.13 (1.1 (7.9 Race.0) HCV genotype 1.25) 4. and laboratory testing every 3 months ● Hepatic ultrasound performed every 12 months to screen for HCC ● Liver biopsy taken at baseline.42 (0. physical examination. % 70. % • White 72.02) SD.51) Mean serum ALT. All rights reserved. U/L (± SD) 104 (74) 110 (80) Cirrhosis on biopsy.6 Mean HCV RNA.8 • Partial response during lead-in 33. and 3. Description of Current Analysis „ Patients enrolled at 10 US study centers from 2000-2004 „ Assessments ● History.5 years „ Primary endpoint ● Liver disease progression.0) Male.5 8.2 30.5 31.0 • Express patients 22.6 22. % • No response during lead-in 30.4 (8.10) 7.2 91. % 95.54) 6. standard deviation.44 (0.2 41.3 Mean Ishak fibrosis score (± SD) 4.54 (2. log10 copies/mL (± SD) 6.3) 50. LLC.6 • Hispanic 7.Eligibility „ Inclusion criteria ● Lack of SVR to previous interferon-based therapy ● Advanced hepatic fibrosis according to liver biopsy (Ishak fibrosis score ≥ 3) „ Exclusion criteria ● History of decompensated cirrhosis or HCC ● Liver disease other than hepatitis C ● Uncontrolled medical or psychiatric conditions ● Contraindications to interferon Baseline Characteristics „ Baseline characteristics generally well balanced across treatment groups Peginterferon No Treatment Characteristic (n = 517) (n = 533) Patients.55 (2. including death. yrs (± SD) 51. HCC.8 17. hepatic decompensation.0 71.9) 27.0 71.08 (1.5 Mean age.6 Mean duration of HCV exposure.4 • Other 1.28) Mean Ishak necroinflammatory score (± SD) 7.7 15.8 (7. % 40.3 • Black 18.7 2. or ≥ 2-point increase in Ishak fibrosis score (for patients with bridging fibrosis at baseline) Copyright © 2009 Clinical Care Options. 2 . yrs (± SD) 28. Child- Turcotte-Pugh of 7 on ≥ 2 consecutive visits.1 (7.7 • Breakthrough/relapse during lead-in 13.

38 -0. among patients with noncirrhotic fibrosis at baseline.46 to -0.90 • Noncirrhotic fibrosis 36. „ Secondary endpoints ● Quality of life ● Serious adverse events ● Events requiring dose reduction ● Increase in Ishak fibrosis score ● Development of HCC „ Statistical analyses ● Log-rank test and Cox proportional hazards used to determine primary outcome ● Kaplan-Meier survival curves used to estimate event rates 1400 days after randomization ƒ Data censored at patient’s last follow-up visit or at 1400 days Main Findings „ No significant differences observed between groups in the rate of any primary outcome regardless of presence or absence of cirrhosis at baseline Peginterferon No Treatment HR Primary Outcome P Value (n = 517) (n = 533) (95% CI) Kaplan-Meier estimate of rate. LLC. comparable rate of progression to cirrhosis between those who did and did not receive peginterferon (28. HR. „ Most common clinical outcomes were increase of ≥ 2 points in Child-Turcotte-Pugh score (10.1 33. confidence interval.01 (0.2 0.55) < .5%).27) .5 1.6%).66 to -0.38 0.4%).78-1.44) < . hepatic encephalopathy (3. variceal hemorrhage (1.27 to 0.03 -1. hazard ratio.20) .9%. 3 .42 0.68-1.2 31.97 (0.00 (-1.5%). ascites (5.05 (-1.03 -0.6%) „ HCC developed in 29 patients (2.001 necroinflammatory score • Mean increase in Ishak 0.81-1.77 fibrosis score Cirrhosis at baseline • Mean decrease in -1.2% vs 31. % 34.8%): 12 treated patients vs 15 untreated patients „ Significant decreases in mean necroinflammatory scores among treated patients with noncirrhotic fibrosis or cirrhosis at baseline ● Despite this. P = .39) • Cirrhosis 30.46) Peginterferon No Treatment Outcome at 3. and spontaneous bacterial peritonitis (0. All rights reserved.7 35.05 (0.001 necroinflammatory score Copyright © 2009 Clinical Care Options.38) CI.04 (-0.5 Yrs Difference (95% CI) P Value (n = 517) (n = 533) Noncirrhotic fibrosis at baseline • Mean decrease in -1.8 1.33 -1.

and patient refusal to continue therapy „ Dose modification for adverse events common ● In patients who did not have other study endpoints. Ann Intern Med.6% vs 31. depression. x ULN • Year 1.21 0. et al.359:2429-2441.001 Mean decrease in ALT.131:174-181.44) < . other adverse events.45 0. N Engl J Med.71 0. but difference failed to meet statistical significance ● 38.61-0.45-0.002 • Year 3. Copyright © 2009 Clinical Care Options.5 0. Ann Intern Med. Moriyama M. All rights reserved.5 0.129:94-99. % P Value (n = 517) (n = 533) Overall 6.0 1. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan.07 0.59 (0. et al.09-0.8% (P = .74 (0. no significant difference in mortality rates between groups ● Significantly higher mortality among treated vs untreated patients with noncirrhotic fibrosis at baseline.8 Years.19 0.87) < . „ HCV RNA and ALT levels significantly decreased with peginterferon treatment Peginterferon No Treatment Difference Outcome P Value (n = 517) (n = 533) (95% CI) Mean decrease in HCV RNA.28 (0. 2. Everson GT.07).5. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon.5 0. Imai Y. „ Overall. upper limit of normal.9 .04 • Cirrhosis 9. % 35. References 1.72) < .47 0. Shiffman ML.001 Normal ALT at Year 3.5 0.001 ULN.39) . Tamura S. Kawata S.1 22. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. LLC. log10 IU/mL • Year 1.5.6 .18 • Noncirrhotic fibrosis 5.6 < . but no significant difference in mortality among those with cirrhosis at baseline Peginterferon No Treatment Mortality at 3.001 • Year 3. only 59% of patients were still receiving the full 90-µg/week dose of peginterferon at Year 3. Di Bisceglie AM. 1999.12 0.24 (0. et al.6 4.81 0.4 . 3. 1998.93 „ Higher proportion of patients receiving peginterferon vs no treatment had ≥ 1 serious adverse event. by Kaplan-Meier analysis „ 157 patients discontinued peginterferon ● Reasons included cytopenias. 2008. Yoshida H. 4 .1 8.12-0. Shiratori Y.

respectively). It remains possible that long-term reductions in HCV RNA could benefit patients with advanced liver disease secondary to HCV. However. in the future. the studies were retrospective or conducted in small patient populations. Regarding safety. long-term usage of peginterferon was poorly tolerated: Only 58. the inclusion of highly potent small-molecule agents that lower the HCV RNA more substantially.5%.7% vs 35. multicenter trial. In this well-designed. ascites. more effective regimens is necessarily incorrect. it is important to note that the findings do not necessarily impugn the concept of long-term maintenance therapy. controlled. in fact. Since there are no therapeutic options for nonresponders other than enrollment in clinical trials.9% of patients enrolled in the treatment arm of the trial and who had not had a clinical event remained on the full dosage of peginterferon after 3. MD Combination therapy with peginterferon alfa and ribavirin is the current standard of care for chronic hepatitis C virus (HCV) infection. in which the goal is not to achieve viral eradication with a defined course of treatment.6%. Although several studies have suggested that such an approach may improve hepatic histology and reduce the rates of hepatocellular carcinoma. but rather to suppress HCV RNA with long-term antiviral therapy while awaiting the development of new medications. The overall death rate was also greater in the treatment group than the observation group (6. clinical outcomes were more frequent in the treatment group than the observation group (36. maintenance therapy has become a management option for nonresponders.5 years. respectively).5 years. Moreover. Unfortunately. it is possible that a subset of patients with prolonged deep viral suppression and marked decreases in liver enzymes may have benefited from maintenance therapy. Therefore. the death rate was significantly greater in the noncirrhotic subgroup who were treated vs those who were untreated (5. respectively).0% vs 1. or hepatic encephalopathy). spontaneous bacterial peritonitis. although the difference did not reach statistical significance. or increased hepatic fibrosis (in patients who did not have cirrhosis at baseline)—were unchanged with maintenance treatment compared with observation (34.1% vs 33. harmful. In fact.[2-4] Despite the paucity of rigorous.[1] Given the large number of HCV- infected patients who do not achieve SVR and given that chronic HCV infection can continue to progress in the absence of viral eradication. the negative results of this study further emphasize the unmet medical need faced by this population. it should not be extrapolated that the concept of long-term HCV RNA reduction by HCV maintenance therapy with different. sustained virologic response (SVR) is still only achieved in approximately 40% of those patients with genotype 1 HCV. clinical outcomes—death. . In addition. in patients with advanced fibrosis. although this difference was not statistically significant. the most common genotype. The dosage of peginterferon selected was arbitrary (based on perceived favorable tolerability). respectively. such therapy may be. controlled data supporting such an approach. However. the putative regimen must be reasonably well tolerated. a worsening Child-Turcotte-Pugh score. although again the difference did not achieve statistical significance. the HALT-C study by Di Bisceglie and colleagues[5] demonstrated a lack of improved histologic or clinical outcomes with long-term peginterferon alfa-2a 90 µg/week maintenance monotherapy vs no treatment in HCV patients with advanced liver disease who did not achieve SVR on previous HCV therapy (Hep JO Di Bisceglie_NEJM_2008). Although the negative results of maintenance therapy in this study are definitive. Such maintenance therapy may require the addition of ribavirin to the regimen or. alternatives to improve clinical outcomes in nonresponders have been sought. hepatic decompensation (variceal hemorrhage.8%. Unfortunately. and ribavirin was not used. Even in this study. hepatocellular carcinoma. One such approach involves the use of maintenance therapy. respectively). 1050 patients with cirrhosis or advanced (bridging) fibrosis who did not achieve SVR after a course of peginterferon alfa and ribavirin were randomized to receive peginterferon monotherapy vs observation for 3.8%. Although serum alanine aminotransferase and HCV RNA levels declined on therapy and histologic necroinflammatory scores improved.9%. serious adverse events occurred more frequently in the treatment group than in the observation group (38.Maintenance Peginterferon alfa-2a Ineffective at Preventing Disease Progression in HCV-Infected Patients Not Achieving SVR Steven Flamm.6% vs 4. P = . The clinical implications of this study are clear: Peginterferon alfa-2a 90 µg/week is ineffective as long-term maintenance therapy for patients with advanced liver disease who have not achieved an SVR after previous peginterferon/ribavirin therapy and cannot be recommended.6% vs 31. randomized.04).

Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Abstract 991. Italy. Kawata S.131:174-181. Everson GT. et al. 5. 1998. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Gastroenterology.117:1164-1172. Lawitz E. 2008. Sulkowski MS. Ann Intern Med. Hofmann CM. 1999.REFERENCES 1. Imai Y.359:2429-2441. Di Bisceglie AM. Milan. A randomized. et al. . 3. Shiffman ML. Tamura S.129:94-99. Moriyama M. 4. Shiratori Y. et al. 2. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Yoshida H. et al. N Engl J Med. Ann Intern Med. Shiffman ML. et al. 1999. Contos MJ. Final results of the IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) phase IIIB study. Shiffman ML. 2008. April 23- 27. Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver. controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.

respectively) ● Among patients with only fibrosis on serial biopsies. controlled US cohort of patients with chronic hepatitis C and advanced fibrosis or cirrhosis Schematic of Study Design Copyright © 2009 Clinical Care Options. smoking status. race.1%. alkaline phosphatase levels. respectively[2-4] „ Limited data from United States on incidence and risk factors for development of HCC in individuals with advanced HCV „ Current study determined HCC incidence and risk factors in prospective.5 years vs those who received no treatment „ HCC more common in patients with cirrhosis vs bridging fibrosis (7.0% vs 4. 8 (17%) developed HCC „ Predictive model for HCC risk developed based on age. All rights reserved. and platelet count Background „ HCC a common cause of liver-related death among individuals chronically infected with HCV ● Primarily in individuals with cirrhosis but occasionally in patients with bridging fibrosis „ Data from studies in Asia and Europe reveal rates of 4% to 10% and 0.Analysis of HALT-C Data Reveals Trends in Hepatocellular Carcinoma Incidence and Risk Factors in the United States „ Analysis of prospectively gathered data from HALT-C randomized trial[1] Summary of Key Conclusions „ Cumulative incidence of hepatocellular carcinoma (HCC) at 5 years approximately 5% in hepatitis C virus (HCV)–infected patients with advanced fibrosis with previous nonresponse to peginterferon/ribavirin ● Annual incidence of HCC: ~ 1% „ No significant difference in HCC incidence between patients who received maintenance peginterferon for 3.0%.5% to 5. LLC. presence of esophageal varices. 1 .

