Hepatitis Journal Options - Volume 3, Issue 2

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
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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
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

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

Kara Nyberg, PhD
Editorial Contributor
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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.

Nancy Reau, 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.
Richard K. Sterling, MD, MSc, FACP, FACG, has disclosed that he has received grants or research
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Schering-Plough, Vertex, and Wako; and has received fees for non-CME services from GlaxoSmithKline,
Roche, Schering-Plough, and Wako.
Mark S. Sulkowski, MD, has disclosed that he has received grants or research support and has served
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LEARNING OBJECTIVES
Recall data on the efficacy of telaprevir in combination with peginterferon/ribavirin in treatment-
naive, genotype 1 patients
Discuss the efficacy and safety of tenofovir vs adefovir for the treatment of HBeAg-positive and
HBeAg-negative chronic hepatitis B patients
Describe the results of long-term maintenance peginterferon alfa-2a therapy in HCV-infected
patients with previous nonresponse
Summarize the efficacy of rifaximin for the treatment of hepatic encephalopathy

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Hepatitis Journal Options – Volume 3, Issue 2
CONTENTS
McHutchinson-NEJM-2009: Telaprevir for chronic HCV genotype 1 infection ............................................. 7
Di Bisceglie-NEJM-2008: Maintenance HCV therapy with low-dose peginterferon .................................. 15
Lok-Gastroenterol-2009: HCC in hepatitis C–related advanced liver disease ........................................... 21
Bacon-Hepatology-2008: Consensus interferon/ribavirin retreatment for peginterferon/ribavirin

nonresponders ............................................................................................................................................ 28
Rossignol-Hepatology-2008: Improved response rates in chronic hepatitis C with nitazoxanide .............. 35
Marcellin-NEJM-2008: Tenofovir for chronic hepatitis B............................................................................. 41
Moucari-Hepatology-2009: Early serum HBsAg drop and SVR in HBeAg-negative patients .................... 49
Maclayton-Ann_Pharmacother-2009: Rifaximin for hepatic encephalopathy............................................. 54
Bajaj-AJG-2009: Effect of fatigue on driving skills in hepatic encephalopathy patients ............................. 61
Posttest ....................................................................................................................................................... 66

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

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

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

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%, 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
10 patients with genotype 1a had V36M and R155K mutations
1 patient with genotype 1b had A156T mutation
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

Most common adverse events were those typically associated with interferon-based
treatment
● Certain of these adverse events occurred more often in TVR-treated arms, including
rash, pruritus, nausea, 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- 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, % (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. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic
HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838.
2. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in
patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767-1777.

Use of Telaprevir in Combination With Peginterferon/Ribavirin in
Genotype 1 HCV
David R. Nelson, 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). Numerous
strategies have been undertaken to try to improve response rates in this population of patients. 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, 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).[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, resulting in a higher SVR rate and a shorter duration of therapy. To test
this assumption, 250 patients were randomly assigned to one of 4 groups: 1) telaprevir plus
peginterferon/ribavirin for 12 weeks, followed by peginterferon/ribavirin alone for 12 weeks (n = 79); 2)
telaprevir plus peginterferon/ribavirin for 12 weeks, followed by peginterferon/ribavirin alone for 36 weeks
(n = 79); 3) telaprevir plus peginterferon/ribavirin for 12 weeks (exploratory group; n = 17); or 4) standard
peginterferon/ribavirin for 48 weeks (control arm; n = 75).
Higher rates of rapid virologic response, end-of-treatment response, 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%, respectively), as well as lower relapse rates in the telaprevir
arms. Twelve patients (7%) receiving telaprevir experienced virologic breakthrough during treatment,
which was primarily attributed to the development of resistance to the protease inhibitor. 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. Another important
observation was that adverse events such as rash, pruritus, nausea, and diarrhea occurred more
frequently in the telaprevir arms vs the control arm. Consistent with this observation, a higher proportion
of telaprevir-treated patients discontinued treatment because of adverse events vs the control arm (21%
vs 11%, respectively).
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, which included many of the same treatment arms as
in PROVE 1 but with slightly different treatment combinations, durations of telaprevir induction, and
patient populations (eg, nonresponders). Whereas all treatment arms in PROVE 1 contained ribavirin,
some arms in PROVE 2 and PROVE 3 did not. Those arms that did not contain ribavirin had much lower
SVR rates because of higher rates of breakthrough or relapse. Therefore, ribavirin will remain a critical
component of HCV therapy for this STAT-C regimen. In addition, 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). Telaprevir-containing therapy lasting 24 weeks appears to be
appropriate for patients with a rapid virologic response, given the very low relapse rate. However, a
treatment duration of only 12 weeks is inferior to 24 weeks due to higher relapse rates. Therefore, these
data suggest that, overall, 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. Combined data from the PROVE studies also suggest that the
addition of STAT-C agents to standard therapy may overcome negative host factors, such as race,
obesity, and cirrhosis.
The findings from the PROVE studies have dramatic implications, as these are the first extensive phase II
data to suggest that a new treatment paradigm is at hand for HCV infection. Although these regimens will
provide greater HCV antiviral activity, the new therapies will be accompanied by additional adverse
events that will make therapy more challenging. In addition, various issues pertaining to resistance will
need to be incorporated into future practice, such as education around compliance and adherence. 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.
Phase III studies of telaprevir in combination with peginterferon/ribavirin are ongoing and will refine the
concepts reported in the PROVE trials. These studies should help to define the optimal duration of triple
therapy, as well as peginterferon/ribavirin consolidation, in addition to the potential utility of a “lead-in”
phase of peginterferon/ribavirin. In addition, the long-term effects of the selection and persistence of
resistance to telaprevir in nonresponders remains to be established. These are clearly encouraging times
for patients with HCV, and the landscape is rapidly changing in their favor.
REFERENCES
1. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for
chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-1838.
2. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for
chronic HCV infection. N Engl J Med. 2009;360:1839-1850.
3. Manns M, Muir A, Adda N, et al. Telaprevir in hepatitis C genotype-1-infected patients with prior
non-response, 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; April 22-26, 2009; Copenhagen, Denmark. Abstract 1044.
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, randomized, controlled trial[1]

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, ALT, and histologic necroinflammatory scores
observed with peginterferon treatment
● However, rate of clinical and histologic disease progression over 3.5 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, 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 3.5 years
Background
Antiviral therapy yields SVR in approximately one half of all treated patients with chronic HCV
infection
● Disease can progress to cirrhosis, liver failure, hepatocellular carcinoma (HCC), 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

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 generally well balanced across treatment groups
Peginterferon No Treatment
Characteristic
(n = 517) (n = 533)
Patients, %
• No response during lead-in 30.2 30.8
• Partial response during lead-in 33.5 31.7
• Breakthrough/relapse during lead-in 13.7 15.0
• Express patients 22.6 22.5
Mean age, yrs (± SD) 51.1 (7.3) 50.1 (7.0)
Male, % 70.0 71.9
Race, %
• White 72.0 71.3
• Black 18.8 17.6
• Hispanic 7.5 8.4
• Other 1.7 2.6
Mean duration of HCV exposure, yrs (± SD) 28.8 (7.9) 27.4 (8.0)
HCV genotype 1, % 95.2 91.6
Mean HCV RNA, log10 copies/mL (± SD) 6.42 (0.54) 6.44 (0.51)
Mean serum ALT, U/L (± SD) 104 (74) 110 (80)
Cirrhosis on biopsy, % 40.2 41.3
Mean Ishak fibrosis score (± SD) 4.08 (1.25) 4.13 (1.28)
Mean Ishak necroinflammatory score (± SD) 7.55 (2.10) 7.54 (2.02)
SD, standard deviation.

Patients enrolled at 10 US study centers from 2000-2004
Assessments
● History, physical examination, and laboratory testing every 3 months
● Hepatic ultrasound performed every 12 months to screen for HCC
● Liver biopsy taken at baseline, 1.5 years, and 3.5 years
Primary endpoint
● Liver disease progression, including death, HCC, hepatic decompensation, Child-
Turcotte-Pugh of 7 on ≥ 2 consecutive visits, or ≥ 2-point increase in Ishak fibrosis
score (for patients with bridging fibrosis at baseline)

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
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, % 34.1 33.8 1.01 (0.81-1.27) .90
• Noncirrhotic fibrosis 36.7 35.5 1.05 (0.78-1.39)
• Cirrhosis 30.2 31.2 0.97 (0.68-1.38)
CI, confidence interval; HR, hazard ratio.
Most common clinical outcomes were increase of ≥ 2 points in Child-Turcotte-Pugh score

(10.4%), ascites (5.6%), hepatic encephalopathy (3.5%), variceal hemorrhage (1.5%), and
spontaneous bacterial peritonitis (0.6%)
HCC developed in 29 patients (2.8%): 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, among patients with noncirrhotic fibrosis at baseline, comparable rate of
progression to cirrhosis between those who did and did not receive peginterferon
(28.2% vs 31.9%; P = .46)
Outcome at 3.5 Yrs Difference (95% CI) P Value
(n = 517) (n = 533)
Noncirrhotic fibrosis at baseline
• Mean decrease in
-1.03 -0.03 -1.00 (-1.46 to -0.55) < .001
necroinflammatory score
• Mean increase in Ishak
0.38 0.42 0.04 (-0.27 to 0.20) .77
fibrosis score
Cirrhosis at baseline
• Mean decrease in
-1.38 -0.33 -1.05 (-1.66 to -0.44) < .001
necroinflammatory score

