59th American Association for the Study of Liver Diseases Meeting 59th AASLD

1




59th American Association for the Study of Liver
Diseases Meeting (59th AASLD)
San Francisco, CA October 31-November 4, 2008
2
Accreditation and Designation
Rush University Medical Center is accredited by
the Accreditation Council for Continuing Medical
Education to provide continuing medical education
for physicians. Rush University Medical Center
designates this educational activity for a
maximum of 1 AMA PRA Category 1 Credit.
Physicians should only claim credit commensurate
with the extent of their participation in the
activity.
Supported by an independent educational grant
from Gilead Sciences Medical Affairs.
3
Faculty CME Course Director
S. Martin Cohen, MD Associate Professor of
Medicine Director, Section of Hepatology Rush
University Medical Center Chicago, Illinois
4
Faculty Content Development
Yves Benhamou, MD Associate Professor of
Hepatology Chief of Department Clinical Research
in Hepatology Hospital of Paris Paris, France
Douglas T. Dieterich, MD, Professor of
Medicine Division of Liver Diseases Mount Sinai
School of Medicine New York, New York
Paul Y. Kwo, MD Associate Professor of Medicine
Division of Gastroenterology Indiana University
School of Medicine Indianapolis, Indiana Mark
S. Sulkowski, MD Associate Professor of
Medicine Johns Hopkins University School of
Medicine Medical Director, Viral Hepatitis
Center Johns Hopkins Medical Institution Baltimore
, Maryland
5
Disclosure Information

• It is the policy of the Rush University Medical
  Center Office of Continuing Medical Education to
  ensure that its CME activities are independent,
  free of commercial bias and beyond the control of
  persons or organizations with an economic
  interest in influencing the content of CME
• Everyone who is in a position to control the
  content of an educational activity must disclose
  all relevant financial relationships with any
  commercial interest (including but not limited to
  pharmaceutical companies, biomedical device
  manufacturers, or other corporations whose
  products or services are related to the subject
  matter of the presentation topic) within the
  preceding 12 months
• If there are relationships that create a conflict
  of interest, these must be resolved by the CME
  Course Director in consultation with the Office
  of Continuing Medical Education prior to the
  participation of the faculty member in the
  development or presentation of course content

6
Disclosure Information CME Course Director

• S. Martin Cohen, MD
• Grants/Research Support Gilead Sciences, Idenix,
  Roche
• Consultant Gilead Sciences, Roche,
  Schering-Plough
• Speakers Bureau Gilead Sciences, Roche,
  Schering-Plough
• Honoraria None
• Stock Shareholder None
• Other Financial or Material Support None

7
Disclosure Information Content Faculty

• Yves Benhamou, MD
• Grants/Research Support Abbott, Idenix,
  Schering-Plough
• Consultant Boehringer Ingelheim, Gilead
  Sciences, Human Genome Sciences, Idenix,
  Novartis, Roche, Valeant, Vertex
• Speakers Bureau Boehringer Ingelheim,
  Bristol-Myers Squibb, Gilead Sciences, Human
  Genome Sciences
• Stock Shareholder None
• Other Financial or Material Support None
• Douglas T. Dieterich, MD
• Grants/Research Support Boehringer Ingelheim,
  Bristol-Myers Squibb, Gilead Sciences, Idenix,
  Roche
• Consultant Boehringer Ingelheim, Bristol-Myers
  Squibb, Gilead Sciences, Idenix, Roche
• Speakers Bureau Boehringer Ingelheim,
  Bristol-Myers Squibb, Gilead Sciences, Idenix,
  Roche
• Stock Shareholder None
• Other Financial or Material Support None

8
Disclosure Information Content Faculty

• Paul Y. Kwo, MD
• Grants/Research Support Celgene, Glaxo Smith
  Klein, Merck, Novartis, Roche, Schering-Plough,
  Valeant, Vertex
• Consultant Bayer, Celgene, Novartis,
  Schering-Plough, Vertex
• Speakers Bureau Roche, Schering-Plough,
  Novartis, Valeant
• Stock Shareholder None
• Other Financial or Material Support None
• Mark S. Sulkowski, MD
• Grants/Research Support Debiopharm, Human Genome
  Sciences, Merck, Roche, Schering-Plough, Valeant,
  Vertex
• Consultant Human Genome Sciences, Merck, Roche,
  Schering-Plough, Vertex, Wyeth
• Speakers Bureau None
• Stock Shareholder None
• Other Financial or Material Support None