LLC. cells/mm3 123.52) .0001 (SD) • Total bilirubin.000 (49.3 (4.2) 50.1 (7.02 Female.40) .4) 3. % • White 63 72 • Black or black Hispanic 29 18 .0001 (SD) • Albumin.04 Genotype 1 HCV.000 (66.29 Copyright © 2009 Clinical Care Options. U/L 128 (66) 98 (44) < .9 (0. depending on enrollment group (highest AFP value in any patient at entry was 315 ng/mL) ● Liver disease other than hepatitis C ● Uncontrolled medical or psychiatric conditions ● Contraindications to interferon Baseline Characteristics „ N = 1005 ● 45 of 1050 HALT-C participants excluded from current analysis due to prevalent HCC (n = 5). or < 12 months of follow-up after enrollment (n = 38) „ Several baseline characteristics differed significantly between patients who developed HCC and those who did not Cox Hazards HCC No HCC Characteristic Proportional (n = 48) (n = 957) P Value Mean age.1) . g/dL (SD) 14.50 • White blood cell count.000) 167.5) .40 Mean HCV RNA.01 • Alkaline phosphatase.9 (1.39 (0.001 cells/mm (SD) • Platelet count. 3 4900 (1500) 5800 (1900) . presumed HCC that showed no radiographic or clinical progression (n = 2). 2 .0 (1.4) 15. mg/dL (SD) 0.6) 30.43 Mean laboratory values • Hemoglobin.7 (7.79 (0.38) 0. % 21 29 . % 92 94 .4) .4) .51) 6. g/dL (SD) 3. U/L (SD) 118 (76) 86 (57) .0 (5.000) < .0001 • ALT.21 Race. years (SD) 52.Eligibility „ Inclusion criteria ● Lack of sustained virologic response to previous interferon-based therapy ● Advanced hepatic fibrosis according to liver biopsy (Ishak fibrosis score ≥ 3) „ Exclusion criteria ● History of decompensated cirrhosis or HCC ƒ All patients confirmed to have no HCC-specific masses at screening by imaging analysis ƒ Serum alpha-fetoprotein (AFP) levels required to be < 200 ng/mL or < 1000 ng/mL at entry.44 (0.85 (0. log10 IU/mL (SD) 6.0002 • AST. All rights reserved. U/L (SD) 134 (109) 106 (76) .7 (0.05 • Hispanic 6 8 • Other 2 2 Mean BMI (SD) 28.

Model for End-Stage Liver Disease.50) 5.24) .5 ● Laboratory assessments performed every 3 months during trial and every 6 months thereafter ƒ Complete blood count. AST.0001 Mean alcohol consumption.04 (1. or univariate Cox proportional hazards ● Multivariate Cox proportional hazards used to estimate risk of HCC Copyright © 2009 Clinical Care Options.5 and 3.08 Esophageal varices.20 (0.78 (SD) Smoking history. g/day 25.88 (0. AST-platelet ratio index. Description of Current Analysis „ Patients enrolled at 10 US study centers „ Assessments ● Liver biopsies at baseline and Years 1. 3 .34) 16. international normalized ratio .0001 • Child-Turcotte-Pugh score 5. All rights reserved. % 83 75 .13 ALT.02 • APRI (SD) 2.0001 (SD) • MELD score (SD) 7. aspartate aminotransferase.19) 7. % 50 24 < .28 (28.83 Cirrhosis.48) < . body mass index. INR 1.08 (39.10 (0. BMI.00 (0.96 (0.29) .42) .89 (29. liver panel.5 „ HCC categorized as definite or presumed ● Definite HCC: histologic confirmation or a new mass on imaging with AFP > 1000 ng/mL ● Presumed AFP: new mass on ultrasound in the absence of histology and AFP < 1000 ng/mL plus 1 of following ƒ 2 imaging studies showing mass lesion with characteristics of HCC ƒ Progressively enlarging lesion on ultrasound leading to death ƒ 1 additional imaging study showing mass lesion with characteristics of HCC that either increased in size or associated with increased AFP „ Statistical analyses ● Kaplan-Meier and log rank tests used to determine incidence of HCC ● Correlation between baseline factors and risk of HCC assessed by t test. INR.43) 25. APR.11) . U/mL (SD) 50.32) 45.22 • Mean DCP.33 (1.86) .56 (1. ng/mL (SD) 23.09) 1.14 HCC markers • Mean AFP.06 Severity of liver disease • AST/ALT ratio (SD) 0. chi-squared test.34) 0. and AFP level ● Ultrasound performed approximately every 6-12 months ƒ Identification of new lesions further evaluated with computed tomography or magnetic resonance imaging ● Endoscopy performed at randomization and at Year 3.70 (2. des-gamma-carboxy prothrombin.6 (223. % 52 40 .03 (33.13) 1. standard deviation. LLC.54 (51.43) < . DCP.69) . SD. MELD. • Prothrombin time.44 (0. alanine aminotransferase.

9 • Patients with fibrosis 5.1 1.04 Alkaline phosphatase.5 4.164 . % (n = 495) (n = 510) Overall HCC incidence 4.1 7.7 years) ● Definite HCC: 77% (n = 37) ● Presumed HCC: 23% (n = 11) ● Diagnosis ƒ Early-stage HCC (T1/T2): 75% (n = 36) ƒ Eligible for potentially curative treatment: 54.1 Annual incidence 1.4 2. HCC incidence higher in patients with cirrhosis vs bridging cirrhosis Bridging Fibrosis Cirrhosis Outcome.1 Annual incidence 0.01 Esophageal varices 2.4 Cumulative incidence • 3 years 1. All rights reserved. U/L 1.8% of patients (n = 48) developed HCC during median follow-up of 4. LLC. cells/mm 0.6 years (maximum: 6.050 .Main Findings „ 4.7 • Patients with cirrhosis 4. 4 . % (n = 597) (n = 408) Overall HCC incidence 3.001 Copyright © 2009 Clinical Care Options.1 8.01 Black race 2.0 Cumulative incidence • 3 years 1.989 . „ Cox proportional hazards model developed to predict risk for HCC ● Final model included variables available in most patients with chronic hepatitis C Variable Hazard Ratio P Value Age 1.02 Ever smoked 2.2% (n = 26) „ Incidence of HCC similar in peginterferon and no-treatment groups Peginterferon No Treatment Outcome.0* *P = .0 „ Although not statistically significant.9 6.114 .6 • 5 years 4.9 • 5 years 5.9 1.07 3 Platelet count.044 .8 1.4 5.0 2.006 .08 vs bridging fibrosis at 5 years.

France: IARC Scientific Publications. 4. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. 2. respectively) Cumulative Incidence of HCC. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. cut points of 0 to log10(1. et al.712 + alkaline phosphatase*0.000 cells/mm3 cells/mm3 3 years 5.049 + black race x 0. 2002. Copyright © 2009 Clinical Care Options. Cancer incidence in five countries.4 4. „ Regression formula for model: age x 0.50) to log10(3. All rights reserved. and > log10(3. Hoofnagle JH. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.6 5 years 13. 2009.1 5. Lok AS.8 Other Outcomes „ Low platelet count (P < .25).7 2.136:138- 148.2 17. 3.000 cells/mm3 > 150.25:3771–3777.3 2. El-Serag HB. 5 . intermediate.0002) highly significant in Kaplan-Meier estimates of cumulative incidence of HCC Platelet Count Cumulative Incidence of HCC. LLC. % Low Risk Intermediate Risk High Risk 3 years 0 1. 2006. 1% to 5%. Seeff LB. Gastroenterology.132:2557–2576.000-149.011 ● According to regression formula. and > 5%. log10(1. Morgan TR.5 6. di Bisceglie AM.50).1 5 years 0. Parkin D. Lyon.000 < 100.6 References 1. and high risk for HCC at 5 years (cumulative incidence < 1%.006 + esophageal varices*0. Oncogene.0001) and esophageal varices (P = . 2007.4 0.777 + ever smoked*0. % 100. Rudolph KL.749 + platelets*-0. Gastroenterol. Seeff LB.25) selected to reflect low.

2% were eligible for potentially curable therapy. This suggests that our current screening recommendations fail to identify nearly one half of tumors at a time when therapy can be of maximal benefit. HCC was identified in 23 patients without cirrhosis at enrollment (48% of all patients with HCC). Yet in this study. Unlike with hepatitis B. .[12] Lok and colleagues unearthed several very important findings in this analysis: 1. Screening is likely necessary for a subset of patients with advanced fibrosis (without cirrhosis) and should ideally be performed every 6 months. and having ever smoked were significant in predicting HCC risk. randomized HALT-C trial (Hep JO Di Bisceglie_NEJM_2008). Only 75% of malignancies were diagnosed at an early stage (T1/T2). The findings indicate that no patient should be receiving maintenance peginterferon solely for liver cancer prevention. this study found that AFP and des-gamma-carboxyprothrombin (DCP) levels on univariate analysis were both significantly associated with HCC. This finding strongly discourages the use of maintenance therapy to decrease malignancy risk. 4. However. black or black plus Hispanic race. reminding us that HCV liver disease is a dynamic condition and that patients should be reassessed at regular intervals for disease progression. intermediate-.9%. Our current practice guidelines do not recommend using alpha-fetoprotein (AFP) levels as a screening tool. the investigators were able to stratify the cohort into low-. however. and high-risk groups for the development of HCC using a mathematical model requiring only routine laboratory results and clinical data. MD Hepatocellular carcinoma (HCC) is a common complication of hepatitis C cirrhosis. This suggests that significant fibrosis is also a risk factor for HCC and that our current screening [13] recommendations should be expanded to include this subset of patients. This important study has several implications.[1-6] Published reports suggest that long-term treatment with peginterferon decreases the risk of progression to HCC. Based on these data. In addition. high alkaline phosphates levels. and only 54. presence of esophageal varices. Some of these patients had progressed to cirrhosis at the time of HCC diagnosis. Patients with a previous nonresponse to peginterferon/ribavirin who received low-dose maintenance peginterferon developed HCC at a rate equal to that of untreated controls. 2. Until the appropriate population for screening can be identified. conflicting data exist regarding the annual incidence of HCC and the factors that predispose hepatitis C virus (HCV)–infected patients to developing this complication.Defining the Incidence and Risk Factors for Hepatocellular Carcinoma in the Setting of HCV Infection Nancy Reau.8% of the HALT-C cohort. the development of HCC in HCV-infected patients without cirrhosis has been viewed as an exception to the rule. with an estimated annual incidence of 1. This suggests that it may be possible to identify patients in need of intensive HCC screening and monitoring. AFP and DCP).1% and a 5-year incidence of 5.[7-10] The current study conducted by Lok and colleagues (Hep JO Lok_Gastroenterol_2009)[11] was performed to help clarify these issues using prospectively gathered data from the large. 3. Screening should be initiated as soon as a patient is considered to be at increased risk for malignancy. Hepatocellular carcinoma developed in 4. this study suggests that our [13] current HCC screening recommendations are not adequate. Older age. all patients with advanced fibrosis should be screened every 6 months for HCC using a combination of imaging and tumor markers (ie. low platelet counts. Patients without cirrhosis developed malignancy.