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, log10
IU/mL
• Year 1.5 0.81 0.07 0.74 (0.61-0.87) < .001
• Year 3.5 0.71 0.12 0.59 (0.45-0.72) < .001
Mean decrease in ALT, x ULN
• Year 1.5 0.45 0.21 0.24 (0.09-0.39) .002
• Year 3.5 0.47 0.19 0.28 (0.12-0.44) < .001
Normal ALT at Year 3.5, % 35.1 22.6 < .001
ULN, upper limit of normal.
Overall, no significant difference in mortality rates between groups

● Significantly higher mortality among treated vs untreated patients with noncirrhotic
fibrosis at baseline, but no significant difference in mortality among those with
cirrhosis at baseline
Mortality at 3.8 Years, % P Value
(n = 517) (n = 533)
Overall 6.6 4.6 .18
• Noncirrhotic fibrosis 5.0 1.9 .04
• Cirrhosis 9.1 8.4 .93
Higher proportion of patients receiving peginterferon vs no treatment had ≥ 1 serious adverse

event, but difference failed to meet statistical significance
● 38.6% vs 31.8% (P = .07), by Kaplan-Meier analysis
157 patients discontinued peginterferon
● Reasons included cytopenias, depression, other adverse events, and patient refusal
to continue therapy
Dose modification for adverse events common
● In patients who did not have other study endpoints, only 59% of patients were still
receiving the full 90-µg/week dose of peginterferon at Year 3.5.
References
1. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C
with low-dose peginterferon. N Engl J Med. 2008;359:2429-2441.
2. Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in
patients with chronic hepatitis C. Ann Intern Med. 1998;129:94-99.
3. Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular
carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in
Japan. Ann Intern Med. 1999;131:174-181.

Maintenance Peginterferon alfa-2a Ineffective at Preventing Disease
Progression in HCV-Infected Patients Not Achieving SVR
Steven Flamm, MD
Combination therapy with peginterferon alfa and ribavirin is the current standard of care for chronic hepatitis C
virus (HCV) infection. Unfortunately, sustained virologic response (SVR) is still only achieved in approximately
40% of those patients with genotype 1 HCV, the most common genotype.[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, alternatives to improve clinical outcomes in nonresponders have been
sought. One such approach involves the use of maintenance therapy, in which the goal is not to achieve viral
eradication with a defined course of treatment, but rather to suppress HCV RNA with long-term antiviral
therapy while awaiting the development of new medications. Although several studies have suggested that
such an approach may improve hepatic histology and reduce the rates of hepatocellular carcinoma, the
studies were retrospective or conducted in small patient populations.[2-4] Despite the paucity of rigorous,
controlled data supporting such an approach, maintenance therapy has become a management option for
nonresponders.
Unfortunately, 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). In this well-designed, randomized, controlled, multicenter trial, 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 3.5 years.
Although serum alanine aminotransferase and HCV RNA levels declined on therapy and histologic
necroinflammatory scores improved, clinical outcomes—death, hepatic decompensation (variceal
hemorrhage, ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy), hepatocellular carcinoma,
a worsening Child-Turcotte-Pugh score, or increased hepatic fibrosis (in patients who did not have cirrhosis at
baseline)—were unchanged with maintenance treatment compared with observation (34.1% vs 33.8%,
respectively). In fact, in patients with advanced fibrosis, clinical outcomes were more frequent in the treatment
group than the observation group (36.7% vs 35.5%, respectively), although this difference was not statistically
significant. The overall death rate was also greater in the treatment group than the observation group (6.6%
vs 4.6%, respectively), although again the difference did not achieve statistical significance. However, the
death rate was significantly greater in the noncirrhotic subgroup who were treated vs those who were
untreated (5.0% vs 1.9%, respectively; P = .04).
Regarding safety, serious adverse events occurred more frequently in the treatment group than in the
observation group (38.6% vs 31.8%, respectively), although the difference did not reach statistical
significance. In addition, long-term usage of peginterferon was poorly tolerated: Only 58.9% 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 3.5 years.
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. Moreover, such therapy may be, in fact, harmful.
Since there are no therapeutic options for nonresponders other than enrollment in clinical trials, the negative
results of this study further emphasize the unmet medical need faced by this population.
Although the negative results of maintenance therapy in this study are definitive, it is important to note that the
findings do not necessarily impugn the concept of long-term maintenance therapy. The dosage of
peginterferon selected was arbitrary (based on perceived favorable tolerability), and ribavirin was not used.
Therefore, it should not be extrapolated that the concept of long-term HCV RNA reduction by HCV
maintenance therapy with different, more effective regimens is necessarily incorrect. It remains possible that
long-term reductions in HCV RNA could benefit patients with advanced liver disease secondary to HCV. Even
in this study, 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. However, the putative regimen
must be reasonably well tolerated. Such maintenance therapy may require the addition of ribavirin to the
regimen or, in the future, the inclusion of highly potent small-molecule agents that lower the HCV RNA more
substantially.
REFERENCES
1. Sulkowski MS, Lawitz E, Shiffman ML, et al. Final results of the IDEAL (Individualized Dosing Efficacy
versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) phase IIIB study. Program and
abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-
27, 2008; Milan, Italy. Abstract 991.
2. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon
therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology.
1999;117:1164-1172.
carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C
in Japan. Ann Intern Med. 1999;131:174-181.
5. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C
with low-dose peginterferon. N Engl J Med. 2008;359:2429-2441.
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]

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 3.5 years vs those who received no treatment
HCC more common in patients with cirrhosis vs bridging fibrosis (7.0% vs 4.1%, respectively)
● Among patients with only fibrosis on serial biopsies, 8 (17%) developed HCC
Predictive model for HCC risk developed based on age, race, alkaline phosphatase levels,
presence of esophageal varices, smoking status, 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 0.5% to 5.0%,
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, controlled US cohort
of patients with chronic hepatitis C and advanced fibrosis or cirrhosis

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
All patients confirmed to have no HCC-specific masses at screening by
imaging analysis
Serum alpha-fetoprotein (AFP) levels required to be < 200 ng/mL or < 1000
ng/mL at entry, 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
N = 1005
● 45 of 1050 HALT-C participants excluded from current analysis due to prevalent HCC
(n = 5), presumed HCC that showed no radiographic or clinical progression (n = 2), 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, years (SD) 52.7 (7.2) 50.1 (7.1) .02
Female, % 21 29 .21
Race, %
• White 63 72
• Black or black Hispanic 29 18 .05
• Hispanic 6 8
• Other 2 2
Mean BMI (SD) 28.3 (4.6) 30.0 (5.5) .04
Genotype 1 HCV, % 92 94 .40
Mean HCV RNA, log10 IU/mL (SD) 6.39 (0.51) 6.44 (0.52) .43
Mean laboratory values
• Hemoglobin, g/dL (SD) 14.9 (1.4) 15.0 (1.4) .50
• White blood cell count,
3 4900 (1500) 5800 (1900) .001
cells/mm (SD)
• Platelet count, cells/mm3
123,000 (49,000) 167,000 (66,000) < .0001
(SD)
• Albumin, g/dL (SD) 3.7 (0.4) 3.9 (0.4) .0002
• AST, U/L (SD) 118 (76) 86 (57) .0001
• ALT, U/L (SD) 134 (109) 106 (76) .01
• Alkaline phosphatase, U/L
128 (66) 98 (44) < .0001
(SD)
• Total bilirubin, mg/dL (SD) 0.85 (0.38) 0.79 (0.40) .29

• Prothrombin time, INR 1.10 (0.09) 1.00 (0.11) .06
Severity of liver disease
• AST/ALT ratio (SD) 0.96 (0.34) 0.88 (0.29) .02
• APRI (SD) 2.70 (2.13) 1.56 (1.48) < .0001
• Child-Turcotte-Pugh score
5.44 (0.50) 5.20 (0.43) < .0001
(SD)
• MELD score (SD) 7.33 (1.19) 7.04 (1.42) .14
HCC markers
• Mean AFP, ng/mL (SD) 23.28 (28.34) 16.89 (29.24) .22
• Mean DCP, U/mL (SD) 50.54 (51.32) 45.6 (223.86) .83
Cirrhosis, % 52 40 .08
Esophageal varices, % 50 24 < .0001
Mean alcohol consumption, g/day
25.03 (33.43) 25.08 (39.69) .78
(SD)
Smoking history, % 83 75 .13
ALT, alanine aminotransferase; APR, AST-platelet ratio index; AST, aspartate aminotransferase; BMI, body mass
index; DCP, des-gamma-carboxy prothrombin; INR, international normalized ratio ; MELD, Model for End-Stage Liver
Disease; SD, standard deviation.