9
Learning Objectives (CME, CE, CPE)

• Upon the completion of this activity,
  participants should be able to
• Discuss significant developments in the diagnosis
  and management of hepatitis B
• Summarize new drugs and treatment strategies for
  hepatitis B
• Describe toxicity of recent hepatitis therapies,
  drug side effects, and strategies for management
• Identify new therapeutic strategies to avoid or
  overcome antiviral resistance
• Highlight diagnosis and management approaches for
  hepatitis B in individuals co-infected with HIV

10
59th American Association for the Study of Liver
Diseases Meeting (59th AASLD)

• San Francisco, CA
• October 31-November 4, 2008

11
Epidemiology and Natural History of HBV Infection

• Douglas Dieterich, MD
• Mount Sinai School of Medicine
• New York, NY

12
Estimated Prevalence of Chronic Hepatitis B in
Foreign-Born Persons Living in the United States

• Centers for Disease Control (CDC) estimates that
  million) are living with CHB
• Published estimates of CHB in foreign-born (FB)
  populations in the U.S. vary and are limited
• Recent studies taking into account all FB
  estimate prevalence of CHB in U.S. at 2.0
  million persons
• Study to determine estimated prevalence of CHB in
  FB persons in U.S.
• U.S. census data used to estimate number of FB
  persons in U.S. from 93 countries/regions
• Published CHB prevalence rates by
  countries/regions used to model low, mid and high
  rates of CHB each
• Number of FB persons with CHB estimated by
  multiplying each FB population by its prevalence
  rate

Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
13
Total and Foreign-Born U.S. Population, 1970-2008

• FB persons living in the U.S. increased from 20
  million in 1990 to 41 million in 2008

4.7 FB
7.9 FB
13.6 FB
450
45
400
40
350
35
300
30
Other Asia Latin America Europe Total US
Population
250
25
Total U.S. Population (millions)
Foreign-born U.S. Population (millions)
200
20
150
15
100
10
50
5
0
0
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
14
Published CHB Prevalence Rates and Low, Mid, and
High CHB Rate Assumptions China
Lower RiskGroups
Higher RiskGroups
CHB Prevalence Rates China
Chinese-bornpersons inNYC
Mid Estimate13.6
Low Estimate10.0
High Estimate17.0
25
20
Chinese-bornpersons inUK
Chinese-bornpersons inSan Francisco
Percent HBsAg-positive
15
10
5
0
Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
15
Published CHB Prevalence Rates and Low, Mid, and
High CHB Rate Assumptions India
Lower RiskGroups
Higher RiskGroups
CHB Prevalence Rates India
Low, Mid and High rate estimate
assumptions Published CHB rate from review or
model Published CHB rate from population
study Number in parentheses sample size
12
Mid Estimate1.0
11
Low Estimate0.2
High Estimate20.
10
9
8
7
Percent HBsAg-positive
6
5
4
3
2
1
0
Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
16
Percent of FB Population and FB with CHB by
Place of Birth
China
Vietnam
Philippines
Korea
India
Other Asia
Mexico
El Salvador
Caribbean
South America
Place of Birth
Other Latin America
Total FB Population () FB with CHB (, mid
estimate)
Western Africa
Eastern Africa
Other Africa
Asia South/Latin America Africa Europe/Oceania Nor
th America
Eastern Europe
Southern Europe
Other Europe
Oceania
North America
0
5
10
15
20
25
30
35
Percent in U.S.
Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
17
Study Results

• Number of FB with CHB in the U.S. ranges from
  850,000 to 2,240,000 persons
• 5262 from Asia
• 1315 from Africa
• 918 from Central America
• Average CHB prevalence rate among the FB is
  2.05.4

Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
18
New CDC RecommendationsHBV Screening for FB
Persons from Countries with Intermediate HBV
Prevalence Rates (2)
CDC List of Countries with Hepatitis B Prevalence
2
Region
HBsAg prevalence 2
Africa
All countries
Asia
All countries
Australia and South Pacific
All countries except Australia and New Zealand
Middle East
All countries except Cyprus and Israel
Eastern Europe
All countries except Hungary
Western Europe
Malta, Spain, and indigenous populations in
Greenland
North America
Alaska Natives and indigenous populations in
Northern Canada
Mexico and Central America
Guatemala and Honduras
South America
Ecuador, Guyana, Suriname, Venezuela, and
Amazonian areas of Bolivia, Brazil, Columbia, and
Peru
Caribbean
Antigua-Barbuda, Dominica, Grenada, Haiti,
Jamaica, St. Kitts-Nevis, St. Lucia, and Turks
and Caicos Islands
September, 2008 change from 8
Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
19
Study of FB Persons in U.S. with CHB Conclusions

• Number of FB with CHB in U.S. may be higher than
  previously thought
• High CHB prevalence rate and related morbidity
  and mortality argue for building surveillance
  systems
• Will help develop programs for prevention,
  earlier diagnosis and linkage to care
• New CDC recommendations extending screening to FB
  persons from countries with intermediate HBV
  prevalence could identify more than 250,000
  additional FB persons with CHB

Welch S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 853.
20
Evaluation of ALT Determination for Assessing
Chronic Hepatitis B (CHB)

• Study of 1,335 CHB patients enrolled into
  registration trials of TDF and ADV to evaluate
• Concordance between 2 ALT values 60 days apart
• Liver histology with a single normal range ALT
  (NRALT)
• Risk factors for significant liver disease
• Association of established (Men 43 U/L Women
  34 U/L) and new (Men 30 U/L Women 19 U/L) ALT
  ULN values with liver disease severity
• Pretreatment ALT measured on 2 occasions
  (screening, baseline)
• All patients had 1 screening ALT ULN
• Intermittent ALT elevation, 1 NRALT (IE ALT)
• Persistent ALT elevation, all ALT values ULN (PE
  ALT)
• All patients had a liver biopsy between screening
  and baseline visits

Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
21
Patient Demographics andDisease Characteristics
IE ALT (n60)
PE ALT (n275)
P value
Age (yrs) mean SD range 40 yrs old
39.4 11.5 20-65 32 (53.3)
38.8 12.0 16-69 607 (47.6)
0.658
Gender ( men)
63
76
0.031
Race ( Asian)
42
41
0.930
HBeAg positive
17 (28)
748 (58.8)
Baseline HBV DNA (log10 copies/mL) mean SD
range
6.3 1.3 3.6-9.0
7.8 1.2 2.2-10.9
Baseline ALT (U/L) mean SD range
44.6 31.6 6-223
144.2 127.0 36-1459
Intermittent ALT elevation, 1 NRALT
Persistent ALT elevation, all ALT values
ULNALT ULN Men 43 U/L Women 34 U/L
Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
22
Liver Histology in Patients with Intermittently
vs. Persistently Elevated ALT
Knodell Fibrosis Score
3
Knodell Necroinflammat
o
r
y
S
c
o
re
6
100
100
80

80
80
P1
993/1247
P0.03
0
56

60
60
of Patients
of Patients
47

33/59
40
40
581/1246
32

19/59
20
20
0
0
I
E A
L
T
P
E A
LT
I
E A
L
T
P
E A
L
T
ALT ULN Men 43 U/L Women 34 U/L
Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
23
Normal ALT at Baseline in IE ALT Patients with
Significant Liver Disease
1
0
0
89

79

8
0
17/19
17
/
1
9
26/33
26
/
3
3
6
0
of Patients with NRALTat Baseline
4
0
at Baseline
2
0
of Patients with NRALT
0
Knodell Fibrosi
s
K
nod
e
l
l
Necroinflammatory
ALT ULN Men 43 U/L Women 34 U/L
Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
24
Results Using Established ALT ULN