2005.42. Degos F. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. 2007. Di Bisceglie AM. Giustina G. et al. Tamura S. 2009. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis.136:138-148. Seeff LB. Shiffman ML.132:2557-2576. Gastroenterology. Oncogene.53:744-749.359:2429-2441. 1992. Alberti A.116:97-102. IHIT Study Group. J Hepatol. Boccato S. et al. France: IARC Scientific Publications. 1997. 6. Lok AS. 1998. 10. Gastroenterology. Management of hepatocellular carcinoma. Sherman M.346:1051-1055. et al. Benvegnù L. El-Serag HB. 4. Morgan TR. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.1208-1236. N Engl J Med. Rudolph KL. Kawata S. 13. Ann Intern Med. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Inhibition of hepatocarcinogenesis by interferon therapy. Kuroki T. Gastroenterology. Yoshida H. 7. Simonetti RG.112:463-472. Moriyama M. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Gios M.REFERENCES 1. et al. Randomised trial of effects of interferon. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. Gut. Bruiz J. Cammà C.on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. et al. 2006. 12. Cancer incidence in five countries. 9. Lyon. Hoofnagle JH. . 3. 1996. 2. Nishiguchi S. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. Lancet 1995.131:174-181. Parkin D. 2002. Imai Y. et al. Nakatani S. Ann Intern Med 1999. 5. Accogli E. 2004. Ann Intern Med. Hepatology. 2008. Mazzella G. Sottili S. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications.24:141-147. Fattovich G. et al. Seeff LB.25:3771-3777. Fiorello F. et al. Shiratori Y. 8. Everson GT. 11.129:94-99. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis: a case-control study.

higher doses. tolerability. and safety of consensus interferon/ribavirin retreatment in HCV-infected patients with prior nonresponse to peginterferon/ribavirin Schematic of Study Design Copyright © 2009 Clinical Care Options. LLC.Consensus Interferon/Ribavirin Beneficial for Specific Groups of Difficult-to-Treat Prior Peginterferon/Ribavirin Nonresponders „ DIRECT trial: multicenter. 1 . and/or a longer duration of therapy „ Current study assessed efficacy. US-based phase III registration trial Summary of Key Conclusions „ Retreatment of peginterferon/ribavirin nonresponders with consensus interferon/ribavirin produced SVR rates of 7% to 11% ● Patient population had numerous poor prognostic factors „ Highest SVR rates (~ 30%) in patients with greater interferon sensitivity (> 2 log10 reduction in HCV RNA during prior therapy) and lower baseline fibrosis scores (F0-F3) „ Consensus interferon/ribavirin safe and relatively well tolerated Background „ Standard of care for chronic hepatitis C: treatment with peginterferon/ribavirin ● More than one third of all patients experience nonresponse to treatment „ Optimal management approach for peginterferon/ribavirin nonresponders not well defined ● Potential strategies include watchful waiting or retreatment using different agents. open-label. All rights reserved. randomized.

standard deviation. All rights reserved. LLC. defined as < 2 log10 decrease in HCV RNA from Weeks 12-24 or detectable HCV RNA at Weeks 24 or 48 ● Documented prior adherence: receipt of ≥ 80% of cumulative standard doses of peginterferon/ribavirin for ≥ 80% of planned treatment duration ● Documented washout period: ≥ 90 days since discontinuation of prior treatment regimen „ Exclusion criteria ● Premature treatment discontinuation. % 95 96 HCV RNA ≥ 850.1 (18. % • < 2 log10 drop in HCV RNA 78 80 • > 2 log10 drop in HCV RNA 15 12 • Unknown 7 8 Median time since peginterferon/ribavirin 448 506 discontinuation. yrs (SD) 51 (6. or peginterferon dose reduction during prior therapy ● Pregnant/lactating women.4 (17. days SD. % 68 68 Hepatic fibrosis (Metavir score).000 IU/mL. % • F0-F2 42 38 • F3 (bridging fibrosis) 36 34 • F4 (cirrhosis) 22 28 Steatosis. „ No-treatment arm included for safety comparison with 2 consensus interferon arms ● 2 consensus interferon 9 µg/day arms and 2 consensus interferon 15 µg/day arms pooled for analysis „ All patients with < 2 log10 decrease in HCV RNA from baseline after 24 weeks of consensus interferon/ribavirin considered nonresponders and withdrawn from therapy Eligibility „ Inclusion criteria ● Chronic infection with HCV of any genotype ● Normal liver function and no prior episodes of hepatic decompensation ● Documented prior nonresponse to peginterferon/ribavirin. kg (SD) 89.59) Male. % • White 64 65 • Black 21 17 Mean weight.65) 50 (6. male partners of pregnant women ● Unlikely to comply with study requirements Baseline Characteristics „ Baseline characteristics well balanced between pooled groups assigned to consensus interferon 9 µg/day or 15 µg/day Consensus Interferon Consensus Interferon Characteristic 9 µg/day + Ribavirin 15 µg/day + Ribavirin (n = 245) (n = 242) Mean age.59) HCV genotype 1.64) 89. 2 . % 52 51 Response to prior therapy. Copyright © 2009 Clinical Care Options. dose interruption. % 68 72 Race.

and 72 „ Primary endpoint ● SVR „ Secondary endpoints ● Factors influencing SVR ● Safety ● Tolerability „ Intent-to-treat analysis Main Findings „ SVR rates of 6.5 SVR 6. 48.9% and 10. % 9 µg/day + Ribavirin 15 µg/day + Ribavirin (n = 245) (n = 242) Patients with complete early virologic 81. 3 . All rights reserved. HCV RNA undetectable at Week 24. 24.3 63.141) „ Approximately 40% to 50% relapse rates observed Consensus Interferon Consensus Interferon Outcome.4 *> 2 log10 drop in HCV RNA at Week 12. % 9 µg/day + Ribavirin 15 µg/day + Ribavirin (n = 245) (n = 242) End-of-treatment response 14. LLC.7% in the consensus interferon 9 µg/day and 15 µg/day arms. and no statistically significant difference in SVR rates between arms in post hoc analysis (P = .6 response Patients with slow response* 11.9 10. SVR rates of 7% and 17% in the consensus interferon 9 µg/day and 15 µg/day arms.Description of Current Analysis „ Patients enrolled at 44 sites in United States and Puerto Rico „ HCV RNA assessed at Weeks 0. respectively ● Study not powered to detect differences between arms.7 35.7 18. Copyright © 2009 Clinical Care Options.7 Relapse rate 52 42 „ Among patients who had no dose modifications. respectively „ Complete early virologic response (defined as HCV RNA negativity at Week 12) associated with increased likelihood of SVR Consensus Interferon Consensus Interferon SVR.

% (n = 244) (n = 242) Fatigue 75 77 Headache 46 39 Nausea 45 45 Influenza-like illness 40 42 Neutropenia 36 44 Insomnia 39 38 Myalgia 24 34 Leukopenia 24 34 Arthralgia 31 31 Depression 27 25 Other Outcomes „ 83.4 • 1-2 log10 decrease in HCV RNA 9.000 IU/mL (16. received ≥ 80% of cumulative dose „ Most common reason for treatment discontinuation in 9 µg/day and 15 µg/day groups was treatment failure (51.1 • < 1 log10 decrease in HCV RNA 8.1% vs 5. 4 . All rights reserved.2 • > 2 log10 decrease in HCV RNA 13.4%.6% and 71. LLC.3 „ Other factors associated with SVR ● SVR rates higher in whites vs blacks (11.7 14. % 9 µg/day + Ribavirin 15 µg/day + Ribavirin (n = 245) (n = 242) Fibrosis score F0-F2 8.3 30 Fibrosis score F3 6.3 7.5 • > 2 log10 decrease in HCV RNA 10.5 12.9%.001) „ Most adverse events grade 2/3 in severity Consensus Interferon Consensus Interferon Adverse Event Occurring in ≥ 25% of 9 µg/day + Ribavirin 15 µg/day + Ribavirin Patients in Either Arm. respectively.0 8.3% and 21. respectively) ● SVR rates higher in patients with nongenotype 1 vs genotype 1 HCV (47. P < .9 • < 1 log10 decrease in HCV RNA 6.7 • 1-2 log10 decrease in HCV RNA 4.8 4.5 • > 2 log10 decrease in HCV RNA 7. respectively).6 8.6 33.0% vs 4.1%.5 • < 1 log10 decrease in HCV RNA 4.8% and 44. „ Highest SVR rates observed in patients with greatest decreases in HCV RNA on prior therapy and low fibrosis scores at baseline (F0-F3) Consensus Interferon Consensus Interferon SVR. respectively. respectively) Copyright © 2009 Clinical Care Options.7% of patients assigned to consensus interferon 9 µg/day and 15 µg/day. followed by adverse events (14.8 11.0 19.001) ● SVR rates higher in patients with baseline HCV RNA < vs > 850.3 Fibrosis score F4 3. P < .1 0 • 1-2 log10 decrease in HCV RNA 0 9.2%.2%.8% vs 6.

LLC. 2009. et al.Feb 2[Epub ahead of print]. Retreating chronic hepatitis C with daily interferon alfacon- 1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.Reference Bacon BR. Shiffman ML. Hepatology. Copyright © 2009 Clinical Care Options. 5 . All rights reserved. Mendes F.

the dose of ribavirin was reduced from 1000-1200 mg/day to 600 mg/day.[3] When patients were classified according to fibrosis score and the level of response to previous peginterferon/ribavirin. It is important to note that the investigators had very strict criteria for ribavirin dose modification in response to anemia. sustained virologic response (SVR) rates in this trial were low. It is those individuals with unfavorable characteristics—cirrhosis. as optimal management of these individuals to prevent disease progression remains to be defined. MD. Although the numbers were small. these are not the patients in dire need of such treatment. approximately 25% had cirrhosis.[2] patients who had a partial response to previous peginterferon/ribavirin treatment (> 2 log10 IU/mL decrease in HCV RNA) were the most responsive to retreatment with consensus interferon/ribavirin. The authors stated that 72% to 84% of patients received at least 80% of the cumulative consensus interferon dose. For patients who experienced a drop in hemoglobin < 10 g/dL. this aspect of the treatment protocol may have attenuated the response rates that could have been achieved had smaller increments in ribavirin dose reduction been employed.0% vs 4. FACP. SVR rates for the 9-µg/day and 15-µg/day doses of consensus interferon were 11% and 23%. depending on how many patients required ribavirin modification. No growth factor support was allowed. more than 50% had steatosis. In this population of patients. It is unclear what probability of response is sufficient or reasonable to warrant putting a patient through the expense. For example. Preliminary results from studies of novel specifically targeted antiviral therapies for HCV (STAT-C) suggest that these agents may produce higher response rates than currently available options when used as part of a retreatment regimen.Consensus Interferon/Ribavirin Retreatment for Peginterferon/Ribavirin Nonresponders Beneficial for Select Group of Patients With Low Baseline Fibrosis Scores and Interferon Sensitivity Richard Sterling. high HCV RNA. reaching only 7% for patients who received consensus interferon 9 µg/day and 11% for patients who received consensus interferon 15 µg/day. nearly 20% of the study population was black. The investigators also found that patients with lower fibrosis scores responded better to treatment than those with higher fibrosis scores (SVR for fibrosis stage F0-F3 vs F4 with the 15-µg/day dose: 13. This finding has been observed in other trials that included treatment-experienced patients. and this should be considered on an individualized basis. steatosis. those who achieved a complete response at Week 12 were more likely to achieve SVR (13/16 [81%] in the 9-ug/day group and 14/22 [64%] in the 15-µg/day group). the investigators found that patients with low fibrosis scores (F0-F3) and a previous reduction in HCV RNA > 2 log10 IU/mL attained SVR rates of 30% or greater with consensus interferon 15 µg/day. Unfortunately. Overall. The current study by Bacon and colleagues[1] tested the antiviral efficacy of consensus interferon plus ribavirin in nearly 500 previous peginterferon/ribavirin nonresponders (Hep JO Bacon_Hepatology_2009). These results are fairly disappointing. One of the many management strategies proposed for nonresponders is treatment with interferon alfacon-1 or consensus interferon. As has been seen in other studies. respectively. those who had a partial response to previous peginterferon/ribavirin and do not have cirrhosis. a clearly defined group of previous peginterferon/ribavirin nonresponders. and black race—for whom disease control is needed most urgently. which probably represents the lower threshold of therapeutic efficacy. MSc. although not unexpected. The investigators conducted several subanalyses to tease apart various groups of nonresponders who may attain more benefit from consensus interferon/ribavirin retreatment than others.5%). and nearly 80% had a < 2 log10 decline in HCV RNA in response to previous therapy—that is. FACG Patients chronically infected with hepatitis C who fail to respond to first-line peginterferon/ribavirin therapy represent an underserved population. the adverse events. Therefore. the results of this study suggest that there may be specific subgroups of patients with a previous nonresponse to peginterferon/ribavirin who might benefit from retreatment with consensus interferon/ribavirin—namely. and the inconvenience of retreatment. The investigators enrolled a very difficult–to-treat population with several unfavorable treatment characteristics. As such. . but adherence to ribavirin was not reported.

Marcellin P.Feb 2:[Epub ahead of print]. 2. 2009. et al. A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment of chronic hepatitis C. 2009. Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.150:528-540. Ahmed F. Am J Gastroenterol. 3. Ann Intern Med. 2005. Mendes F. Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial. Bacon BR.REFERENCES 1. Shiffman ML. Jacobson IM. Freilich B. et al.100:2453-2462. . Gonzalez SA. Jensen DM. et al. Hepatology.