Patients enrolled at 10 US study centers
Assessments
● Liver biopsies at baseline and Years 1.5 and 3.5
● Laboratory assessments performed every 3 months during trial and every 6 months
thereafter
Complete blood count, liver panel, and AFP level
● Ultrasound performed approximately every 6-12 months
Identification of new lesions further evaluated with computed tomography or
magnetic resonance imaging
● Endoscopy performed at randomization and at Year 3.5
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
2 imaging studies showing mass lesion with characteristics of HCC
Progressively enlarging lesion on ultrasound leading to death
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, chi-squared
test, or univariate Cox proportional hazards
● Multivariate Cox proportional hazards used to estimate risk of HCC

Main Findings
4.8% of patients (n = 48) developed HCC during median follow-up of 4.6 years (maximum:
6.7 years)
● Definite HCC: 77% (n = 37)
● Presumed HCC: 23% (n = 11)
● Diagnosis
Early-stage HCC (T1/T2): 75% (n = 36)
Eligible for potentially curative treatment: 54.2% (n = 26)
Incidence of HCC similar in peginterferon and no-treatment groups
Outcome, %
(n = 495) (n = 510)
Overall HCC incidence 4.5 4.9
• Patients with fibrosis 5.0 2.7
• Patients with cirrhosis 4.1 8.1
Annual incidence 1.1 1.0
Cumulative incidence
• 3 years 1.9 1.9
• 5 years 5.4 5.0
Although not statistically significant, HCC incidence higher in patients with cirrhosis vs
bridging cirrhosis
Bridging Fibrosis Cirrhosis

Outcome, %
(n = 597) (n = 408)
Overall HCC incidence 3.9 6.1
Annual incidence 0.8 1.4
Cumulative incidence
• 3 years 1.4 2.6
• 5 years 4.1 7.0*
*P = .08 vs bridging fibrosis at 5 years.
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 1.050 .01
Black race 2.044 .04
Alkaline phosphatase, U/L 1.006 .01
Esophageal varices 2.164 .02
Ever smoked 2.114 .07
3
Platelet count, cells/mm 0.989 .001

Regression formula for model: age x 0.049 + black race x 0.712 + alkaline
phosphatase*0.006 + esophageal varices*0.777 + ever smoked*0.749 + platelets*-0.011
● According to regression formula, cut points of 0 to log10(1.50), log10(1.50) to
log10(3.25), and > log10(3.25) selected to reflect low, intermediate, and high risk for
HCC at 5 years (cumulative incidence < 1%, 1% to 5%, and > 5%, respectively)
Cumulative Incidence of HCC, % Low Risk Intermediate Risk High Risk

3 years 0 1.5 6.1
5 years 0.4 4.2 17.8
Other Outcomes
Low platelet count (P < .0001) and esophageal varices (P = .0002) highly significant in
Kaplan-Meier estimates of cumulative incidence of HCC
Platelet Count
Cumulative Incidence of HCC, % 100,000-149,000
< 100,000 cells/mm3 > 150,000 cells/mm3
cells/mm3
3 years 5.3 2.4 0.6
5 years 13.1 5.7 2.6
References
1. Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, et al. Incidence of hepatocellular carcinoma and
associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138-
148.
2. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
Gastroenterol. 2007;132:2557–2576.
3. Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and
hepatitis C endemicity. Oncogene. 2006;25:3771–3777.
4. Parkin D. Cancer incidence in five countries. Lyon, France: IARC Scientific Publications; 2002.

Defining the Incidence and Risk Factors for Hepatocellular Carcinoma
in the Setting of HCV Infection
Nancy Reau, MD
Hepatocellular carcinoma (HCC) is a common complication of hepatitis C cirrhosis. However, conflicting

data exist regarding the annual incidence of HCC and the factors that predispose hepatitis C virus
(HCV)–infected patients to developing this complication.[1-6] Published reports suggest that long-term
treatment with peginterferon decreases the risk of progression to HCC.[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, randomized HALT-C trial (Hep JO Di
Bisceglie_NEJM_2008).[12]
Lok and colleagues unearthed several very important findings in this analysis:
1. 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. This finding
strongly discourages the use of maintenance therapy to decrease malignancy risk.
2. Hepatocellular carcinoma developed in 4.8% of the HALT-C cohort, with an estimated annual
incidence of 1.1% and a 5-year incidence of 5.9%. Based on these data, the investigators were able to
stratify the cohort into low-, intermediate-, and high-risk groups for the development of HCC using a
mathematical model requiring only routine laboratory results and clinical data. Older age, black or black
plus Hispanic race, high alkaline phosphates levels, low platelet counts, presence of esophageal varices,
and having ever smoked were significant in predicting HCC risk. This suggests that it may be possible to
identify patients in need of intensive HCC screening and monitoring.
3. Patients without cirrhosis developed malignancy. Unlike with hepatitis B, the development of HCC
in HCV-infected patients without cirrhosis has been viewed as an exception to the rule. Yet in this study,
HCC was identified in 23 patients without cirrhosis at enrollment (48% of all patients with HCC). 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. Some of these patients had
progressed to cirrhosis at the time of HCC diagnosis, reminding us that HCV liver disease is a dynamic
condition and that patients should be reassessed at regular intervals for disease progression. Screening
should be initiated as soon as a patient is considered to be at increased risk for malignancy.
4. Only 75% of malignancies were diagnosed at an early stage (T1/T2), and only 54.2% 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.
This important study has several implications. The findings indicate that no patient should be receiving
maintenance peginterferon solely for liver cancer prevention. In addition, this study suggests that our
[13]
current HCC screening recommendations are not adequate. Screening is likely necessary for a subset
of patients with advanced fibrosis (without cirrhosis) and should ideally be performed every 6 months. Our
current practice guidelines do not recommend using alpha-fetoprotein (AFP) levels as a screening tool;
however, this study found that AFP and des-gamma-carboxyprothrombin (DCP) levels on univariate
analysis were both significantly associated with HCC. Until the appropriate population for screening can
be identified, all patients with advanced fibrosis should be screened every 6 months for HCC using a
combination of imaging and tumor markers (ie, AFP and DCP).
REFERENCES
1. Benvegnù L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a

prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744-749.
2. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C:
a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463-472.
3. Simonetti RG, Cammà C, Fiorello F, et al. Hepatitis C virus infection as a risk factor for
hepatocellular carcinoma in patients with cirrhosis: a case-control study. Ann Intern Med.
1992;116:97-102.
4. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular

carcinogenesis. Gastroenterology. 2007;132:2557-2576.
5. Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and
hepatitis C endemicity. Oncogene. 2006;25:3771-3777.
6. Parkin D. Cancer incidence in five countries. Lyon, France: IARC Scientific Publications; 2002.
carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic
hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy.
Ann Intern Med 1999;131:174-181.
9. Mazzella G, Accogli E, Sottili S, et al. Alpha interferon treatment may prevent hepatocellular
carcinoma in HCV-related liver cirrhosis. J Hepatol. 1996;24:141-147.
10. Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon- on incidence of
hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051-1055.
11. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk
factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138-148.
12. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic
hepatitis C with low-dose peginterferon. N Engl J Med. 2008;359:2429-2441.
13. Bruiz J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42;1208-1236.

Consensus Interferon/Ribavirin Beneficial for Specific Groups of Difficult-to-Treat
Prior Peginterferon/Ribavirin Nonresponders
DIRECT trial: multicenter, randomized, open-label, US-based phase III registration trial

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,
higher doses, and/or a longer duration of therapy
Current study assessed efficacy, tolerability, and safety of consensus interferon/ribavirin
retreatment in HCV-infected patients with prior nonresponse to peginterferon/ribavirin

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, 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, dose interruption, or peginterferon dose
reduction during prior therapy
● Pregnant/lactating women, male partners of pregnant women
● Unlikely to comply with study requirements
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, yrs (SD) 51 (6.65) 50 (6.59)
Male, % 68 72
Race, %
• White 64 65
• Black 21 17
Mean weight, kg (SD) 89.1 (18.64) 89.4 (17.59)
HCV genotype 1, % 95 96
HCV RNA ≥ 850,000 IU/mL, % 68 68
Hepatic fibrosis (Metavir score), %
• F0-F2 42 38
• F3 (bridging fibrosis) 36 34
• F4 (cirrhosis) 22 28
Steatosis, % 52 51
Response to prior therapy, %
• < 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, days

Patients enrolled at 44 sites in United States and Puerto Rico
HCV RNA assessed at Weeks 0, 24, 48, and 72
Primary endpoint
● SVR
Secondary endpoints
● Factors influencing SVR
● Safety
● Tolerability
Main Findings
SVR rates of 6.9% and 10.7% in the consensus interferon 9 µg/day and 15 µg/day arms,
respectively
● Study not powered to detect differences between arms, and no statistically significant
difference in SVR rates between arms in post hoc analysis (P = .141)
Approximately 40% to 50% relapse rates observed

Outcome, % 9 µg/day + Ribavirin 15 µg/day + Ribavirin
(n = 245) (n = 242)
End-of-treatment response 14.7 18.5
SVR 6.9 10.7
Relapse rate 52 42
Among patients who had no dose modifications, SVR rates of 7% and 17% in the consensus
interferon 9 µg/day and 15 µg/day arms, respectively
Complete early virologic response (defined as HCV RNA negativity at Week 12) associated
with increased likelihood of SVR

SVR, % 9 µg/day + Ribavirin 15 µg/day + Ribavirin
(n = 245) (n = 242)
Patients with complete early virologic
81.3 63.6
response
Patients with slow response* 11.7 35.4
*> 2 log10 drop in HCV RNA at Week 12, HCV RNA undetectable at Week 24.