• No Demographic or Disease Characteristics
  associated with Significant Liver Disease
• In patients with IE ALT using established ALT,
  none of the following associated with Knodell
  fibrosis score 3 or Knodell necroinflammatory
  score 6
• Age (below/above 40 years old)
• Gender
• Asian/non-Asian ethnicity
• HBeAg status
• HBV viral genotype
• Baseline ALT
• Baseline HBV DNA

Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
25
Patients with Elevated ALTLiver Fibrosis and
Eligibility for CHB Tx
Est. ALT ULN
New ALT ULN
100
90
88
90
80
72
65
70
60
50
40
30
20
10
0
Knodell Fibrosis Score ?3
Eligibility for Tx
ALT ULN Men 43 U/L Women 34 U/L ALT ULN
Men 30 U/L Women 19 U/L
Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
26
Study of ALT in CHB Conclusions

• Patients with IE ALT with established ALT ULN
  often have significant liver disease, which
  cannot be excluded by a single normal ALT test
• Early repeat testing of normal ALT (e.g., 2
  months interval) in CHB patients may
• reveal elevated ALT
• identify patients with underlying liver disease
• Using New ALT ULN
• Most patients with significant underlying liver
  disease have ALT 2 X ULN
• 34 more patients are eligible for treatment

Heathcote EJ, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 850.
27
Age Specific Prognosis AfterHBeAg Seroconversion

• Cohort Study of CHB prognosis in different age
  groups following spontaneous HBeAg seroconversion
• 441 HBeAg seroconversion followed 1 year
• At seroconversion
• 388
• 53 40 years of age
• Annual Incidence of CHB-related complications for
  entire population
• 1.9 Hepatitis relapse
• 0.2 Development of cirrhosis
• 0.6 Development of hepatocellular carcinoma
• All significantly higher among HBeAg
  seroconverters 40 years
• Hepatitis relapse (P0.005)
• Development of cirrhosis (P
• Development of hepatocellular carcinoma (P0.024)
• Conclusion After HBeAg seroconversion, patients
  are still at risk for CHB-related complications,
  especially if 40 years at seroconversion

Chen Y-C, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 815.
28
Perinatal Transmission of HBVEffect of Viral
load and HBeAg Status

• Study to evaluate the rate of and maternal
  virologic factors associated with HBV perinatal
  transmission
• HBsAg pregnant women identified during antenatal
  screening
• 87 HBeAg 202 HBV DNA positive
• All infants routinely offered HBIG and HBV
  vaccination
• 124 infants tested for HBV at 9 months of age
• HBV transmission in 3 infants (2.4)
• All had mothers with HBV DNA 8 log10 c/mL and
  HBeAg
• Transmission rate 7.2 HBV DNA 8 log10 c/mL and
  5.5 HBeAg
• All uninfected infants were anti-HBs positive and
  HBsAg negative
• Perinatal transmission can occur despite
  prophylactic measures, primarily in HBeAg women
  with HBV DNA 8 log10 c/mL

Wiseman E, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 827.
29
High Prevalence of Hepatic Steatosis and Impact
on Fibrosis in HBV

• Retrospective Study to evaluate effect of hepatic
  steatosis on HBV progression
• 220 CHB pts (63 male 68 Asian 51 HBeAg)
• Overall, 34 with hepatic steatosis
• Hepatic steatosis associated with
• Male gender (40 vs. 24, P0.034)
• Older age (44 vs. 36 yrs, P
• Higher BMI (27 vs. 24, P
• Pts with hepatic steatosis more likely to have
• Hepatic fibrosis (70 vs. 56, P0.005)
• Bridging fibrosis/cirrhosis (29 vs. 16,
  P0.022)
• Similar trends for HBeAg-positive and -negative
  CHB
• No differences regarding hepatic inflammation,
  iron deposition, elevated ALT, or HBV DNA
• Conclusion Hepatic steatosis is a significant
  factor in CHB-related disease

Bleibel W, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 831.
30
Predictors of Liver-Related Morbidity and
Mortality in CHB
Baseline Characteristics (n1093)

• Retrospective study of HBsAg-positive pts
  referred to Hepatology Department of French
  Hospital since 1980 (N1300)
• Pts co-infected with HIV, HDV and HCV excluded
  (n207)
• Cox Regression analysis used to determine
  predictors of liver-related mortality and
  morbidity
• Factors assessed
• Age
• Sex
• Ethnic origin
• Alcohol consumption
• Baseline HBeAg status
• ALT
• Serum HBV DNA