LLC. All rights reserved. with or without ribavirin.Nitazoxanide Improves Rates of Response to Peginterferon/Ribavirin in Treatment-Naive Patients With Genotype 4 HCV „ Randomized. open-label. phase II trial[1] Summary of Key Conclusions „ Addition of nitazoxanide to peginterferon/ribavirin significantly increased rates of sustained virologic response (SVR) and rapid virologic response (RVR) in treatment-naive patients chronically infected with genotype 4 hepatitis C virus (HCV) „ No increase in adverse events observed with coadministration of nitazoxanide with peginterferon/ribavirin Background „ Relatively poor response rates to standard of care for HCV necessitate development of novel therapies „ Nitazoxanide an anti-infective compound of the thiazolide class ● Originally developed as an antiparasitic drug ● No major adverse events „ Documented activity of nitazoxanide against HCV ● Potent inhibition of HCV replicons and infectious clones in vitro[2] ● Activity as monotherapy in phase II study in patients with genotype 4 HCV[3] ● Increased virologic response rates in combination with peginterferon „ Nitazoxanide mechanism of action against HCV involves induction of double-stranded RNA- activated protein kinase phosphorylation[4] ● Results in increased intracellular concentrations of phosphorylated eukaryotic initiation factor 2α. in treatment-naive patients with genotype 4 HCV[1] Schematic of Study Design Copyright © 2009 Clinical Care Options. controlled. 1 . which controls host cell defenses against viral infection „ Current study assessed efficacy and safety of nitazoxanide plus peginterferon alfa-2a.

0-57.5 (21. and 24 posttreatment „ HCV RNA levels assessed using 2 assays ● HCV RNA considered undetectable if not detected by either assay ● Lower limit of detection of assays: 615 IU/mL and 12 IU/mL „ Primary endpoint ● SVR „ Secondary endpoints ● RVR. % 89 96 90 White.0-55.004) „ All patients infected with genotype 4 HCV Nitazoxanide + Nitazoxanide + Peginterferon/Ribavirin Characteristic Peginterferon Peginterferon/Ribavirin (n = 40) (n = 28) (n = 28) Median age. SD.1-6.0 (2. LLC.3) score (SD) Fibrosis or cirrhosis.1) 5. alanine aminotransferase.0-54.5) (range) Median ALT. defined as undetectable HCV RNA 12 weeks after start of combination therapy ● End-of-treatment response (ETR) Copyright © 2009 Clinical Care Options.5 (4.4-6. yrs (range) 37.Eligibility „ Inclusion criteria ● 18 years of age or older ● Chronic HCV infection „ Exclusion criteria ● Previous interferon-based treatment ● Other causes of liver disease ● Hepatitis B virus coinfection ● Concomitant medical conditions that would compromise completion of therapy ● History of alcohol abuse or alcohol consumption > 40 g/day ● Unable to take oral medications ● Unable to use contraception Baseline Characteristics „ Baseline characteristics generally well balanced across treatment groups. 12. All rights reserved.004 Description of Current Analysis „ Patients enrolled at 2 centers in Egypt between March and August 2006 „ Patients assessed every 4 weeks during treatment and at Weeks 4. standard deviation. U/L (range) 55 (14-359) 64 (14-213) 69 (18-324) Mean Knodell necroinflammation 4.0) Male.6 (4.0) 39.7 (4. log10 IU/mL 5. 8.0) 37.3) 5.5 (22. % 4 11 3 ALT.2-6.0) 3. defined as undetectable HCV RNA 4 weeks after start of combination therapy ● Complete early virologic response (cEVR). except for significantly lower body mass index (BMI) among patients treated with nitazoxanide plus peginterferon/ribavirin vs those treated with peginterferon/ribavirin (P = .1 (3. 2 . *P = .2) 4.0 (20. % 93 100 98 Median BMI (range) 27 (19-37) 25 (18-33)* 28 (18-37) Median HCV RNA.3 (2.

P = .023) and RVR (64% vs 38%.032) „ Mean reduction in HCV RNA significantly greater at 4 weeks after start of combination therapy for patients who received nitazoxanide vs those who did not (P = . respectively.74 4. log10 IU/mL ALT normalization in patients who achieved SVR. P = . respectively. All rights reserved. ● ALT normalization ● Safety „ Intent-to-treat analysis Main Findings „ Statistically significantly higher response rates with nitazoxanide plus peginterferon/ribavirin vs peginterferon/ribavirin for both SVR (79% vs 50%. LLC. 3 . respectively) „ Exploratory analysis of per-protocol population yielded similar response rates to those obtained by intent-to-treat analysis „ Modest but statistically significant HCV RNA reductions observed during nitazoxanide lead-in phase in patients assigned to these 2 arms ● HCV RNA decrease from baseline to Week 12: 0.048) ● cEVR and ETR rates comparable between groups „ Higher SVR also seen with nitazoxanide plus peginterferon vs peginterferon/ribavirin but difference not statistically significant (61% vs 50%.50 2.008 for trend) „ Rates of ALT normalization comparable across groups among patients who achieved SVR Nitazoxanide + Nitazoxanide + Peginterferon/Ribavirin Outcome Peginterferon Peginterferon/Ribavirin (n = 40) (n = 28) (n = 28) Mean decrease in HCV RNA 4 weeks after start of combination 3.86 therapy.27 log10 IU/mL (P = . % ƒ Abnormal at baseline 75 69 68 ƒ Normal at baseline 20 31 27 Copyright © 2009 Clinical Care Options.

Keeffe EB. LLC. 4 . et al. Elfert A. and ribavirin. 2008. thrombocytopenia. % Peginterferon Peginterferon/Ribavirin (n = 24) (n = 22) (n = 22) < 25 75 93 71 25-30 75 83 71 > 30 67 75 63 References 1. 2008. Elazar M. Elfert A. placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Clinical trial: randomized.136:856-862. California. 2008. Liu M. San Francisco. peginterferon. 3. double-blind. McKenna S. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide. 2009. Rossignol JF. El-Gohary Y. Aliment Pharmacol Ther. Abstract 1881. Copyright © 2009 Clinical Care Options.28:574-580. 4. October 31-November 4. Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Keeffe EB. Program and abstracts of the 59th Annual Meeting of the American Association for the Study of Liver Diseases. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR phosphorylation. Rossignol JF. SVR rates higher for patients who received nitazoxanide vs those who did not ● Subgroup size too small to assess statistical significance Nitazoxanide + Nitazoxanide + Peginterferon/Ribavirin SVR According to BMI. El-Gohary Y. Lui P. and neutropenia ● Only significant difference in adverse events across groups was higher rate of anemia in patients who received ribavirin (P = .002) Other Outcomes „ Among per-protocol population stratified by baseline BMI. „ Lower baseline HCV RNA independently predicted SVR in patients receiving peginterferon/ribavirin ● No other significant predictors of SVR identified for any treatment groups „ Most common adverse events included those typically associated with peginterferon/ribavirin: anemia. Kabil SM. Korba BE. 2. Rossignol JF. Glenn JS. All rights reserved. Antimicrob Agents Chemother.52:4069-4071. Gastroenterology. Elazar M.

27 log10 IU/mL) and no evidence of ALT reduction. Rossignol and colleagues reported that. response rates to peginterferon plus ribavirin for patients infected with genotype 1 or 4 HCV are suboptimal.Improved Response Rates in Chronic Hepatitis C With the Use of Nitazoxanide: A Look at Phase II Data Mark S. led to this study. a third treatment arm of standard peginterferon/ribavirin therapy (n = 40) was also included for comparison. in current and future treatment paradigms. nitazoxanide was given as monotherapy for 12 weeks. The rationale for this application emerged from observations of AIDS patients with cryptosporidiosis who were coinfected with hepatitis B virus and/or HCV. and conduct of the study at only 2 sites. and then peginterferon with or without ribavirin was added for an additional 36 weeks of treatment. inclusion of only patients infected with genotype 4 HCV (as opposed to genotype 1 HCV). Limitations of the study include small sample sizes for the nitazoxanide groups (n = 28 for each nitazoxanide arm). reaching only 40% to 60%. The development of a well-tolerated. Sulkowski. controlled phase II trial (Hep JO Rossignol-Gastroenterol- 2009-CS). . Larger follow-up studies are currently under way in the United States in persons infected with genotype 1 HCV. Rossignol and colleagues[3] conducted a randomized. Subsequent work conducted in vitro demonstrated a reduction in HCV replication in the genotype 1 replicon model with the addition of nitazoxanide. including the current standard of care (ie. Traditionally. Furthermore. as long-term treatment of these individuals with nitazoxanide produced reductions in serum alanine aminotransferase (ALT) levels. Although this clinical trial raises the prospect of using nitazoxanide in the clinical management of HCV. if any. in contrast to the original observation in HIV-infected persons that. In total. 96 treatment-naive patients chronically infected with genotype 4 HCV were randomly assigned to receive nitazoxanide and peginterferon alfa-2a. The enhanced SVR rates observed in the nitazoxanide-containing arms was largely because of a markedly reduced rate of virologic relapse after treatment discontinuation (15% for nitazoxanide plus peginterferon and 4% for nitazoxanide plus peginterferon and ribavirin vs 33% for peginterferon and ribavirin alone). HCV protease inhibitors) in combination with peginterferon plus ribavirin. In the 2 nitazoxanide-containing arms.023). the increased rate of SVR was achieved without any increase in adverse effects. it is interesting to note that the investigators saw no reduction in ALT levels during the 12- week lead-in phase of nitazoxanide. MD Nitazoxanide is an orally available drug used for the treatment of parasites. If the findings of this study are confirmed in larger studies. which will address the limitations of the current clinical trial. there has been interest in using nitazoxanide for the treatment of hepatitis C virus (HCV) infection. it does not provide definitive evidence of its role. orally available agent that can enhance the rate of SVR to peginterferon plus ribavirin would be of major benefit for persons with negative baseline predictors of response to the current standard of care. The SVR rate for patients who received nitazoxanide plus peginterferon and ribavirin was 79% compared with a rate of 50% for standard peginterferon and ribavirin therapy (P = . thereby enhancing the effect of interferon. Recently. nitazoxanide may be an important adjuvant therapy to enhance the response to interferon-based HCV treatment. the open-label design (both subjects and investigators were aware of the treatment assignment). which results in an increased intracellular concentration of phosphorylated eukaryotic initiation factor 2-alfa. including Cryptosporidium and Giardia.[2] To more rigorously assess the safety and efficacy of nitazoxanide for the treatment of HCV. the addition of peginterferon with or without ribavirin yielded higher sustained virologic response (SVR) rates compared with standard 48-week treatment with peginterferon and ribavirin. with ribavirin (n = 28) or without ribavirin (n = 28). although nitazoxanide monotherapy was associated with only a very modest decrease in HCV RNA (-0.[1] Recent findings suggest that the mechanism of action of nitazoxanide may be to induce double-stranded RNA-activated protein kinase phosphorylation. peginterferon plus ribavirin) and future treatment approaches featuring specifically targeted antiviral therapies for HCV (eg. in part. Of note. with the majority of subjects (75 of 96) enrolled at 1 site.

Glenn JS. 2009. Potential for hepatitis C virus resistance to nitazoxanide or tizoxanide.48:1151A. El-Gohary Y.52:4069-4071. 2. Rossignol JF. . 2008. Elazar M. Liu M. Gastroenterology. and ribavirin. Keeffe EB. McKenna S. 3. Hepatology. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide.REFERENCES 1. peginterferon. Elazar M.136:856-862. Elfert A. Rossignol JF. et al. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR phosphorylation. 2008. Antimicrob Agents Chemother. Lui P. Korba BE.

phase III trials Summary of Key Conclusions „ Tenofovir superior to adefovir for the composite primary endpoint of HBV DNA suppression < 400 copies/mL with histologic improvement in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B treated for 48 weeks ● Significantly more HBeAg-positive patients achieved secondary endpoints of ALT normalization and HBsAg loss with tenofovir vs adefovir „ No emergence of tenofovir resistance observed in any patient during 48 weeks of treatment ● Emergence of adefovir resistance in 2% of patients „ Safety of tenofovir comparable with that of adefovir Background „ Oral agents with potent antiviral activity. Turkey as monotherapy for chronic HBV infection „ Current study summarized results of 2 trials that compared efficacy and safety of tenofovir vs adefovir in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B Schematic of Study Design Copyright © 2009 Clinical Care Options.Tenofovir Demonstrates Superior Efficacy. Similar Safety vs Adefovir in HBeAg- Positive and HBeAg-Negative Chronic Hepatitis B „ Studies 102 and 103: randomized. Canada. Australia. long-term safety. double-blind. All rights reserved. and high genetic barrier to resistance needed for long-term treatment of chronic HBV infection „ Tenofovir a nucleotide analogue that blocks DNA synthesis activity of viral polymerase ● Approved in United States and more than 50 other countries for use in combination therapy of HIV-1 ● Recently approved in United States. Europe. LLC. 1 .

hepatitis D virus. 2 . or HIV ● Hepatocellular carcinoma ● Impaired renal function (creatinine clearance < 70 mL/min) ● Anemia or neutropenia ● Liver decompensation or liver failure Copyright © 2009 Clinical Care Options. „ Patients who completed 48-week trial and who underwent second liver biopsy eligible to receive open-label tenofovir for up to 7 more years Eligibility „ Inclusion criteria ● Age 18-69 years ● Compensated liver disease ● Knodell necroinflammatory score ≥ 3 ● HBsAg positivity for ≥ 6 months (indicating chronicity of infection) ● Additional criteria for HBeAg-negative patients ƒ ALT > 1 and < 10 x upper limit of normal ƒ HBV DNA > 105 copies/mL ƒ < 12 weeks of treatment with any nucleos(t)ide or receipt of lamivudine or emtricitabine for ≥ 12 weeks ● Additional criteria for HBeAg-positive patients ƒ ALT > 2 and < 10 x upper limit of normal ƒ HBV DNA > 106 copies/mL ƒ < 12 weeks of treatment with any nucleos(t)ide „ Exclusion criteria ● Coinfection with HCV. LLC. All rights reserved.