Highest SVR rates observed in patients with greatest decreases in HCV RNA on prior
therapy and low fibrosis scores at baseline (F0-F3)

SVR, % 9 µg/day + Ribavirin 15 µg/day + Ribavirin
(n = 245) (n = 242)
Fibrosis score F0-F2 8.7 14.9
• < 1 log10 decrease in HCV RNA 6.3 7.4
• 1-2 log10 decrease in HCV RNA 9.0 19.2
• > 2 log10 decrease in HCV RNA 13.3 30
Fibrosis score F3 6.8 11.1
• < 1 log10 decrease in HCV RNA 8.6 8.7
• 1-2 log10 decrease in HCV RNA 4.5 12.5
• > 2 log10 decrease in HCV RNA 7.6 33.3
Fibrosis score F4 3.8 4.5
• < 1 log10 decrease in HCV RNA 4.1 0
• 1-2 log10 decrease in HCV RNA 0 9.5
• > 2 log10 decrease in HCV RNA 10.0 8.3
Other factors associated with SVR

● SVR rates higher in whites vs blacks (11.0% vs 4.2%, respectively)
● SVR rates higher in patients with nongenotype 1 vs genotype 1 HCV (47.8% vs
6.9%, respectively; P < .001)
● SVR rates higher in patients with baseline HCV RNA < vs > 850,000 IU/mL (16.1%
vs 5.4%; P < .001)
Most adverse events grade 2/3 in severity

Adverse Event Occurring in ≥ 25% of
9 µg/day + Ribavirin 15 µg/day + Ribavirin
Patients in Either Arm, %
(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
83.6% and 71.7% of patients assigned to consensus interferon 9 µg/day and 15 µg/day,
respectively, received ≥ 80% of cumulative dose
Most common reason for treatment discontinuation in 9 µg/day and 15 µg/day groups was
treatment failure (51.8% and 44.2%, respectively), followed by adverse events (14.3% and
21.1%, respectively)

Reference
Bacon BR, Shiffman ML, Mendes F, et al. Retreating chronic hepatitis C with daily interferon alfacon-
1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results. Hepatology. 2009;Feb
2[Epub ahead of print].

Consensus Interferon/Ribavirin Retreatment for
Peginterferon/Ribavirin Nonresponders Beneficial for Select Group of
Patients With Low Baseline Fibrosis Scores and Interferon Sensitivity
Richard Sterling, MD, MSc, FACP, FACG
Patients chronically infected with hepatitis C who fail to respond to first-line peginterferon/ribavirin therapy
represent an underserved population, as optimal management of these individuals to prevent disease
progression remains to be defined. One of the many management strategies proposed for nonresponders
is treatment with interferon alfacon-1 or consensus interferon. 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).
Overall, sustained virologic response (SVR) rates in this trial were low, reaching only 7% for patients who
received consensus interferon 9 µg/day and 11% for patients who received consensus interferon 15
µg/day. These results are fairly disappointing, although not unexpected. The investigators enrolled a very
difficult–to-treat population with several unfavorable treatment characteristics. For example, nearly 20% of
the study population was black, approximately 25% had cirrhosis, more than 50% had steatosis, and
nearly 80% had a < 2 log10 decline in HCV RNA in response to previous therapy—that is, a clearly
defined group of previous peginterferon/ribavirin nonresponders.
The investigators conducted several subanalyses to tease apart various groups of nonresponders who
may attain more benefit from consensus interferon/ribavirin retreatment than others. As has been seen in
other studies,[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. In this population of patients, SVR rates for the 9-µg/day and 15-µg/day doses of
consensus interferon were 11% and 23%, respectively. Although the numbers were small, 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 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: 13.0% vs 4.5%). This finding has been observed in other
trials that included treatment-experienced patients.[3] When patients were classified according to fibrosis
score and the level of response to previous peginterferon/ribavirin, 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.
The authors stated that 72% to 84% of patients received at least 80% of the cumulative consensus
interferon dose, but adherence to ribavirin was not reported. It is important to note that the investigators
had very strict criteria for ribavirin dose modification in response to anemia. For patients who experienced
a drop in hemoglobin < 10 g/dL, the dose of ribavirin was reduced from 1000-1200 mg/day to 600
mg/day, which probably represents the lower threshold of therapeutic efficacy. No growth factor support
was allowed. Therefore, depending on how many patients required ribavirin modification, 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.
It is unclear what probability of response is sufficient or reasonable to warrant putting a patient through
the expense, the adverse events, and the inconvenience of retreatment, and this should be considered on
an individualized basis. As such, 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, those who had a partial response to previous
peginterferon/ribavirin and do not have cirrhosis. Unfortunately, these are not the patients in dire need of
such treatment. It is those individuals with unfavorable characteristics—cirrhosis, steatosis, high HCV
RNA, and black race—for whom disease control is needed most urgently. 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.
REFERENCES
1. Bacon BR, Shiffman ML, Mendes F, et al. Retreating chronic hepatitis C with daily interferon
alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results.
Hepatology. 2009;Feb 2:[Epub ahead of print].
2. Jacobson IM, Gonzalez SA, Ahmed F, et al. A randomized trial of pegylated interferon alpha-2b
plus ribavirin in the retreatment of chronic hepatitis C. Am J Gastroenterol. 2005;100:2453-2462.
3. Jensen DM, Marcellin P, Freilich B, et al. Re-treatment of patients with chronic hepatitis C who do
not respond to peginterferon-alpha2b: a randomized trial. Ann Intern Med. 2009;150:528-540.
Nitazoxanide Improves Rates of Response to Peginterferon/Ribavirin in
Treatment-Naive Patients With Genotype 4 HCV
Randomized, open-label, controlled, phase II trial[1]

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, which controls host cell defenses against viral infection
Current study assessed efficacy and safety of nitazoxanide plus peginterferon alfa-2a, with or
without ribavirin, in treatment-naive patients with genotype 4 HCV[1]

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 generally well balanced across treatment groups, except for
significantly lower body mass index (BMI) among patients treated with nitazoxanide plus
peginterferon/ribavirin vs those treated with peginterferon/ribavirin (P = .004)
All patients infected with genotype 4 HCV
Nitazoxanide + Nitazoxanide +
Peginterferon/Ribavirin
Characteristic Peginterferon Peginterferon/Ribavirin
(n = 40)
(n = 28) (n = 28)
Median age, yrs (range) 37.5 (21.0-55.0) 37.5 (22.0-54.0) 39.0 (20.0-57.0)
Male, % 89 96 90
White, % 93 100 98
Median BMI (range) 27 (19-37) 25 (18-33)* 28 (18-37)
Median HCV RNA, log10 IU/mL
5.6 (4.4-6.1) 5.5 (4.1-6.3) 5.7 (4.2-6.5)
(range)
Median ALT, U/L (range) 55 (14-359) 64 (14-213) 69 (18-324)
Mean Knodell necroinflammation
4.1 (3.0) 3.3 (2.2) 4.0 (2.3)
score (SD)
Fibrosis or cirrhosis, % 4 11 3
ALT, alanine aminotransferase; SD, standard deviation.
*P = .004

Patients enrolled at 2 centers in Egypt between March and August 2006
Patients assessed every 4 weeks during treatment and at Weeks 4, 8, 12, 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, defined as undetectable HCV RNA 4 weeks after start of combination therapy
● Complete early virologic response (cEVR), defined as undetectable HCV RNA 12
weeks after start of combination therapy
● End-of-treatment response (ETR)

● ALT normalization
● Safety
Main Findings
Statistically significantly higher response rates with nitazoxanide plus peginterferon/ribavirin
vs peginterferon/ribavirin for both SVR (79% vs 50%, respectively; P = .023) and RVR (64%
vs 38%, respectively; P = .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%, 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: 0.27 log10 IU/mL (P = .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 = .008 for trend)
Rates of ALT normalization comparable across groups among patients who achieved SVR
Outcome Peginterferon Peginterferon/Ribavirin
(n = 40)
(n = 28) (n = 28)
Mean decrease in HCV RNA
4 weeks after start of combination 3.74 4.50 2.86
therapy, log10 IU/mL
ALT normalization in patients who
achieved SVR, %
Abnormal at baseline 75 69 68
Normal at baseline 20 31 27

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, thrombocytopenia, 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, SVR rates higher for patients who
received nitazoxanide vs those who did not
● Subgroup size too small to assess statistical significance
SVR According to BMI, % Peginterferon Peginterferon/Ribavirin
(n = 24)
(n = 22) (n = 22)
< 25 75 93 71
25-30 75 83 71
> 30 67 75 63
References
1. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C
genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology. 2009;136:856-862.
2. Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS. Potential for hepatitis C virus resistance to
nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069-4071.
3. Rossignol JF, Kabil SM, El-Gohary Y, Elfert A, Keeffe EB. Clinical trial: randomized, double-blind,
placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis
C genotype 4. Aliment Pharmacol Ther. 2008;28:574-580.
4. Elazar M, Liu M, McKenna S, et al. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR
phosphorylation. Program and abstracts of the 59th Annual Meeting of the American Association for the
Study of Liver Diseases; October 31-November 4, 2008; San Francisco, California. Abstract 1881.