HBeAg-
HBeAg
P value
Median Follow-up (Years)
5.0
6.7

Mean Age (Years)
39.6
35.0

Male ()
69.0
68.5
0.89
Caucasian/African/Asian ()
22.1/52.4/25.5
30.0/20.5/49.5

Alcohol 0/50/50 g/day ()
83.2/11.5/5.3
80.6/15.3/4.1
0.27
HBV DNA
47.8/20.9/19.0
3.0/7.0/84.5

Median ALT (IU/L)
32
62.5
0.09
Anti-HBV Tx ()
46.7
81.0

Liver Decompensation ()
8.0
11.0
0.16
HCC ()
3.8
3.5
0.84
Liver-related Death ()
3.2
3.5
0.86
Liver Transplantation ()
0.3
1.0
0.21
Ngo Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 1944.
31
Factors Associated withComplications of HBV
1.00
ALT 1.00
HBV DNA 0.75
0.75
HBV DNA 4 log
ALT 2xULN
0.50
0.50
0.25
0.25
Elevated ALT
HBV DNA Level
0.00
0.00
667
800
533
400
267
133
0
667
800
533
400
267
133
0
Survival without Complications ()
Female
1.00
1.00
35 years of age
0.75
Male
0.75
0.50
0.50
0.25
0.25
Age
Gender
0.00
0.00
667
800
533
400
267
133
0
667
800
533
400
267
133
0
Follow-up (Months)
Follow-up (Months)
Ngo Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 1944.
32
Multivariate Analysis of Factors Associated with
Liver-related Morbidity and Mortality
Factor
Risk Ratio
95 CI
P value
Age 35 years
1.06
1.04-1.07
Male Gender
1.95
1.07-3.55
0.03
Elevated ALT
1.00
1.00-1.00
0.0001
Alcohol 50 g/day
1.00
1.00-1.01
0.0004
HBV DNA 4 log
1.81
1.07-3.03
0.03

• Conclusions
• In chronic HBsAg carriers, liver-related
  morbidity and mortality are associated with
  elevated HBV DNA and ALT, older age, male gender,
  and alcohol consumption
• Reduction of alcohol consumption and HBV
  treatment may reduce liver-related morbidity and
  mortality in HBsAg carriers

Ngo Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 1944.
33
Therapeutic Strategies for HBV Treatment

• Paul Kwo, MD
• University of Indiana
• Indianapolis, IN

34
Tenofovir versus Adefovir inAsian Patients

• TDF has shown superior efficacy to ADV in
  treatment-naïve, CHB patients in 2 pivotal
  studies
• Efficacy and safety of TDF among Asian, CHB
  patients participating in TDF studies GS-174-0102
  (HBeAg) and GS-174-0103 (HBeAg) were reported

8 Years
Open-label
Double Blind
TDF 300 mg (n426)
RANDOMIZATION 21
TDF 300 mg
ADV 10 mg (n215)
Week 2405-year Liver Biopsy
Week 48 Liver BiopsyPaired biopsies in 391 TDF
(92) and 192 ADV (89)
Pre-treatment Liver Biopsy
Week 72 option forFTCTDF if viremic
Lee S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 980.
35
Tenofovir versus Adefovir in Asian Patients
Results

• 189 Asian pts were enrolled across the 2 studies
• Asians comprised 30 of all patients
• 127/426 (30) on TDF
• 62/215 (29) on ADV
• TDF demonstrated superior HBV DNA suppression
  relative to ADV in Asian patients following 48
  weeks of randomized treatment
• Efficacy, safety and resistance analyses were
  consistent with the results of the overall studies

TDF
ADV
1
0
0
MissingFailure

8
5
9
0

7
7
8
0


7
2
7
1
6
5

7
0
P
1
6
0
Percentage ()
5
0

4
2
4
0
e
3
0
P
2
0
1
0
0
H
B
V
D
N
A

400
c
/
m
l
N
o
r
m
a
l
A
L
T
H
i
s
t
o
l
og
i
c
r
e
s
pon
s
e
(
6
9
I
U
/
m
l
)
Lee S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 980.
36
Study 102 Two Year TDF Treatment and ADV Switch
Data in HBeAg(-) with CHB