4 (1. % • Europe 55 54 63 61 • North America 27 27 21 23 • Australia/New Zealand 18 19 16 16 HBV genotype. and in patients with virologic breakthrough ƒ Impact of mutations at conserved sites on drug susceptibility assessed phenotypically „ Primary endpoint ● HBV DNA < 400 copies/mL and histologic improvement (decrease in Knodell necroinflammation score of ≥ 2 points without worsening fibrosis) at Week 48 Copyright © 2009 Clinical Care Options.1) 8. log10 copies/mL (SD) 8. yr (SD) 34 (11) 34 (12) 44 (11) 43 (10) Male.3 (1.64 (1. % • White 52 51 64 65 • Asian 36 36 25 24 • Black 7 6 3 3 Geographic region. in patients with HBV DNA > 400 copies/mL at Week 48.2) score (SD) Mean Knodell fibrosis score (SD) 2.3 (2.3 (1.3) 7.2) 2.08) 8.86 (1. All rights reserved.2) Previous treatment.93) 6.3 (2. % 68 71 77 78 Race.2) 2.9 (2.31) 6. % • Lamivudine or emtricitabine 5 1 17 18 • Interferon 17 14 17 18 SD. Europe.June 2006 at 106 clinical sites in 15 countries across North America.27) Mean ALT.98 (1.2) 2. standard deviation. 3 .Baseline Characteristics „ Baseline characteristics well balanced between groups for each trial „ HBeAg-negative patients usually older and with lower baseline HBV DNA than HBeAg- positive patients HBeAg-Positive Patients HBeAg-Negative Patients Characteristic Tenofovir Adefovir Tenofovir Adefovir (n = 176) (n = 90) (n = 250) (n = 125) Mean age.88 (0. LLC.4) 7. and Asia-Pacific „ Assessments ● Liver biopsy performed within 6 months before screening and between Weeks 44-48 ● HBV DNA and laboratory values assessed every 4 weeks ● HBeAg and HBsAg assessed every 12 weeks ● Genotypic resistance analysis performed in all patients at baseline.4 (1. IU/mL (SD) 142 (103) 155 (121) 128 (101) 164 (146) Mean Knodell necroinflammatory 8. Description of Current Analysis „ Patients recruited from May 2005 .8 (2. % • A 24 20 12 11 • B 14 11 9 14 • C 25 30 12 10 • D 32 35 64 63 • Other/unknown 7 5 6 2 Mean HBV DNA.

All rights reserved. LLC. 4 . although significantly more patients had HBsAg loss with tenofovir vs adefovir ● No HBsAg loss or seroconversion among HBeAg-negative patients Copyright © 2009 Clinical Care Options. significantly higher proportion of patients treated with tenofovir reached primary endpoint „ HBV DNA < 400 copies/mL attained by significantly more patients treated with tenofovir vs adefovir in both trials ● Tenofovir associated with comparable rates of HBV DNA < 400 copies/mL regardless of whether or not patient previously treated with lamivudine „ Similar histologic improvement between arms in both trials „ ALT normalization attained by significantly more HBeAg-positive patients treated with tenofovir vs adefovir ● Rates of ALT normalization comparable between groups among HBeAg-negative patients „ Similar rates of HBeAg seroconversion observed among HBeAg-positive patients treated with tenofovir and adefovir. „ Secondary endpoints ● HBV DNA < 400 copies/mL ● Histologic improvement ● ALT normalization ● HBeAg and HBsAg loss and seroconversion ● Resistance mutations ● Safety „ Intent-to-treat analysis Main Findings „ In both trials.

-.03 76 77 .32 72 69 . % (n = 426) (n = 215) Any adverse event 74 73 Grade 2-4 adverse events 30 32 Serious adverse events 6 7 Treatment-related serious adverse events 2 2 • ALT flare 1 2 • Thrombocytopenia <1 0 • Toxic myopathy 0 <1 Adverse event leading to treatment discontinuation 1 1 Laboratory abnormalities • Grade 3 ALT 3 1 • Grade 4 ALT 3 2 • Serum creatinine increase ≥ 0. serious adverse events.2 0 .27 78 74 . All rights reserved.27 necroinflammation • Worsened fibrosis 2 3 . HBeAg-Positive Patients HBeAg-Negative Patients Outcome at Week 48.02 0 0 -- „ No tenofovir-associated resistance mutations identified in any tenofovir-treated patients during 48 weeks ● 4 (2%) of 215 adefovir-treated patients had adefovir resistance mutations by 48 weeks ƒ Mutations consistent with previous exposure to lamivudine or infection with lamivudine-resistant virus „ Safety profile of tenofovir and adefovir similar in both trials regarding incidence of adverse events. LLC. 5 .96 ALT normalization 68 54 .86 HBeAg seroconversion 21 18 . -- HBsAg loss 3. % Tenofovir Adefovir Tenofovir Adefovir P Value P Value (n = 176) (n = 90) (n = 250) (n = 125) HBV DNA < 400 copies/mL 76 13 < .29 • Reduced 78 71 .001 93 63 < .5 mg/dL above baseline 0 <1 • Creatinine clearance < 50 mL/min 0 0 Copyright © 2009 Clinical Care Options.001 Histologic improvement 74 68 .36 -.36 6 9 . and laboratory abnormalities ● Nausea only adverse event occurring more often with tenofovir vs adefovir (9% vs 3%) ƒ Nausea associated with tenofovir all grade 1 with the exception of 1 case of grade 2 nausea „ Incidence of ALT flares similar between treatment arms in combined analysis ● Nearly all ALT flares associated with tenofovir occurred during first 8 weeks of treatment ● Limited to ALT increases > 10 x upper limit of normal and twice baseline level ● All flares resolved within 4-8 weeks without treatment interruption or discontinuation ● Grade 4 flares associated with HBeAg loss or seroconversion in 63% of patients „ No evidence of renal toxicity in any patient treated with tenofovir Tenofovir Adefovir Safety Outcome.

359:2442-2455. Copyright © 2009 Clinical Care Options. 2008.Reference Marcellin P. et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. Heathcote EJ. Buti M. N Engl J Med. 6 . All rights reserved. LLC.

Still. In addition. the potency of the 10-mg daily dose of adefovir approved by the FDA for hepatitis B virus (HBV) infection is inferior to that observed in separate studies of currently approved nucleoside analogues. in HBV DNA suppression. Fifth. which limits the ability to generalize the findings to all racial populations and HBV genotypes. Both agents are nucleotide analogues and share similar molecular structures. Tenofovir is associated with potent virologic suppression. These trials were well powered and had meaningful primary and secondary endpoints. and the dose of tenofovir administered was safe and did not cause significant renal toxicity. especially in the HBeAg-negative study. evaluation of long-term tenofovir use is still necessary. No genotypic resistance to tenofovir was observed during 1 year of treatment.[2] The investigators found that tenofovir resulted in excellent virologic suppression in both hepatitis B e antigen (HBeAg)–negative (93%) and HBeAg-positive (76%) patients with chronic hepatitis B. although understanding of that phenomenon is complicated by evidence that initiating antiretroviral therapy per se is associated with bone loss. Third. tenofovir was equally effective for treatment-naive and lamivudine-experienced patients. similar to other oral agents for chronic hepatitis B.[5-7] The effect of tenofovir on bone density needs further clarification for patients with chronic hepatitis B. entecavir. (Ongoing monitoring of the safety of tenofovir in pregnancy is needed before routine use in pregnant women can be recommended. MD. needs to be [3. the relatively high rate of HBsAg loss may reflect the higher proportion of white patients with HBV genotypes A and D in the study. Therefore. it is important to examine and document hepatic steatosis in liver biopsies and evaluate whether NAFLD contributes to the persistent serum aminotransferase elevation. but the 1-year rates of HBsAg loss are < 1% for most nucleos(t)ides. Among HBeAg- positive patients. approximately 25% to 30% of patients failed to achieve a complete biochemical response with tenofovir. and in cases of HBV/HIV-coinfection. the rate of HBeAg seroconversion (21%) was similar to that of adefovir and other approved agents.) Regarding second-line use. All 5 patients were white and were infected with HBV genotype A or D. Second. These properties make tenofovir an attractive first-line therapy for chronic hepatitis B. The relationship between HBV genotype. the results of these studies show that tenofovir is superior to adefovir regarding efficacy and similar to adefovir regarding safety. meaning that the safety of prolonged tenofovir use in those with renal insufficiency needs further observation. tenofovir has applicability for patients who develop resistance to nucleoside analogues and likely adefovir with the rtA181V/T mutation. Moreover. including for young women of reproductive age. .[1] 5 HBeAg-positive patients (3%) achieved HBsAg loss with tenofovir. tenofovir does not have cross-resistance with nucleoside analogues and remains effective against HBV with the adefovir- associated mutation rtA181V/T in vitro. No HBeAg-negative patient had HBsAg loss with tenofovir. there are several important unresolved issues to note. the clinical relevance of the tenofovir- associated rtA194T mutation previously noted in vitro. such as lamivudine. although the lack of tenofovir-associated resistance after 1 year of treatment is promising. Hepatitis B surface antigen (HBsAg) loss is the most desirable endpoint of HBV therapy. and telbivudine. histologic improvement. Sixth. MSc. In the study by Marcellin and colleagues. making the findings robust. First. only patients with creatinine clearance ≥ 70 mL/min were included in the trials. and HBsAg loss/seroconversion needs to be studied further. blacks and Asians were relatively underrepresented. tenofovir is significantly associated with reduced bone mineral density in patients with HIV. The current randomized studies by Marcellin and colleagues[1] assessed the efficacy and safety of tenofovir vs adefovir for the treatment of chronic hepatitis B (Hep JO Marcellin_NEJM_2008_CS).Tenofovir for Chronic Hepatitis B Daryl T-Y Lau. In conclusion. tenofovir has been designated as an FDA Class B medication. Fourth. duration of infection. Given that nonalcoholic fatty liver disease (NAFLD) is prevalent. In particular. The lack of correlation between antiviral potency and rate of HBeAg seroconversion underscores the importance of the immune response in HBeAg clearance. indicating that it is “probably safe” during pregnancy. MPH and Wissam Bleibel.4] monitored with long-term use of the medication. and the absence of virologic resistance over 48 weeks. MD Tenofovir has been approved by the US Food and Drug Administration (FDA) for HIV therapy since 2001 and has recently been approved for the treatment of chronic hepatitis B. However.