Improved Response Rates in Chronic Hepatitis C With the Use of
Nitazoxanide: A Look at Phase II Data
Mark S. Sulkowski, MD
Nitazoxanide is an orally available drug used for the treatment of parasites, including Cryptosporidium
and Giardia. Recently, there has been interest in using nitazoxanide for the treatment of hepatitis C virus
(HCV) infection. The rationale for this application emerged from observations of AIDS patients with
cryptosporidiosis who were coinfected with hepatitis B virus and/or HCV, as long-term treatment of these
individuals with nitazoxanide produced reductions in serum alanine aminotransferase (ALT) levels.
Subsequent work conducted in vitro demonstrated a reduction in HCV replication in the genotype 1
replicon model with the addition of nitazoxanide.[1] Recent findings suggest that the mechanism of action
of nitazoxanide may be to induce double-stranded RNA-activated protein kinase phosphorylation, which
results in an increased intracellular concentration of phosphorylated eukaryotic initiation factor 2-alfa,
thereby enhancing the effect of interferon.[2]
To more rigorously assess the safety and efficacy of nitazoxanide for the treatment of HCV, Rossignol
and colleagues[3] conducted a randomized, controlled phase II trial (Hep JO Rossignol-Gastroenterol-
2009-CS). In total, 96 treatment-naive patients chronically infected with genotype 4 HCV were randomly
assigned to receive nitazoxanide and peginterferon alfa-2a, with ribavirin (n = 28) or without ribavirin (n =
28); a third treatment arm of standard peginterferon/ribavirin therapy (n = 40) was also included for
comparison. In the 2 nitazoxanide-containing arms, nitazoxanide was given as monotherapy for 12
weeks, and then peginterferon with or without ribavirin was added for an additional 36 weeks of
treatment.
Traditionally, response rates to peginterferon plus ribavirin for patients infected with genotype 1 or 4 HCV
are suboptimal, reaching only 40% to 60%. Rossignol and colleagues reported that, although
nitazoxanide monotherapy was associated with only a very modest decrease in HCV RNA (-0.27 log10
IU/mL) and no evidence of ALT reduction, 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. 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 =
.023). 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). Of note, the increased rate of SVR was achieved without any increase in adverse effects.
Although this clinical trial raises the prospect of using nitazoxanide in the clinical management of HCV, it
does not provide definitive evidence of its role, if any, in current and future treatment paradigms.
Limitations of the study include small sample sizes for the nitazoxanide groups (n = 28 for each
nitazoxanide arm), the open-label design (both subjects and investigators were aware of the treatment
assignment), inclusion of only patients infected with genotype 4 HCV (as opposed to genotype 1 HCV),
and conduct of the study at only 2 sites, with the majority of subjects (75 of 96) enrolled at 1 site.
Furthermore, it is interesting to note that the investigators saw no reduction in ALT levels during the 12-
week lead-in phase of nitazoxanide, in contrast to the original observation in HIV-infected persons that, in
part, led to this study. Larger follow-up studies are currently under way in the United States in persons
infected with genotype 1 HCV, which will address the limitations of the current clinical trial.
The development of a well-tolerated, 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. If the findings of this study are confirmed in larger studies,
nitazoxanide may be an important adjuvant therapy to enhance the response to interferon-based HCV
treatment, including the current standard of care (ie, peginterferon plus ribavirin) and future treatment
approaches featuring specifically targeted antiviral therapies for HCV (eg, HCV protease inhibitors) in
combination with peginterferon plus ribavirin.
REFERENCES
1. Korba BE, Elazar M, Lui P, Rossignol JF, Glenn JS. Potential for hepatitis C virus resistance to
nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069-4071.
2. Elazar M, Liu M, McKenna S, et al. Nitazoxanide (NTZ) is an inducer of eIF2a and PKR
phosphorylation. Hepatology. 2008;48:1151A.
3. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis
C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology.
2009;136:856-862.
Tenofovir Demonstrates Superior Efficacy, Similar Safety vs Adefovir in HBeAg-
Positive and HBeAg-Negative Chronic Hepatitis B
Studies 102 and 103: randomized, double-blind, phase III trials

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, long-term safety, 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, Canada, Europe, Australia, 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

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
ALT > 1 and < 10 x upper limit of normal
HBV DNA > 105 copies/mL
< 12 weeks of treatment with any nucleos(t)ide or receipt of lamivudine or
emtricitabine for ≥ 12 weeks
● Additional criteria for HBeAg-positive patients
ALT > 2 and < 10 x upper limit of normal
HBV DNA > 106 copies/mL
< 12 weeks of treatment with any nucleos(t)ide
Exclusion criteria
● Coinfection with HCV, hepatitis D virus, or HIV
● Hepatocellular carcinoma
● Impaired renal function (creatinine clearance < 70 mL/min)
● Anemia or neutropenia
● Liver decompensation or liver failure

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, yr (SD) 34 (11) 34 (12) 44 (11) 43 (10)
Male, % 68 71 77 78
Race, %
• White 52 51 64 65
• Asian 36 36 25 24
• Black 7 6 3 3
Geographic region, %
• Europe 55 54 63 61
• North America 27 27 21 23
• Australia/New Zealand 18 19 16 16
HBV genotype, %
• 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, log10 copies/mL (SD) 8.64 (1.08) 8.88 (0.93) 6.86 (1.31) 6.98 (1.27)
Mean ALT, IU/mL (SD) 142 (103) 155 (121) 128 (101) 164 (146)
Mean Knodell necroinflammatory
8.3 (2.1) 8.3 (2.3) 7.8 (2.4) 7.9 (2.2)
score (SD)
Mean Knodell fibrosis score (SD) 2.3 (1.2) 2.4 (1.2) 2.3 (1.2) 2.4 (1.2)
Previous treatment, %
• Lamivudine or emtricitabine 5 1 17 18
• Interferon 17 14 17 18

Patients recruited from May 2005 - June 2006 at 106 clinical sites in 15 countries across
North America, Europe, 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, in patients with
HBV DNA > 400 copies/mL at Week 48, and in patients with virologic breakthrough
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

Secondary endpoints
● HBV DNA < 400 copies/mL
● Histologic improvement
● ALT normalization
● HBeAg and HBsAg loss and seroconversion
● Resistance mutations
● Safety
Main Findings
In both trials, 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, although significantly more patients had HBsAg loss with tenofovir vs
adefovir
● No HBsAg loss or seroconversion among HBeAg-negative patients

HBeAg-Positive Patients HBeAg-Negative Patients
Outcome at Week 48, % Tenofovir Adefovir Tenofovir Adefovir
P Value P Value
(n = 176) (n = 90) (n = 250) (n = 125)
HBV DNA < 400 copies/mL 76 13 < .001 93 63 < .001
Histologic improvement 74 68 .32 72 69 .29
• Reduced
78 71 .27 78 74 .27
necroinflammation
• Worsened fibrosis 2 3 .36 6 9 .96
ALT normalization 68 54 .03 76 77 .86
HBeAg seroconversion 21 18 .36 -- -- --
HBsAg loss 3.2 0 .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
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, serious adverse events, and laboratory abnormalities
● Nausea only adverse event occurring more often with tenofovir vs adefovir (9% vs
3%)
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, %
(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 ≥ 0.5 mg/dL above baseline 0 <1
• Creatinine clearance < 50 mL/min 0 0

Reference
Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic
hepatitis B. N Engl J Med. 2008;359:2442-2455.