• Randomized, Double-Blind, Comparison of TDF vs.
  ADV for HBeAg(-) Chronic Hepatitis B
• HBV DNA 105 c/mL and ALT ULN and
• Knodell Necroinflammatory score 3
• LAM Experienced or Naïve

• Week 48 Phase 3 data showed TDF superior to ADV
• HBV DNA (p
• 96 week data presented

Marcellin P, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 146.
37
Study 102 HBV DNA LAM Exp. 97 100
LAM Exp. 93 96

• TDF demonstrated durable, potent antiviral
  activity through Week 96
• 99 of patients on therapy had HBV DNA copies/mL
• No resistance to TDF detected after 2 years on
  TDF monotherapy

Marcellin P, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 146.
38
Study 103 Two Year TDF Treatment and ADV Switch
Data in HBeAg() with CHB

• Randomized, Double-Blind, Comparison of TDF vs.
  ADV for HBeAg() Chronic Hepatitis B
• HBV DNA 106 c/mL and ALT 2x and
• Knodell Necroinflammatory score 3
• Nucleos(t)ide Naïve

• Week 48 Phase 3 data showed TDF superior to ADV
• HBV DNA (p
• 96 week data presented

Heathcote E, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 158.
39
Study 103 HBV DNA On treatment analysis
ITT analysis
Randomized Double Blind
Open Label
Randomized Double Blind
Open Label
100
100
100
100
89
P0.374
90
90
85
78
80
80
P0.801
78
70
70
60
60
Percentage ()
Percentage ()
50
50
50
50
40
40
30
30
20
20
20
20
10
10
0
0
0
0
0
96
8
16
24
32
40
48
56
64
72
80
88
0
96
8
16
24
32
40
48
56
64
72
80
88
Weeks on Study
Weeks on Study
176 90
142 79
173 88
165 85
166 84
160 85
148 83
144 81
TDF-TDF n ADV-TDF n
176 90
165 86
174 89
170 88
172 88
171 90
168 89
164 87
TDF-TDF n ADV-TDF n

• TDF demonstrated durable, potent antiviral
  activity through Week 96
• 82 of pts viremic on ADV at week 48 were c/mL on TDF at week 96
• No resistance to TDF detected after 2 years on
  TDF monotherapy

Heathcote E, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 158.
40
Long Term Use of Tenofovir Reduces Liver Fibrosis
in HIV/HBV Co-Infection

• Study assessed the effect of TDF on liver
  fibrosis
• 130 co-infected patients treated with TDF and
  followed for a median of 29.5 months
• At baseline, 45 patients presented with
  Fibrometer stage F0-F1, 29 with stage F2, and 56
  patients with stage F3-F4
• Assessments included
• Fibrometer (platelets, prothrombin time, AST,
  a2 macroglobulin, hyaluronic acid, urea, age)
• Paired liver biopsies

Lacombe K, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 914.
41
Reduction in Fibrosis Scores by Fibrometer and
Paired Liver Biopsies
Fibrometer Paired Liver
biopsies
F0-F1(remained,n8)
1.00
0.80
n7
n0
F3-F4
DAVG Fibrometer Score
0.60
F2
F2(remained,n6)
F0-F1
n1
0.40
0.20
n4
n1
0
12
24
36
T
i
m
e
a
f
t
e
r
t
r
e
a
t
m
e
n
t
i
n
i
t
i
a
t
i
o
n
(
m
o
n
t
h
s)
F3-F4(remained,n11)

• Conclusion In HIV-HBV co-infection
  population, TDF induced a significant decrease in
  fibrosis and histologic activity level after mean
  treatment duration of 29.6 months

Lacombe K, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 914.
42
HBV Genotype is the Strongest Predictor of
Response to Interferon-Alfa Treatment