Hepatology. Buti M. Trautwein C. 2005. Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual Meeting. et al. Sheldon J. Management of hepatitis B: summary of a clinical research workshop. Gallant JE. et al. J Acquir Immune Defic Syndr.10:727-734. Amini-Bavil-Olyaee S. Washington. Fleischer R. emtricitabine. AIDS.REFERENCES 1. 5. Herbers U. et al. Grund B.22:2155-2163. 2008. DeJesus E. Marcellin P. October 25-28. 6. Abstract H-2312a.359:2442-2455. N Engl J Med. Doo E. Selection of hepatitis B virus polymerase mutations in HIV- coinfected patients treated with tenofovir. 2008.45:1056-1075. The rtA194T polymerase mutation impacts viral replication and susceptibility to tenofovir in hepatitis B e antigen-positive and hepatitis B e antigen-negative hepatitis B virus strains.47:74-78. 2007. Arribas JR. Antivir Ther. 3. 2008. Gallant JE. Pozniak AL. Hepatology. Sheldon J. and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144- week analysis. Continuous antiretroviral therapy (ART) decreases bone mineral density: results from the SMART study. a thymidine analogue-containing regimen in antiretroviral-naive patients. Carr A. . 2. 2009. 2008. Tenofovir disoproxil fumarate. Heathcote EJ. Camino N. 4. The 3-year renal safety of a tenofovir disoproxil fumarate vs. Luedde T.49:1158-1165. Lok AS. 7. Rodés B. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. et al. Winston JA. Hoofnagle JH. Tacke F. DC. Liang TJ.

likely due to adverse effects and mode of administration (injection) „ Better understanding of predictors of response to peginterferon may help identify patients most likely to benefit from this treatment „ Current study assessed on-treatment kinetics of HBsAg in HBeAg-negative patients treated with peginterferon to determine predictors for SVR Summary of Study Design „ HBeAg-negative patients with biopsy-confirmed chronic hepatitis B consecutively enrolled ● Patients received peginterferon alfa-2a 180 µg/week for 48 weeks „ Patients assessed every 4 weeks during treatment and every 12 weeks thereafter ● HBV DNA and HBsAg quantified at baseline and Weeks 12. 72. All rights reserved. 48.5-8. and potential for HBsAg loss ● Finite treatment duration an advantage over nucleos(t)ide analogue treatment „ However.5 log10 IU/mL decrease at Week 12 and > 1. single-arm study Summary of Key Conclusions „ Peginterferon-treated patients with chronic hepatitis B who achieved early reductions in serum HBsAg had higher likelihood of achieving SVR ● Threshold HBsAg responses: > 0. 24. and 96 ƒ HBsAg measured using 2-step chemiluminescent immunoassay Baseline Characteristics „ N = 48 ● Median age: 44 years (interquartile range [IQR]: 38-53) ● Male: 83% ● White: 67% ● HBV genotype ƒ A: 27% ƒ B: 17% ƒ C: 12% ƒ D: 29% ƒ E: 14% ● Median HBV DNA: 7.0 log10 copies/mL (IQR: 5.0 log10 IU/mL decrease at Week 24 ● Serum HBsAg did not decrease in patients who failed to achieve SVR „ Small subset of patients who achieved SVR went on to attain HBsAg loss „ Larger studies needed to confirm findings Background „ Peginterferon alfa-2a one of several approved first-line treatment options for chronic hepatitis B ● High probability of HBeAg seroconversion (in HBeAg-positive patients). 20% to 30% SVR rate. LLC. peginterferon used for first-line treatment in < 10% of all cases.0) ● Median ALT: 98 IU/mL (IQR: 60-240) ● Liver necroinflammation (Metavir A2-A3): 50% ● Liver fibrosis (Metavir F3-F4): 50% ● No patients coinfected with HCV or HIV Copyright © 2009 Clinical Care Options.Early HBsAg Loss Predicts SVR in HBeAg-Negative Patients Treated With Peginterferon alfa-2a „ Prospective. 1 .

9) 4.3)* 5. Copyright © 2009 Clinical Care Options. † P ≥ .5 log10 IU/mL ƒ Mean decrease at Week 24: 1. log10 IU/mL (± SD) (n = 3) (n = 9) Week 12 0. LLC.9) 3. followed by steeper decline among those who attained HBsAg loss ● Serum HBsAg continued to decline slightly in patients with no HBsAg loss after end of treatment Patients With SVR and Patients With SVR but Mean Decrease in Serum HBsAg Over HBsAg Loss No HBsAg Loss Time. 2 .2 (± 1.7)† Week 24 2.5 ± 0.0 (± 1.4) Week 24 2.7 (± 1. All rights reserved. log10 copies/mL (± SD) (n = 18) (n = 12) (n = 18) Week 12 2. followed by slow continuous decline off of treatment HBsAg Decrease > 0.5 log10 IU/mL at HBsAg Decrease > 1 log10 IU/mL at Predictive Value for SVR.1 ± 1.1 (± 1.2 (± 2.0) 0.0 (± 0.1 (± 1.4 (± 0.9) 1.2 log10 IU/mL ● Serum HBsAg did not decrease in any patient who failed to achieve SVR ● Patients with viral relapse showed slight decrease in HBsAg on treatment.006) „ Patients who attained SVR experienced marked decrease in HBV DNA during first 24 weeks of treatment compared with nonresponders ● Viral kinetics during first 24 weeks similar between patients who maintained SVR and patients who relapsed Mean Decrease in HBV DNA Over Nonresponders Patients With SVR Relapsers Time.2 (± 1.8) 2.01 vs patients with SVR.4)† *P ≤ .0) Other Findings „ High ALT the only baseline factor associated with SVR according to univariate analysis ● Median baseline ALT in patients with vs without SVR: 220 vs 90 IU/mL (P = .0 (± 1.6 log10 IU/mL ƒ Mean decrease at Week 48: 2.5) Week 48 2.8 (± 0.7)* 4.Main Findings „ 30 patients (62%) achieved end-of-treatment response ● 12 patients (25%) achieved SVR ● 18 patients relapsed „ On-treatment serum HBsAg decreases correlated with SVR ● Patients who achieved SVR demonstrated marked decrease in serum HBsAg during treatment ƒ Mean decrease at Week 12: 0. % Week 12 Week 24 Positive predictive value 89 92 Negative predictive value 90 97 „ Among patients with SVR.9 (± 1. HBsAg kinetics during the last 24 weeks of treatment differed between patients who attained HBsAg loss (n = 3) and those who did not (n = 9) ● Similar HBsAg decline in both groups through Week 12.8 ± 0.1 vs patients with SVR.

All rights reserved. Lada O.Reference Moucari R. LLC. 2009. Mackiewicz V. 3 . Hepatology. et al. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients.49:1151-1157. Copyright © 2009 Clinical Care Options.

Early HBsAg Drop: A Tool to Predict SVR in HBeAg-Negative Patients Receiving Peginterferon alfa-2a Ira M. Overall. For the clinician. . however. may provide a valuable tool that can guide the use of peginterferon therapy for HBeAg-negative chronic hepatitis B by providing a robust negative predictive value at an early time point. particularly if confirmed in other studies. The major implication of the study is that a decline in serum HBsAg is an important marker of sustained suppression of HBV DNA (ie. This event may be a greater decline in intrahepatic cccDNA levels. a decline in HBsAg appears to be a prerequisite for attaining SVR. Indeed. In other words. Notably. relapsers had only a minimal decline in HBsAg titers on therapy compared with sustained responders. This indicator would signal whether peginterferon therapy should be stopped or switched to an oral agent.to 2-year courses of oral therapy. MD In a study by Moucari and colleagues.0 log10 IU/mL at Weeks 12 and 24. whatever biologic events are necessary for SVR to occur are reflected in a decline in HBsAg titer.5 log10 IU/mL and 1. Jacobson. all 3 achieved SVR and differed from the other 9 patients with SVR in that they had an even steeper decline in HBsAg titers during the latter 24 weeks of therapy. this paper is an important addition to recent literature focusing on the significance of serum HBsAg titer in patients with chronic hepatitis B. The most important result from this study is the finding that only patients with a decline in HBsAg at Weeks 12 and 24 of treatment had a chance of attaining sustained virologic response (SVR). but it predicts failure to maintain that response after peginterferon therapy is stopped. respectively. Three of the 48 patients in the study had HBsAg loss. and positive predictive values of 89% and 92%. an acknowledged advantage of its use is the potential for SVR following a finite period of therapy in HBeAg- negative patients—a property not currently associated with 1. respectively. those with eventual relapse were found to have similar HBV DNA reductions during this time period as did those with eventual SVR. Many clinicians in the United States do not use peginterferon for chronic hepatitis B. Nevertheless. at which time it is futile to continue treating with peginterferon and ribavirin if HCV RNA has not declined by > 2 log10 IU/mL. Conversely. which has [2] previously been suggested to correlate with serum HBsAg decline. These data led investigators to determine that a decrease in serum HBsAg of 0. had negative predictive values for SVR of 90% and 97%. possibly because of a greater degree of immunologically mediated loss of HBV-infected hepatocytes. However. SVR) after peginterferon is discontinued in patients who become HBV DNA negative while receiving therapy. Although HBV DNA reductions during the first 24 weeks of therapy were predictably greater in patients attaining SVR vs nonresponders.[1] the on-treatment kinetics of serum hepatitis B surface antigen (HBsAg) were assessed in patients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B who were treated with peginterferon alfa-2a for 48 weeks (Hep JO Moucari_Hepatology_2009). (This is analogous to the 12-week time point in HCV therapy.) A current limitation of this approach is the lack of widespread availability of quantitative HBsAg testing in commercial labs. Failure to achieve a decline in HBsAg level does not preclude the possibility of virologic response while receiving treatment. it is hoped that studies such as this will stimulate further investigation of the importance of HBsAg levels in the context of both natural history and as a potential early marker for therapeutic outcomes. patients with no significant decline in HBsAg failed to achieve SVR. respectively. the results of the Moucari and colleagues study. The ultimate application of such data would be the derivation of negative and positive predictive values sufficiently robust to facilitate practical decisions about continuing or stopping treatment. The rationale was to determine if the degree of decline in serum HBsAg titer at pivotal time points predicts which patients can be expected to have sustained suppression of HBV DNA after treatment is stopped.

Moucari R. Tse AM. Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients.49:1151-1157. et al. Serum hepatitis B surface antigen quantitation can reflect hepatitis B virus in the liver and predict treatment response. 2007. Chan HL. . Mackiewicz V. 2009. Hepatology. Lada O. Wong VW.REFERENCES 1. 2.5:1462-1468. et al. Clin Gastroenterol Hepatol.

and blood ammonia level ● HE grade determined by West Haven Criteria[3] Copyright © 2009 Clinical Care Options. but Large Randomized Studies Still Needed „ Combined analysis of rifaximin studies[1] Summary of Key Conclusions „ Results from 14 clinical studies show efficacy of rifaximin superior to that of lactulose. prospective trials Background „ Neuropsychiatric syndrome HE observed in some patients with liver dysfunction ● Thought to occur when toxins accumulate in the gut. nonabsorbable disaccharides and antibiotics) ƒ Meta-analysis of 22 randomized trials called into question efficacy of nonabsorbable disaccharides[2] „ Rifaximin a nonabsorbable antibiotic currently approved for treatment of traveler’s diarrhea ● Broad-spectrum antimicrobial activity and low potential for drug-drug interactions „ Current study an extensive review of literature assessing rifaximin efficacy and safety for treatment of HE[1] Summary of Study Design „ Literature search conducted to identify all English-language articles and abstracts on clinical studies assessing rifaximin efficacy and safety for the treatment of HE ● Studies had to compare rifaximin with placebo or an active drug for HE „ Studies identified included ● 1 dose-finding study ● 9 open-label studies ● 4 double-blind studies „ 2 additional studies assessing cost-effectiveness of rifaximin also included in analysis „ Endpoints assessed in most studies included changes in portal systemic encephalopathy (PSE) index and improvement in HE grade ● 5 components to PSE score: mental status. electroencephalogram (EEG) abnormalities. presence and intensity of asterixis. LLC. similar to that of paromomycin. time taken to perform the number connection test.Literature Supports Use of Rifaximin for Hepatic Encephalopathy. All rights reserved. with only mild gastrointestinal (GI) upset typically observed „ Cost of rifaximin markedly higher than that of conventional therapies. and similar or greater to that of neomycin for hepatic encephalopathy (HE) ● Improvement in clinical signs/symptoms of HE often occurred faster with rifaximin vs comparator drugs „ Rifaximin very well tolerated. randomized. but reductions in frequency and duration of hospitalizations may make rifaximin cost-effective „ Efficacy and safety of rifaximin for HE needs confirmation in large. eventually infiltrating brain tissue and altering neurotransmission ● Current treatment options include agents that reduce gut toxin levels (eg. 1 .

2 . 1200. All rights reserved. but statistically significant only in 1200- and 2400-mg/day arms ● Rifaximin well tolerated with no patients withdrawing from study „ Lactulose comparator studies ● Studies demonstrated improved outcomes with rifaximin vs lactulose ƒ However. but rifaximin associated with significantly Randomized to rifaximin faster time to improvement vs lactulose 58 patients with Bucci et al[4] 1. lactulose underdosed (ie.2 g/day vs Paik et al[7] • Similar improvement in ammonia levels patients with HE lactulose 90 mL/day for 7 observed in both arms days • Rifaximin well tolerated with no patients withdrawing from study Copyright © 2009 Clinical Care Options. and EEG irregularities in both arms.2 g/day vs lactulose • Improvements in ammonia level occurred grade 1-3 HE 30 g/day for 15 days significantly faster in rifaximin vs lactulose arm • No significant differences in adverse events between arms Randomized to open-label • Improvements in ammonia level occurred 21 patients with rifaximin 1. asterixis. LLC.2 g/day plus grade 1-3 HE days of treatment lactulose for 15 days • HE grades improved in 81% of rifaximin- treated patients vs 72% of lactulose-treated Randomized to open-label patients 54 Korean rifaximin 1.2 g/day vs Festi et al[5] faster in rifaximin vs lactulose arm grade 1 HE lactulose 40 g/day for 21 • Rifaximin well tolerated days Open-label treatment with 55 patients with • Significant improvement in HE signs after 2-3 Puxeddu et al[6] rifaximin 1. or 2400 mg/day for 7 days ● All doses improved PSE index vs baseline. < 90-120 mL/day) in most studies ● 1 study of rifaximin-lactulose combination therapy revealed rapid efficacy Study Population Treatment Major Outcomes • Significant improvement in mental status.Main Findings „ Dose-finding study ● 54 patients with HE randomized to receive rifaximin 600.