Tenofovir for Chronic Hepatitis B
Daryl T-Y Lau, MD, MSc, MPH and Wissam Bleibel, 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. 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). Both agents are nucleotide analogues and
share similar molecular structures. However, 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, such as lamivudine, entecavir, and telbivudine, in HBV DNA
suppression.[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. Moreover,
tenofovir was equally effective for treatment-naive and lamivudine-experienced patients. Among HBeAg-
positive patients, the rate of HBeAg seroconversion (21%) was similar to that of adefovir and other
approved agents. The lack of correlation between antiviral potency and rate of HBeAg seroconversion
underscores the importance of the immune response in HBeAg clearance. Hepatitis B surface antigen
(HBsAg) loss is the most desirable endpoint of HBV therapy, but the 1-year rates of HBsAg loss are < 1%
for most nucleos(t)ides. In the study by Marcellin and colleagues,[1] 5 HBeAg-positive patients (3%)
achieved HBsAg loss with tenofovir. All 5 patients were white and were infected with HBV genotype A or
D. No HBeAg-negative patient had HBsAg loss with tenofovir. No genotypic resistance to tenofovir was
observed during 1 year of treatment, and the dose of tenofovir administered was safe and did not cause
significant renal toxicity.
These trials were well powered and had meaningful primary and secondary endpoints, making the
findings robust. Still, there are several important unresolved issues to note. First, blacks and Asians were
relatively underrepresented, especially in the HBeAg-negative study, which limits the ability to generalize
the findings to all racial populations and HBV genotypes. Second, the relatively high rate of HBsAg loss
may reflect the higher proportion of white patients with HBV genotypes A and D in the study. The
relationship between HBV genotype, duration of infection, and HBsAg loss/seroconversion needs to be
studied further. Third, similar to other oral agents for chronic hepatitis B, approximately 25% to 30% of
patients failed to achieve a complete biochemical response with tenofovir. Given that nonalcoholic fatty
liver disease (NAFLD) is prevalent, it is important to examine and document hepatic steatosis in liver
biopsies and evaluate whether NAFLD contributes to the persistent serum aminotransferase elevation.
Fourth, although the lack of tenofovir-associated resistance after 1 year of treatment is promising,
evaluation of long-term tenofovir use is still necessary. In particular, the clinical relevance of the tenofovir-
associated rtA194T mutation previously noted in vitro, and in cases of HBV/HIV-coinfection, needs to be
[3,4]
monitored with long-term use of the medication. Fifth, only patients with creatinine clearance ≥ 70
mL/min were included in the trials, meaning that the safety of prolonged tenofovir use in those with renal
insufficiency needs further observation. Sixth, tenofovir is significantly associated with reduced bone
mineral density in patients with HIV, although understanding of that phenomenon is complicated by
evidence that initiating antiretroviral therapy per se is associated with bone loss.[5-7] The effect of tenofovir
on bone density needs further clarification for patients with chronic hepatitis B.
In conclusion, the results of these studies show that tenofovir is superior to adefovir regarding efficacy
and similar to adefovir regarding safety. Tenofovir is associated with potent virologic suppression,
histologic improvement, and the absence of virologic resistance over 48 weeks. In addition, tenofovir has
been designated as an FDA Class B medication, indicating that it is “probably safe” during pregnancy.
These properties make tenofovir an attractive first-line therapy for chronic hepatitis B, including for young
women of reproductive age. (Ongoing monitoring of the safety of tenofovir in pregnancy is needed before
routine use in pregnant women can be recommended.) Regarding second-line use, tenofovir does not
have cross-resistance with nucleoside analogues and remains effective against HBV with the adefovir-
associated mutation rtA181V/T in vitro. Therefore, tenofovir has applicability for patients who develop
resistance to nucleoside analogues and likely adefovir with the rtA181V/T mutation.
REFERENCES
1. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for
chronic hepatitis B. N Engl J Med. 2008;359:2442-2455.
2. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a
clinical research workshop. Hepatology. 2007;45:1056-1075.
3. Sheldon J, Camino N, Rodés B, et al. Selection of hepatitis B virus polymerase mutations in HIV-
coinfected patients treated with tenofovir. Antivir Ther. 2005;10:727-734.
4. Amini-Bavil-Olyaee S, Herbers U, Sheldon J, Luedde T, Trautwein C, Tacke F. 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. Hepatology.
2009;49:1158-1165.
5. Gallant JE, Winston JA, DeJesus E, et al. The 3-year renal safety of a tenofovir disoproxil
fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients. AIDS.
2008;22:2155-2163.
6. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and
efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-
week analysis. J Acquir Immune Defic Syndr. 2008;47:74-78.
7. Grund B, Carr A. Continuous antiretroviral therapy (ART) decreases bone mineral density: results
from the SMART study. Program and abstracts of the 48th Annual ICAAC/IDSA 46th Annual
Meeting; October 25-28, 2008; Washington, DC. Abstract H-2312a.
Early HBsAg Loss Predicts SVR in HBeAg-Negative Patients Treated With
Peginterferon alfa-2a
Prospective, single-arm study

Peginterferon-treated patients with chronic hepatitis B who achieved early reductions in
serum HBsAg had higher likelihood of achieving SVR
● Threshold HBsAg responses: > 0.5 log10 IU/mL decrease at Week 12 and > 1.0 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, and potential for HBsAg loss
● Finite treatment duration an advantage over nucleos(t)ide analogue treatment
However, peginterferon used for first-line treatment in < 10% of all cases, 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, 24, 48, 72, and 96
HBsAg measured using 2-step chemiluminescent immunoassay
N = 48
● Median age: 44 years (interquartile range [IQR]: 38-53)
● Male: 83%
● White: 67%
● HBV genotype
A: 27%
B: 17%
C: 12%
D: 29%
E: 14%
● Median HBV DNA: 7.0 log10 copies/mL (IQR: 5.5-8.0)
● 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
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
Mean decrease at Week 12: 0.8 ± 0.5 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, 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, %
Week 12 Week 24
Positive predictive value 89 92
Negative predictive value 90 97
Among patients with SVR, 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, 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, log10 IU/mL (± SD)
(n = 3) (n = 9)
Week 12 0.7 (± 1.0) 0.8 (± 0.4)
Week 24 2.0 (± 0.9) 1.4 (± 0.5)
Week 48 2.9 (± 1.8) 2.0 (± 1.0)
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 = .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, log10 copies/mL (± SD) (n = 18) (n = 12) (n = 18)
Week 12 2.2 (± 1.7)* 4.1 (± 1.9) 3.0 (± 1.7)†
Week 24 2.2 (± 2.3)* 5.1 (± 1.9) 4.2 (± 1.4)†
*P ≤ .01 vs patients with SVR.
†
P ≥ .1 vs patients with SVR.

Reference
Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained
virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology.
2009;49:1151-1157.

Early HBsAg Drop: A Tool to Predict SVR in HBeAg-Negative Patients
Receiving Peginterferon alfa-2a
Ira M. Jacobson, MD
In a study by Moucari and colleagues,[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). 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. 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 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). Conversely,
patients with no significant decline in HBsAg failed to achieve SVR. Although HBV DNA reductions during
the first 24 weeks of therapy were predictably greater in patients attaining SVR vs nonresponders, those
with eventual relapse were found to have similar HBV DNA reductions during this time period as did those
with eventual SVR. Notably, however, relapsers had only a minimal decline in HBsAg titers on therapy
compared with sustained responders. Three of the 48 patients in the study had HBsAg loss; 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. These data led investigators to determine that a
decrease in serum HBsAg of 0.5 log10 IU/mL and 1.0 log10 IU/mL at Weeks 12 and 24, respectively, had
negative predictive values for SVR of 90% and 97%, respectively, and positive predictive values of 89%
and 92%, respectively.
The major implication of the study is that a decline in serum HBsAg is an important marker of sustained
suppression of HBV DNA (ie, SVR) after peginterferon is discontinued in patients who become HBV DNA
negative while receiving therapy. Indeed, a decline in HBsAg appears to be a prerequisite for attaining
SVR. Failure to achieve a decline in HBsAg level does not preclude the possibility of virologic response
while receiving treatment, but it predicts failure to maintain that response after peginterferon therapy is
stopped. In other words, whatever biologic events are necessary for SVR to occur are reflected in a
decline in HBsAg titer. This event may be a greater decline in intrahepatic cccDNA levels, which has
[2]
previously been suggested to correlate with serum HBsAg decline, possibly because of a greater
degree of immunologically mediated loss of HBV-infected hepatocytes.
Many clinicians in the United States do not use peginterferon for chronic hepatitis B. However, 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- to 2-year courses of oral therapy. For the
clinician, the results of the Moucari and colleagues study, particularly if confirmed in other studies, 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. This indicator would
signal whether peginterferon therapy should be stopped or switched to an oral agent. (This is analogous
to the 12-week time point in HCV therapy, at which time it is futile to continue treating with peginterferon
and ribavirin if HCV RNA has not declined by > 2 log10 IU/mL.) A current limitation of this approach is the
lack of widespread availability of quantitative HBsAg testing in commercial labs. Nevertheless, this paper
is an important addition to recent literature focusing on the significance of serum HBsAg titer in patients
with chronic hepatitis B. Overall, 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.
REFERENCES
1. Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained
virological response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatology.
2009;49:1151-1157.
2. Chan HL, Wong VW, Tse AM, et al. Serum hepatitis B surface antigen quantitation can reflect
hepatitis B virus in the liver and predict treatment response. Clin Gastroenterol Hepatol.
2007;5:1462-1468.
Literature Supports Use of Rifaximin for Hepatic Encephalopathy, but Large
Randomized Studies Still Needed
Combined analysis of rifaximin studies[1]