• Pooled analysis evaluating effect of HBV genotype
  on treatment outcome following IFN-a for 6-12
  mos. for CHB (N1,229)
• Standard interferon-a (n298), pegylated
  interferon-a (n491), pegylated interferon-a with
  lamivudine (n440)
• HBeAg Status positive (n703), negative (n526)
• HBV genotypes A (n174), B (n245), C (n464), D
  (n346)
• HBV genotype determined by direct sequencing of X
  or S gene
• Sustained virologic response determined 6 mos.
  after Tx and defined as
• Normalization of ALT
• HBV DNA
• In HBeAg, HBeAg seroconversion

Erhardt A, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 883.
43
HBV Genotypes as Predictors of Response to
Interferon-Alfa Multivariate Analysis
Independent Predictors for SVR
SVR by Genotype and HBeAg status
OR (95 CI)
P value
60
HBV genotype
50
A vs. D
3.620 (2.316-5.657)
0.0001
40
B vs. D
2.621 (1.618-4.245)
0.0001
SVR
30
C vs. D
3.184 (2.054-4.936)
0.0001
20
ALT 5 vs. 5 xULN
1.432 (1.056-1.940)
0.02
10
HBeAg neg. vs. pos.
2.124 (1.527-2.966)
0.0001
0
Genotype A
Genotype B
Genotype C
Genotype D

• Conclusion Multivariate analysis adjusted for
  treatment identified genotype D, HBeAg negative
  status, and elevated ALT level as independent
  predictors for failing to achieve SVR

Erhardt A, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 883.
44
ETV-060 Histologic Assessment of Long-term ETV
Treatment in CHB

• Open-label, rollover study assessed histologic
  improvement in patients who had evaluable liver
  biopsies after receiving at least 3 years of ETV
  therapy
• Subset of studies that enrolled nucleoside-naïve
  (n66) or LAM-refractory (n84) pts
• Histologic improvement defined as
• ?2-point decrease in Knodell necroinflammatory
  NI score
• 1-point decrease in Knodell fibrosis score
• Thirty-seven naive patients and 27 LAM-refractory
  patients had biopsies from 3 required time points
  (baseline, Week 48, and Week 148)

Katano Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 889.
45
Results of Histologic Assessment ofLong-term ETV
in CHB
1 point decrease Knodell fibrosis score
2 point decrease Knodell NI score


100
100
100
89
Nucleoside naïve
LAM-refractory
84
80
80
58

60
60
Patient
47

32
40
40
17
20
12
20
0
0
Week 48
Week 148
Week 48
Week 148

• Liver histology improved significantly after 3
  years of continuous ETV Tx
• Treatment beyond 48 weeks resulted in continued
  improvement in fibrosis scores in both naïve and
  LAM-refractory patients

Pbaseline)
Katano Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 889.
46
Studies ETV-022/-901 Entecavir Therapy in
HBeAg() CHB
Study Design
Week 48
Week 144
Week 96
5 Years
11 RespondersAt Week 48 or who became responders
during Year 2 who relapsed during off-treatment
follow-up
R74
R37
ETVN354
243
151 Virologic RespondersAt Week 96
VR247
VR198
21 Non-respondersAt Week 48 or who became
non-responders during Year 2
NR19
NR8
Non-responders NRHBV DNA 0.7 MEq/mL by bDNA
Responders RHBV DNA HBeAg loss
Virologic Responders VRHBV DNA bDNA and HBeAg()
Han S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 893.
47
Studies ETV-022/-901Baseline Characteristics
ETV-022(n354)
ETV-901 (n146)
Age, mean (years)
35
36
Male ()
77
80
Race Asian () Non-Asian ()
58 42
6436
HBV DNA by PCR, mean (log10 copies/mL)
9.62
9.91
ALT, mean (U/L)
140
122
HBV genotype ()
A B C D
Other
13
13
4
26
27
10
30
19
27
31
Han S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 893.
48
Studies ETV-022/-901 Proportion with HBV DNA
ETV-022
HBeAg() ETV Long-term Cohort (ETV-022?ETV-901)
Year 1
Year 2
Year 3
Year 4
Year 5
Year 1
100
94
91
89
83
80
67
60
55
Proportion of patients () HBV DNA 40
20
0
n
236/354
80/146
116/140
116/131
98/108
88/94
Han S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 893.
49
Studies ETV-022/-901Long-term HBV DNA
Suppression
HBeAg() ETV Long-term Cohort (ETV-022 ? ETV-901)
12
10
8
Mean HBV DNA (log10 copies/mL)
6
4
300 copies/mL
2
0
0
Year 1
Year 2
Year 3
Year 4
Year 5
n
146
146
140
131
108
94