2 g/day Miglio et al days of treatment grade 1-2 HE vs neomycin 3 g/day for • Similar improvement in ammonia levels 14 days/mo for 6 mos observed in both groups Copyright © 2009 Clinical Care Options. • Both groups showed similar significant [5] 35 patients with label rifaximin 1. P < . EEG abnormalities. but difference not statistically significant PSE • Mean improvement in HE significantly greater with rifaximin vs lactitol (70. „ Lactitol comparator studies demonstrated improved outcomes with rifaximin vs lactitol Study Population Treatment Major Outcomes • Both the rifaximin and lactitol groups had significant decreases in PSE index vs baseline but difference between arms significantly 103 patients with favored rifaximin grade 1-3 HE. 3 .05) and blood ammonia (92% vs 40% vs 91%.2 g/day vs lactitol 60 patients attained clinical resolution (53% vs and evidence of g/day for 5-10 days 37%). respectively. P < .2 g/day chronic/permane vs neomycin 4. < Randomized to rifaximin • Higher proportion of rifaximin.5 g/day • No significant difference between groups in HE Di Piazza et al[11] nt recurrent HE for 7 days for 4 grade improvement symptoms treatments + 4 washout periods Randomized to open. 1.5%.0% vs 61. P = NS) 40 patients with Randomized to rifaximin • Improvements in HE clinical syndromes chronic grade I-II ± sorbitol vs lactitol vs Loguerico et al[9] occurred significantly faster in rifaximin arms HE for ≥ 2 rifaximin ± lactitol for 15 • Significantly more patients in rifaximin- months days/mo for 3 mos containing arms attained improvement in mental status (67% vs 20% vs 55%. Randomized to rifaximin [10] 30 patients with ammonia levels.05) „ Neomycin comparator studies demonstrated comparable efficacy between rifaximin and neomycin Study Population Treatment Major Outcomes • Both groups showed similar improvements in psychometric performance. although rates numerically higher in rifaximin arms (33% vs 20% vs 36%.2 g/day vs neomycin 3 grade 1-3 HE • Significantly lower ammonia levels seen with g/day for 21 days rifaximin vs neomycin on Days 14 and 21 • No adverse events in rifaximin group Randomized to open- 14 patients with label rifaximin 1.2 g/day improvements in clinical HE syndromes Festi et al grade 1 HE vs neomycin 3 g/day for • Incidence of asterixis and EEG abnormalities 21 days lower with rifaximin vs neomycin • Both groups showed similar significant Randomized to open- improvements in HE signs/symptoms after 30 [12] 49 patients with label rifaximin 1. All rights reserved. P < .01) • HE normalization in all arms. and PSE index Pedretti et al 1. LLC.vs lactitol-treated Mas et al[8] 2 days of onset.

10. Ferrieri A. 1991. Lee KS. et al. Pedretti G.2 g/day vs paromomycin 1. Rodes J. for the treatment of hepatic encephalopathy: a double-blind. Han KH. 11. Curr Med Res Opin.23:403-407. Mazzella G.13:274-281 7. Puxeddu A. Orsini M. et al. Quartini M.13:593-601.49:53-62. 6. Ital J Gastroenterol. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized. Missale G. Aliment Pharmacol Ther. 1991. Curr Med Res Opin. De Girolamo V. „ 3 studies compared open-label rifaximin 1. Filippazzo MG. 2007.54:598-609. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. 2003. Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics: a double-blind. 1995. nomenclature and diagnosis of hepatic encephalopathy. double-dummy.38:51-58. 4. Ann Pharmacother. randomised trial. Double-blind. Maclayton DO. J Hepatol. 12. Als-Nielsen B. fewer days of hospitalization. Fiaccadori F. 5. Calzetti C. double-blind. 4 . Federico A. Ferrieri A.328:1046. Yonsei Med J. 8. All rights reserved. 1993. LLC. double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Mullen KD. Ferrieri A. 2004. Copyright © 2009 Clinical Care Options. Minerva Gastroenterol Dietol. Paik YH. controlled clinical trial.23:175-178. Loguercio C. Eaton-Maxwell A. Curr Ther Res. annual cost of hospitalization was $5327 lower for rifaximin-treated patients due to fewer hospitalizations and reduced lengths of stay[16] ● Patients receiving rifaximin vs lactulose had better adherence. Massimetti A. Rifaximin for treatment of hepatic encephalopathy. Rifaximin versus neomycin in the treatment of portosystemic encephalopathy. 1993. with minor GI upset usually reported as the most common adverse event Other Outcomes „ 2 studies evaluated costs associated with rifaximin[16. Palmieri GC. 2003. 3. Valenza LM. randomized trial.25(suppl 1):11-16. Rossellini SR. BMJ. et al.46:399-407. Mas A. Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. and lower hospitalization charges References 1. 1997. Rifaximin. Curr Med Res Opin. et al. a non-absorbable rifamycin. 2008. Rifaximin in the treatment of chronic hepatic encephalopathy. Valpiani D. Miglio F.Dec 17:[Epub ahead of print]. 2.13:109-118. Di Piazza S.17] ● In 1 study. Gluud C. Review of the final report of the 1998 Working Party on definition. although total monthly drug cost was $570 higher for rifaximin vs lactulose. Cyclic treatment of chronic hepatic encephalopathy with rifaximin: results of a double-blind clinical study.5 g/day for 5-15 days in patients with HE[13-15] ● Similar improvements in ammonia levels seen in both groups in all studies „ Rifaximin well tolerated across studies. Del Vecchio Blanco C. Ital J Gastroenterol. 2005. Sunyer L. fewer hospitalizations. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Gluud LL. Bucci L. 9. Festi D.

14. 1984. Copyright © 2009 Clinical Care Options. 16. Phillips JA. Eftimiadi C. et al. A non-absorbable rifamycin for treatment of hepatic encephalopathy. Parini P. De Marco F.36:668-674. et al. et al. Rifaximin in collateral treatment of portal-systemic encephalopathy: a preliminary report.13.11:387-392. LLC. Testa R. Cipolla A. Sukkar GS.38:3552-3555. 17. 2006. 1992. Neff GW. Transplant Proc.52:737-741. Amato PS. Dig Dis Sci. Leevy CB. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy.52:34-39. 15. D’Arienzo A. Zacharias VC. 1985. Drugs Exp Clin Res. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Effect of paromomycin in the treatment of portal-systemic encephalopathy. All rights reserved. Kemmer N. Curr Ther Res. 5 . Ronci M. Curr Ther Res. 2007.

alternatives to lactulose are being sought for use in the first-line or second-line treatment setting.The Use of Rifaximin in Hepatic Encephalopathy Jasmohan Bajaj. phase III trial of rifaximin has been completed in the United States (N = 299). but the associated adverse effects often lead to poor tolerance and compliance. placebo-controlled. This is an important and significant trial with potential for great impact. showed that no patients withdrew from either arm.[8. a major inherent problem with all HE studies is that there is no objective way to quantify HE—a factor that severely limits the ability to compare outcomes across studies. Finally. rifaximin proved to be more cost-effective than lactulose overall by reducing the costs associated with hospitalization. they found that rifaximin is at least as effective as nonabsorbable disaccharides for the treatment of acute or chronic HE and may be better tolerated. Moreover.9] These 2 studies reported fewer hospitalizations for patients with advanced HE who were treated with rifaximin vs lactulose. Maclayton and Eaton-Maxwell also included in their review 2 clinical trials that used a slightly more reliable endpoint: hospitalization. and neomycin.12] Much like the present study. none of these studies was adequately powered to determine noninferiority. as the patient populations may vary considerably based on the degree of HE present. Paromomycin and neomycin are not currently used in the United States. MSc Lactulose is the current standard of care for patients with hepatic encephalopathy (HE). limiting the generalizability of the results. but several smaller trials have been conducted in Europe. The investigators identified a rifaximin dose-finding study and several comparator studies in which rifaximin was measured against a variety of nonabsorbable disaccharides. These studies then went on to report that even though the cost of rifaximin per tablet is much higher than the cost of lactulose.[13] Any systematic review. It is widely acknowledged that there is a paucity of well-conducted clinical trials to indicate the optimal treatment of cirrhosis complications. Toward this end. lactitol. Despite these limitations.[5-7] However. the findings of the Maclayton study help to confirm what clinicians have long suspected: Rifaximin is a viable alternative for the treatment of HE. MD. thereby supporting the use of the lower 1200-mg/day dose. the studies included in the review were typically conducted at a single study center. the study also [5] revealed that both doses produced similar significant improvements in HE outcomes. Although this is a well- conducted study with a large patient population.[1-3] As such. and lactitol is not currently available in the United States. Therefore. which assessed rifaximin doses of 1200 mg/day and 2400 mg/day. a large. Until those studies are available. All of the studies included in this analysis had relatively small patient populations. 6 tablets per day are needed to achieve this dosing. the patients enrolled constitute a select group that may not be representative of typical patients with HE. paromomycin. One such alternative agent currently being used by many physicians is rifaximin (a nonabsorbable antibiotic currently approved for the treatment of traveler’s diarrhea). Three studies comparing rifaximin with lactulose found that the 2 agents were fairly similar in efficacy regarding performance improvements on psychometric tests and blood ammonia level reductions. particularly HE. Since rifaximin is currently available in the United States as 200-mg tablets. No large clinical trials of rifaximin for the treatment of HE have been published in the United States. the data of interest to US hepatologists pertain to the rifaximin dose-finding study and the comparator studies with lactulose. . this does not necessarily translate to equivalence of the agents. Other meta-analyses of trials comparing rifaximin with nonabsorbable disaccharides have been conducted in the past couple of years. given its widespread availability. Preliminary results showed that rifaximin 1100 mg/day (given as a 550-mg tablet twice daily) reduced the [14] risk of HE breakthrough and the risk of worsening HE symptoms vs placebo.[4-9] Maclayton and Eaton-Maxwell[10] undertook a comprehensive review of these published clinical studies assessing rifaximin for the treatment of HE to assess its efficacy and safety in this setting (Hep JO Maclayton_Ann_Pharmacother_2009_CS). is only as good as the studies that it reviews. including lactulose. but the definition of the role of rifaximin in HE needs to be further studied in large. randomized controlled trials. However. randomized. suggesting that both doses were well tolerated. When a small study fails to identify any difference in efficacy between agents.[11. such as the Maclayton study. in that the patients in the trial had to have experienced ≥ 2 HE episodes in the past 6 months and currently be in remission. The dose-finding study. the Maclayton study provides reasonable assurance that rifaximin is a sound treatment option. Additional larger studies are still needed to better determine the efficacy of rifaximin for the treatment of HE.

2009. double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy.41:1464-1472. et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Lee KS. Transplant Proc. Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. 2006. Kalaitzakis E. Phillips JA. Abstract 177. Bajaj J. Neff GW.13:109-118. Bucci L. 14. 2000. Zheng MH. Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind. Wang L. Olsson R. 8. Copenhagen. Williams R. Chen YP. Yonsei Med J. et al.52:737-741. Kalaitzakis E. 4. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Hepatology. April 22-26. 10. Paik YH. et al. Warnes TW. Denmark. Program and abstracts of the 44th Annual Meeting of the European Association for the Study of the Liver. 7. Scand J Gastroenterol. Ann Pharmacother. Lawrence KR. Mazzella G.Dec 17[Epub ahead of print]. Sigal S. Gastrointestinal adverse effects of lactulose can precipitate recurrent hepatic encephalopathy through non-compliance or overuse. 2008. Mullen K. Curr Ther Res. Heuman D. Björnsson E. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis.20:1064-1070. Eur J Gastroenterol Hepatol. Bass N.48:1-3. placebo-controlled trial. 2008. Zacharias VC. Abstract 93.12:203-208. April 22-26. Festi D. 2006. 1993.46:949-950. Lactulose treatment for hepatic encephalopathy. Program and abstracts of the 44th Annual Meeting of the European Association for the Study of the Liver.46:399-407.54:598-609. Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Simrén M. 2009. Maclayton DO.28:1019-1032.REFERENCES 1. Jiang LM. Jiang Q. randomized. 9. Klee JA. 6. Rifaximin for treatment of hepatic encephalopathy. 3. 12. 2. Dig Dis Sci. 5. 2008. 2008. Morgan MY. 2007. Rifaximin is effective in maintaining remission in hepatic encephalopathy: results of a large. Gastrointestinal symptoms in patients with liver cirrhosis: associations with nutritional status and health-related quality of life. 13. James OF. 2007. . Palmieri GC. 2005.38:3552-3555. The need for better clinical trials. et al. et al. 11. Orsini M. dose-finding multi-centre study. Han KH. and health-related quality of life. Denmark. Jiang XH. Curr Med Res Opin. Eur J Gastroenterol Hepatol. Sanyal A. Rifaximin for the treatment of hepatic encephalopathy. Copenhagen. Leevy CB. Kamath PS. Bell D. 1993. randomized. Hepatology. Double-blind. Pharmacotherapy. Gavis E. gastrointestinal symptoms. Eaton-Maxwell A. Kemmer N.