Results from 14 clinical studies show efficacy of rifaximin superior to that of lactulose, similar
to that of paromomycin, 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, with only mild gastrointestinal (GI) upset typically observed
Cost of rifaximin markedly higher than that of conventional therapies, but reductions in
frequency and duration of hospitalizations may make rifaximin cost-effective
Efficacy and safety of rifaximin for HE needs confirmation in large, randomized, prospective
trials
Background
Neuropsychiatric syndrome HE observed in some patients with liver dysfunction
● Thought to occur when toxins accumulate in the gut, eventually infiltrating brain
tissue and altering neurotransmission
● Current treatment options include agents that reduce gut toxin levels (eg,
nonabsorbable disaccharides and antibiotics)
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]

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, presence and intensity of asterixis, time
taken to perform the number connection test, electroencephalogram (EEG)
abnormalities, and blood ammonia level
● HE grade determined by West Haven Criteria[3]

Main Findings
Dose-finding study
● 54 patients with HE randomized to receive rifaximin 600, 1200, or 2400 mg/day for 7
days
● All doses improved PSE index vs baseline, 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
However, lactulose underdosed (ie, < 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,
asterixis, and EEG irregularities in both arms,
but rifaximin associated with significantly
Randomized to rifaximin faster time to improvement vs lactulose
58 patients with
Bucci et al[4] 1.2 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 1.2 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 1.2 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
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

Lactitol comparator studies demonstrated improved outcomes with rifaximin vs lactitol

• 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, < Randomized to rifaximin
• Higher proportion of rifaximin- vs lactitol-treated
Mas et al[8] 2 days of onset, 1.2 g/day vs lactitol 60
patients attained clinical resolution (53% vs
and evidence of g/day for 5-10 days
37%), but difference not statistically significant
PSE
• Mean improvement in HE significantly greater
with rifaximin vs lactitol (70.0% vs 61.5%,
respectively; P < .01)
• HE normalization in all arms, although rates
numerically higher in rifaximin arms (33% vs
20% vs 36%; 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%; P < .05) and blood
ammonia (92% vs 40% vs 91%; P < .05)
Neomycin comparator studies demonstrated comparable efficacy between rifaximin and

neomycin

• Both groups showed similar improvements in
psychometric performance, EEG abnormalities,
Randomized to rifaximin
[10] 30 patients with ammonia levels, and PSE index
Pedretti et al 1.2 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
chronic/permane vs neomycin 4.5 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- • Both groups showed similar significant
[5] 35 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 1.2 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

3 studies compared open-label rifaximin 1.2 g/day vs paromomycin 1.5 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, with minor GI upset usually reported as the most
common adverse event
Other Outcomes
2 studies evaluated costs associated with rifaximin[16,17]
● In 1 study, although total monthly drug cost was $570 higher for rifaximin vs
lactulose, 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, fewer hospitalizations,
fewer days of hospitalization, and lower hospitalization charges
References
1. Maclayton DO, Eaton-Maxwell A. Rifaximin for treatment of hepatic encephalopathy. Ann
Pharmacother. 2008;Dec 17:[Epub ahead of print].
2. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy:

systematic review of randomised trials. BMJ. 2004;328:1046.
3. Mullen KD. Review of the final report of the 1998 Working Party on definition, nomenclature and
diagnosis of hepatic encephalopathy. Aliment Pharmacol Ther. 2007;25(suppl 1):11-16.
4. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin and
lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin.
1993;13:109-118.
5. Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment of chronic hepatic encephalopathy:
results of a multicenter study of efficacy and safety. Curr Ther Res. 1993;54:598-609.
6. Puxeddu A, Quartini M, Massimetti A, Ferrieri A. Rifaximin in the treatment of chronic hepatic

encephalopathy. Curr Med Res Opin. 1995;13:274-281
7. Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of hepatic
encephalopathy: a prospective randomized study. Yonsei Med J. 2005;46:399-407.
8. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic
encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol.
2003;38:51-58.
9. Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vecchio Blanco C. Cyclic treatment of chronic
hepatic encephalopathy with rifaximin: results of a double-blind clinical study. Minerva Gastroenterol
Dietol. 2003;49:53-62.
10. Pedretti G, Calzetti C, Missale G, Fiaccadori F. Rifaximin versus neomycin on hyperammoniemia in

chronic portal systemic encephalopathy of cirrhotics: a double-blind, randomized trial. Ital J Gastroenterol.
1991;23:175-178.
11. Di Piazza S, Filippazzo MG, Valenza LM, et al. Rifaximin versus neomycin in the treatment of
portosystemic encephalopathy. Ital J Gastroenterol. 1991;23:403-407.
12. Miglio F, Valpiani D, Rossellini SR, Ferrieri A. Rifaximin, a non-absorbable rifamycin, for the treatment
of hepatic encephalopathy: a double-blind, randomised trial. Curr Med Res Opin. 1997;13:593-601.

13. De Marco F, Amato PS, D’Arienzo A. Rifaximin in collateral treatment of portal-systemic
encephalopathy: a preliminary report. Curr Ther Res. 1984;36:668-674.
14. Testa R, Eftimiadi C, Sukkar GS, et al. A non-absorbable rifamycin for treatment of hepatic
encephalopathy. Drugs Exp Clin Res. 1985;11:387-392.
15. Parini P, Cipolla A, Ronci M, et al. Effect of paromomycin in the treatment of portal-systemic
encephalopathy. Curr Ther Res. 1992;52:34-39.
16. Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus
lactulose in the management of hepatic encephalopathy. Transplant Proc. 2006;38:3552-3555.
17. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of
hepatic encephalopathy. Dig Dis Sci. 2007;52:737-741.

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

symptoms, and health-related quality of life. Hepatology. 2007;46:949-950.
2. Kalaitzakis E, Simrén M, Olsson R, et al. Gastrointestinal symptoms in patients with liver

cirrhosis: associations with nutritional status and health-related quality of life. Scand J
Gastroenterol. 2006;41:1464-1472.
3. Bajaj J, Bell D, Sanyal A, Gavis E, Heuman D. Gastrointestinal adverse effects of lactulose can
precipitate recurrent hepatic encephalopathy through non-compliance or overuse. Program and
abstracts of the 44th Annual Meeting of the European Association for the Study of the Liver; April
22-26, 2009; Copenhagen, Denmark. Abstract 177.
4. Williams R, James OF, Warnes TW, Morgan MY. Evaluation of the efficacy and safety of rifaximin
in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre
study. Eur J Gastroenterol Hepatol. 2000;12:203-208.
5. Bucci L, Palmieri GC. Double-blind, double-dummy comparison between treatment with rifaximin
and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res
Opin. 1993;13:109-118.
6. Festi D, Mazzella G, Orsini M, et al. Rifaximin in the treatment of chronic hepatic encephalopathy:
results of a multicenter study of efficacy and safety. Curr Ther Res. 1993;54:598-609.
7. Paik YH, Lee KS, Han KH, et al. Comparison of rifaximin and lactulose for the treatment of
hepatic encephalopathy: a prospective randomized study. Yonsei Med J. 2005;46:399-407.
8. Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus
lactulose in the management of hepatic encephalopathy. Transplant Proc. 2006;38:3552-3555.
9. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the
treatment of hepatic encephalopathy. Dig Dis Sci. 2007;52:737-741.
10. Maclayton DO, Eaton-Maxwell A. Rifaximin for treatment of hepatic encephalopathy. Ann
Pharmacother. 2008;Dec 17[Epub ahead of print].
11. Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus nonabsorbable
disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J
Gastroenterol Hepatol. 2008;20:1064-1070.
12. Lawrence KR, Klee JA. Rifaximin for the treatment of hepatic encephalopathy. Pharmacotherapy.
2008;28:1019-1032.
13. Kamath PS. The need for better clinical trials. Hepatology. 2008;48:1-3.
14. Bass N, Mullen K, Sigal S, et al. Rifaximin is effective in maintaining remission in hepatic
encephalopathy: results of a large, randomized, placebo-controlled trial. Program and abstracts of
the 44th Annual Meeting of the European Association for the Study of the Liver; April 22-26,
2009; Copenhagen, Denmark. Abstract 93.
Fatigue Experienced by Patients With Hepatic Encephalopathy Associated With
Impaired Driving Performance
Observational study with age- and education-matched controls

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, among other
impairments
● MHE: deficits in executive functions and visuomotor coordination
● OHE: cognitive dysfunction, psychomotor slowing, 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

Individuals consecutively enrolled from hepatology clinics at Medical College of Wisconsin
● Inclusion criteria
Cirrhotic
Current driver
For patients with MHE: minimental status examination score > 25
● Exclusion criteria
Psychoactive drug use
Alcohol abuse within < 3 months
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- and education-matched individuals from
community
Assessments
● Psychometric testing
Using Wechler’s adult intelligence scale-III: number connection test-A,
number connection test-B, digit symbol test, and block design test
Inhibitory control test
● American Medical Association survey for evaluation of driving safety in older adults

● Driving simulation lasting ≥ 28 minutes
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
100 cirrhotic patients and 67 age- 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, yrs (SD) 51 (4) 55 (6) 52 (7)
Mean education, yrs (SD) 12 (5) 14 (6) 13 (2)
Child-Pugh-Turcotte distribution (A, B, C) 23,4,0 43,6,2 18,4,0
Variceal bleeding, % 19 22 22
Chronic hepatitis C, % 67 63 64
Alcoholic etiology, % 19 16 22
Average bowel movements/day* 1 1 3
*P = .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

Only patients with MHE showed statistically significant increase in collisions in second half of
driving simulator vs first half (mean: 1.3 vs 0.7 collisions, respectively), indicative of fatigue
● MHE patients also showed statistically significant worsening of speeding violations
(mean: 1.2 vs 0.6 violations, respectively) and center crossings (mean: 7.6 vs 4.3
crossings, 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, 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%; P = .02) and controls (6%; P = .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, Hafeezullah M, Zadvornova Y, et al. The effect of fatigue on driving skills in patients with hepatic
encephalopathy. Am J Gastroenterol. 2009;Mar 10:[Epub ahead of print].

Innovative Investigation of Fatigue, 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. Possibly related to
some of these symptoms, several studies have shown that cirrhotic patients have impaired driving
abilities compared with the general population.[1-3] The current study conducted by Bajaj and colleagues[4]
was able to elucidate some of these nonspecific, 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).
Bajaj and colleagues enrolled 100 patients with cirrhosis and classified them as having overt HE, minimal
HE, or no evidence of minimal HE. Individuals with or without minimal HE were classified as such based
on the results of several psychometric tests, whereas individuals with overt HE were defined as having
demonstrated overt signs of HE and were currently receiving chronic treatment with lactulose. A group of
67 healthy age-matched and education-matched individuals from the community served as controls. In
addition to undergoing psychometric testing, all study participants underwent a driving simulation and
completed the American Medical Association (AMA) survey for evaluating driving safety in older adults.
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. 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. The effect of
fatigue on collision rates was quite dramatic. Patients with minimal HE had a statistically significantly
higher collision rate compared with the other groups, 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, indicating
fatigue. 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, as one of its 20 questions, asks if
patients feel tired after driving. Using that information, the investigators identified a very strong correlation
between actual self-reported fatigue after driving and collisions during the driving simulator, which were
more frequent in both overt HE patients and minimal HE patients vs controls and cirrhotic patients without
minimal HE.
As a physician who specializes in 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. It has been the
assumption that driving problems observed in cirrhotic patients are reversible with treatment. Indeed, the
very definition of HE is that the brain dysfunction caused by liver disease is reversible. Although this study
did not directly ask whether HE is reversible with lactulose therapy, it perhaps raises the possibility that it
is not.
In summary, 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, it appears that patients with
even minimal HE have greater impairment than either cirrhotics with no HE or healthy controls. For the
latter question, follow-up studies are needed to confirm the reversibility of driving deficits in cirrhotics with
HE following treatment. If one of our standard treatments is not reversing it, this is cause for concern.
REFERENCES
1. Bajaj JS, Saeian K, Hafeezullah M, Hoffmann RG, Hammeke TA. Patients with minimal hepatic
encephalopathy have poor insight into their driving skills. Clin Gastroenterol Hepatol.
2008;6:1135-1139.
2. Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill impairment: another dimension of
the driving difficulties in minimal hepatic encephalopathy. Hepatology. 2008;47:596-604.
3. Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K. Minimal hepatic encephalopathy: a vehicle for
accidents and traffic violations. Am J Gastroenterol. 2007;102:1903-1909.
4. Bajaj JS, Hafeezullah M, Zadvornova Y, et al. The effect of fatigue on driving skills in patients with
hepatic encephalopathy. Am J Gastroenterol. 2009;Mar 10[Epub ahead of print].
To receive free CME credit for this article,
Please complete the following Posttest online at:
clinicaloptions.com/HEPJO
POSTTEST
Click on the appropriate response below.
1. Which of the following statements is TRUE regarding results of the PROVE 1 study, 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. Coadministering telaprevir with peginterferon/ribavirin resulted in significantly higher

sustained virologic response (SVR) rates vs standard therapy
B. Coadministering telaprevir with peginterferon/ribavirin resulted in significantly lower SVR
rates vs standard therapy
C. Coadministering telaprevir with peginterferon/ribavirin resulted in similar SVR rates vs
standard therapy
2. Is the following statement TRUE or FALSE? In the literature review by Maclayton and
colleagues, rifaximin displayed superior efficacy to other treatment options for hepatic
encephalopathy, including lactulose, paromomycin, and neomycin.
A. True
B. False
3. According to 2 randomized, double-blind, phase III trials of tenofovir vs adefovir for the
treatment of chronic hepatitis B, 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. Tenofovir was superior to adefovir regarding the primary endpoint for HBeAg-positive patients
but not for HBeAg-negative patients
C. Tenofovir was superior to adefovir regarding the primary endpoint for both HBeAg-negative
and HBeAg-positive patients
D. Tenofovir was not superior to adefovir regarding the primary endpoint in either HBeAg-
negative or HBeAg-positive patients
4. 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. Maintenance therapy resulted in reductions in alanine aminotransferase and HCV RNA levels
but without improvement in clinical outcomes
B. Maintenance therapy resulted in reductions in hepatic decompensation and hepatocellular
carcinoma
C. Maintenance therapy had no measureable effect on biochemical markers or clinical outcomes

5. According to the results of the DIRECT trial of consensus interferon for the treatment of
HCV nonresponders, which of the following statements is TRUE?
A. 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. SVR rates were highest for patients who had an HCV RNA decrease of > 2 log10 during
C. SVR rates were highest for patients who had an HCV RNA decrease of 1-2 log10 during
D. SVR rates were highest for patients who had an HCV RNA decrease of 1-2 log10 during

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JOURNAL OPTIONS COLLECTION

Hepatitis Journal Options – Volume 3, Issue 2

PROGRAM DIRECTOR FACULTY

Jointly sponsored by Postgraduate Institute for

This activity is supported by educational grants from:

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

Daryl T-Y Lau, MD, MSc, MPH

Richard K. Sterling, MD, MSc, FACP, FACG

Taryn O’Loughlin Gross, PhD

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

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

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

Edward King, MA, has no significant financial relationships to disclose.

Taryn O’Loughlin Gross, PhD, has no significant financial relationships to disclose.

Kara Nyberg, PhD, has no significant financial relationships to disclose.

DISCLOSURE OF UNLABELED USE

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 4

INSTRUCTIONS FOR CREDIT

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 5

McHutchinson-NEJM-2009: Telaprevir for chronic HCV genotype 1 infection ............................................. 7

Di Bisceglie-NEJM-2008: Maintenance HCV therapy with low-dose peginterferon .................................. 15

Lok-Gastroenterol-2009: HCC in hepatitis C–related advanced liver disease ........................................... 21

Bacon-Hepatology-2008: Consensus interferon/ribavirin retreatment for peginterferon/ribavirin

Rossignol-Hepatology-2008: Improved response rates in chronic hepatitis C with nitazoxanide .............. 35

Marcellin-NEJM-2008: Tenofovir for chronic hepatitis B............................................................................. 41

Maclayton-Ann_Pharmacother-2009: Rifaximin for hepatic encephalopathy............................................. 54

Bajaj-AJG-2009: Effect of fatigue on driving skills in hepatic encephalopathy patients ............................. 61

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 6

 PROVE 1: multicenter, randomized, double-blind, placebo-controlled, phase IIb trial

Summary of Key Conclusions

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

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

12-Wk TVR + 24- 12-Wk TVR + 48-

Description of Current Analysis

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

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 4

12-Wk TVR + 24- 12-Wk TVR + 48-

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 5

 HALT-C: prospective, randomized, controlled trial[1]

Summary of Key Conclusions

Schematic of Study Design

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

Description of Current Analysis

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

 Most common clinical outcomes were increase of ≥ 2 points in Child-Turcotte-Pugh score

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

Peginterferon No Treatment Difference

 Overall, no significant difference in mortality rates between groups

 Higher proportion of patients receiving peginterferon vs no treatment had ≥ 1 serious adverse

Copyright © 2009 Clinical Care Options, LLC. All rights reserved. 4

 Analysis of prospectively gathered data from HALT-C randomized trial[1]

Summary of Key Conclusions

Schematic of Study Design

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

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

Description of Current Analysis

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

PROVE 1: multicenter, randomized, double-blind, placebo-controlled, phase IIb trial

HALT-C: prospective, randomized, controlled trial[1]

Most common clinical outcomes were increase of ≥ 2 points in Child-Turcotte-Pugh score

Overall, no significant difference in mortality rates between groups

Higher proportion of patients receiving peginterferon vs no treatment had ≥ 1 serious adverse

Analysis of prospectively gathered data from HALT-C randomized trial[1]

Cox proportional hazards model developed to predict risk for HCC

Other factors associated with SVR

Randomized, open-label, controlled, phase II trial[1]

Exploratory analysis of per-protocol population yielded similar response rates to those

Studies 102 and 103: randomized, double-blind, phase III trials

No tenofovir-associated resistance mutations identified in any tenofovir-treated patients

Prospective, single-arm study

Combined analysis of rifaximin studies[1]

Neomycin comparator studies demonstrated comparable efficacy between rifaximin and

Observational study with age- and education-matched controls