LLC. All rights reserved.and education-matched individuals from community „ Assessments ● Psychometric testing ƒ Using Wechler’s adult intelligence scale-III: number connection test-A. and fatigue „ Individuals with attention deficits commonly develop fatigue while driving ● Unknown whether fatigue experienced in hepatic encephalopathy affects driving performance „ Current study assessed effect of fatigue on driving performance in individuals with MHE and OHE by comparing them with cognitively normal cirrhotic patients and healthy controls Summary of Study Design „ Individuals consecutively enrolled from hepatology clinics at Medical College of Wisconsin ● Inclusion criteria ƒ Cirrhotic ƒ Current driver ƒ For patients with MHE: minimental status examination score > 25 ● Exclusion criteria ƒ Psychoactive drug use ƒ Alcohol abuse within < 3 months ƒ For patients with MHE: asterixis on physical exam and placement of transvenous intrahepatic portosystemic shunt „ Cirrhotic patients classified into 3 groups ● Those with OHE receiving chronic treatment with lactulose ● Those with MHE based on the results of psychometric testing ● Those without MHE based on the results of psychometric testing „ Cirrhotic patients compared with healthy age. psychomotor slowing. among other impairments ● MHE: deficits in executive functions and visuomotor coordination ● OHE: cognitive dysfunction. 1 . and block design test ƒ Inhibitory control test ● American Medical Association survey for evaluation of driving safety in older adults Copyright © 2009 Clinical Care Options. digit symbol test. number connection test-B.and education-matched controls Summary of Key Conclusions „ Individuals with minimal hepatic encephalopathy (MHE) demonstrated worsening driving simulator performance over time due to presumed subclinical cognitive changes with concomitant fatigue „ Self-reported driving-associated fatigue higher in individuals with MHE and overt hepatic encephalopathy (OHE) vs cirrhotic individuals with no MHE or controls ● Actual driving-associated fatigue predicted driving simulator collisions „ Driving simulator performance and psychometric testing results similarly impaired between treated patients with OHE and untreated patients with MHE Background „ Individuals with cirrhosis and MHE or OHE experience attention deficits.Fatigue Experienced by Patients With Hepatic Encephalopathy Associated With Impaired Driving Performance „ Observational study with age.

*P = . yrs (SD) 12 (5) 14 (6) 13 (2) Child-Pugh-Turcotte distribution (A.02 Main Findings „ Driving performance significantly impaired in cirrhotic patients with OHE and MHE vs cirrhotics with no MHE or controls ● Average speed and length of run not significantly different between any groups ● Driving performance similarly impaired for individuals with OHE and those with MHE Copyright © 2009 Clinical Care Options.4. yrs (SD) 51 (4) 55 (6) 52 (7) Mean education. All rights reserved. % 67 63 64 Alcoholic etiology.4. C) 23. LLC.6. B.2 18.0 43. 2 .and education-matched controls included in study ● All individuals drove a similar number of miles/week (mean: 33-45 miles/week) No MHE MHE OHE Characteristic (n = 27) (n = 51) (n = 22) Mean age. standard deviation. % 19 22 22 Chronic hepatitis C. ● Driving simulation lasting ≥ 28 minutes ƒ Fatigue determined by performing within-group comparison of outcomes during first half of simulator with outcomes in second half „ Primary endpoint ● Number of collisions on driving simulator „ Secondary endpoints ● Speeding tickets ● Center crossings ● Road-edge excursions Baseline Characteristics „ 100 cirrhotic patients and 67 age. % 19 16 22 Average bowel movements/day* 1 1 3 SD.0 Variceal bleeding.

respectively) and center crossings (mean: 7.02) and controls (6%. P = . indicative of fatigue ● MHE patients also showed statistically significant worsening of speeding violations (mean: 1.2 vs 0. respectively).3 crossings. Zadvornova Y. The effect of fatigue on driving skills in patients with hepatic encephalopathy. 3 . LLC. respectively) in second vs first half „ Psychometric performance of patients with OHE and MHE statistically significantly impaired vs those with no MHE and controls (data not shown for controls) ● Psychometric performance similarly impaired for individuals with OHE vs those with MHE „ Among cirrhotic patients.3 vs 0.03) ● All patients who admitted to fatigue on questionnaire had collisions during driving simulator ● No collisions observed in individuals who denied fatigue on questionnaire Reference Bajaj JS.Mar 10:[Epub ahead of print]. All rights reserved. P = . 2009. et al. Hafeezullah M. significant correlations identified between impairment on psychometric tests (for all but block design test and number connection test-B) and driving simulator collisions „ Significantly higher proportions of cirrhotic patients with OHE (27%) and MHE (25%) reported feeling tired after driving on American Medical Association questionnaire compared with cirrhotic patients with no MHE (4%. Copyright © 2009 Clinical Care Options.6 vs 4.7 collisions.6 violations. „ Only patients with MHE showed statistically significant increase in collisions in second half of driving simulator vs first half (mean: 1. Am J Gastroenterol.

all study participants underwent a driving simulation and completed the American Medical Association (AMA) survey for evaluating driving safety in older adults. or no evidence of minimal HE. I found it extraordinarily interesting that previous overt HE patients who were well maintained on lactulose (as evidenced by the lack of outward signs of HE) still performed very poorly on the psychometric and driving simulator tests—that is worrisome. the investigators identified a very strong correlation between actual self-reported fatigue after driving and collisions during the driving simulator. Using that information. the findings from this study raise 2 very important questions: 1) Do patients with even minimal HE have impairments that would impact their driving skills and 2) is treatment of HE sufficient to improve driving skills to a reasonably safe level? For the former question. overlapping symptoms in cirrhotics by focusing on the effects of HE and fatigue as they pertain to driving ability (Hep JO Di Bajaj_AJG_2009). asks if patients feel tired after driving. Hepatic Encephalopathy. and Driving Ability Kevin Mullen. MD Fatigue and depression are very difficult to differentiate from the effects of mild hepatic encephalopathy (HE) in patients with cirrhosis since patients often report a general feeling of malaise. It has been the assumption that driving problems observed in cirrhotic patients are reversible with treatment. The investigators were able to further hone in on those patients who experience actual fatigue when driving through their implementation of the AMA survey which.Innovative Investigation of Fatigue. The investigators employed a clever strategy to assess fatigue during the driving simulator by comparing performance during the second half of the simulation with performance during the first half. In addition to undergoing psychometric testing. indicating fatigue. For the latter question.[1-3] The current study conducted by Bajaj and colleagues[4] was able to elucidate some of these nonspecific. this is cause for concern. As a physician who specializes in HE. the very definition of HE is that the brain dysfunction caused by liver disease is reversible. which were more frequent in both overt HE patients and minimal HE patients vs controls and cirrhotic patients without minimal HE. Indeed. and this was the only group to show a statistically significant increase in collisions during the second half of the driving simulation vs the first. If one of our standard treatments is not reversing it. several studies have shown that cirrhotic patients have impaired driving abilities compared with the general population. Patients with minimal HE had a statistically significantly higher collision rate compared with the other groups. as one of its 20 questions. minimal HE. whereas individuals with overt HE were defined as having demonstrated overt signs of HE and were currently receiving chronic treatment with lactulose. Possibly related to some of these symptoms. it appears that patients with even minimal HE have greater impairment than either cirrhotics with no HE or healthy controls. . it perhaps raises the possibility that it is not. follow-up studies are needed to confirm the reversibility of driving deficits in cirrhotics with HE following treatment. In summary. Patients with minimal or overt HE performed significantly more driving errors and experienced significantly more vehicular collisions compared with controls or cirrhotic patients without minimal HE. Individuals with or without minimal HE were classified as such based on the results of several psychometric tests. A group of 67 healthy age-matched and education-matched individuals from the community served as controls. The effect of fatigue on collision rates was quite dramatic. Bajaj and colleagues enrolled 100 patients with cirrhosis and classified them as having overt HE. Although this study did not directly ask whether HE is reversible with lactulose therapy.

Hafeezullah M.47:596-604. Bajaj JS. Zadvornova Y. Saeian K. Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy.Mar 10[Epub ahead of print]. 2008.102:1903-1909. Hafeezullah M. Bajaj JS. Am J Gastroenterol. Saeian K.REFERENCES 1. Bajaj JS. Hoffmann RG.6:1135-1139. Hoffmann RG. 3. Hepatology. 2007. Hoffmann RG. 4. 2. et al. Bajaj JS. 2008. 2009. Clin Gastroenterol Hepatol. Patients with minimal hepatic encephalopathy have poor insight into their driving skills. Hafeezullah M. Hafeezullah M. et al. . The effect of fatigue on driving skills in patients with hepatic encephalopathy. Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations. Am J Gastroenterol. Hammeke TA.

True B. which assessed the efficacy and safety of coadministering 12 weeks of telaprevir with 24 or 48 total weeks of peginterferon/ribavirin vs standard 48-week treatment with peginterferon/ribavirin in treatment-naive patients with genotype 1 hepatitis C virus (HCV)? A. According to 2 randomized. Please complete the following Posttest online at: clinicaloptions. Tenofovir was not superior to adefovir regarding the primary endpoint in either HBeAg- negative or HBeAg-positive patients 4. Coadministering telaprevir with peginterferon/ribavirin resulted in significantly higher sustained virologic response (SVR) rates vs standard therapy B. Tenofovir was superior to adefovir regarding the primary endpoint for both HBeAg-negative and HBeAg-positive patients D. All rights reserved. Maintenance therapy resulted in reductions in alanine aminotransferase and HCV RNA levels but without improvement in clinical outcomes B. 1. double-blind. Maintenance therapy resulted in reductions in hepatic decompensation and hepatocellular carcinoma C. rifaximin displayed superior efficacy to other treatment options for hepatic encephalopathy. phase III trials of tenofovir vs adefovir for the treatment of chronic hepatitis B. Is the following statement TRUE or FALSE? In the literature review by Maclayton and colleagues. A. Which of the following statements is TRUE regarding results of the PROVE 1 study. and neomycin. Which of the following statements is TRUE regarding the results of the HALT-C trial of maintenance peginterferon alfa-2a monotherapy in previous HCV nonresponders? A. False 3. To receive free CME credit for this article. Tenofovir was superior to adefovir regarding the primary endpoint for HBeAg-positive patients but not for HBeAg-negative patients C. Coadministering telaprevir with peginterferon/ribavirin resulted in similar SVR rates vs standard therapy 2. including lactulose. 7 . Maintenance therapy had no measureable effect on biochemical markers or clinical outcomes Copyright © 2009 Clinical Care Options. Coadministering telaprevir with peginterferon/ribavirin resulted in significantly lower SVR rates vs standard therapy C. LLC. paromomycin.com/HEPJO POSTTEST Click on the appropriate response below. which of the following statements is TRUE regarding the combined primary endpoint of HBV DNA suppression < 400 copies/mL with histologic improvement? A. Tenofovir was superior to adefovir regarding the primary endpoint for hepatitis B e antigen (HBeAg)–negative patients but not for HBeAg-positive patients B.

8 . SVR rates were highest for patients who had an HCV RNA decrease of 1-2 log10 during previous therapy and a baseline fibrosis score of F3-F4 D. According to the results of the DIRECT trial of consensus interferon for the treatment of HCV nonresponders. SVR rates were highest for patients who had an HCV RNA decrease of > 2 log10 during previous therapy and a baseline fibrosis score of F3-F4 B. All rights reserved. which of the following statements is TRUE? A.5. SVR rates were highest for patients who had an HCV RNA decrease of > 2 log10 during previous therapy and a baseline fibrosis score of F0-F2 C. SVR rates were highest for patients who had an HCV RNA decrease of 1-2 log10 during previous therapy and a baseline fibrosis score of F0-F2 Copyright © 2009 Clinical Care Options. LLC.