• Conclusion Long-term treatment with ETV results
  in durable suppression of HBV DNA replication
  with 1 person developing ETV resistance over 5
  years of surveillance

Han S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 893.
50
Studies ETV-022, -027 and -901 Long-term ETV
Reverses Fibrosis/Cirrhosis in CHB

• Long-term histologic results for a subset of
  patients (n57) treated with ETV for a median of
  280 weeks
• Nucleoside-naïve HBeAg() and HBeAg(-) patients
  treated with ETV in studies ETV-022 or ETV-027
  who
• had a liver biopsy in study ETV-901 and
• received a minimum of 3 years cumulative ETV
  therapy
• Co-primary endpoints
• Histologic improvement (2-point decrease in
  Knodell necroinflammatory score and no worsening
  of Knodell fibrosis score) compared to baseline
• Improvement in Ishak fibrosis score (1-point
  decrease) compared to baseline

Liaw Y-F, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 894.
51
Distribution of Ishak FibrosisScores at
Baseline, Year 1, and Years 37
60
Ishak Fibrosis Score
50
40
Patients (n)
30
20
10
0
Baseline
Week 48
Long
-
term

• 96 of patients in the Long-term Histology Cohort
  who received continuous treatment with ETV
  achieved histologic improvement
• All patients with advanced fibrosis/cirrhosis at
  baseline (Ishak fibrosis score 4) demonstrated
  an improvement in fibrosis

Liaw Y-F, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 894.
52
Continued LdT Results in High Rates of Maintained
Response in HBeAg-positive Patients

• Study evaluating maintained treatment response to
  LdT at week 156
• HBeAg-positive CHB patients on LdT who achieved
  HBeAg seroconversion and undetectable HBV DNA by
  week 104 and followed to week 156

Maintained Treatment Response (HBeAg
seroconversion and HBV DNA
66/86 (76.7)
Maintained PCR Negativity (HBV DNA
73/88 (83.0)
ALT Normalization
77/85 (90.6)
Maintained HBeAg Loss
88/88 (100.0)
Maintained HBeAg Seroconversion
80/86 (93.0)
HBsAg Loss
3/88 (3.4)
HBsAg Seroconversion
1/88 (1.1)
Maintained HBeAg loss and HBV DNA copies/mL
88/88 (100.0)
Maintained HBeAg seroconversion and HBV DNA log10 copies/mL
71/86 (82.6)
Virologic Failure (HBV DNA 1000 copies/mL)
8/88 (9.1)

• Continued telbivudine treatment in patients
  results in high rates of maintained treatment
  responses and control of CHB at 3 years
• Long-term telbivudine treatment can lead to HBeAg
  clearance/seroconversion

Gane E, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 942.
53
Cost-effectiveness Simulation Analysis of TDF,
LAM, ADV and ETV in HBeAg-Negative, CHB Patients

• Study evaluating the impact of initiating
  treatment with TDF, LAM, ADV and ETV on cost and
  quality of life in HBeAg(-) patients in the
  United States
• Simulation analysis using a Markov model
  developed to predict incidence and cost of
  CHB-related complications
• Patients assumed to be treatment-naïve at
  initiation of Tx
• Assigned levels of viral suppression and risk of
  developing viral resistance specific to their
  treatment
• Patients who became resistant could switch or
  add-on another treatment
• Patients who developed resistance to initial and
  subsequent treatments were assumed to discontinue
  treatment and incidence of complications was
  modeled assuming no further viral suppression

Deniz H, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 976.
54
Results of Cost-effectivenessSimulation Analysis
 
TDF
LAM
ADV
ETV
Total pharmacy and medical cost per patient (US)
117,794
152,336
138,950
141,409
Cost of inital and subsequent HBV treatments (US)
94,781
101,990
105,449
117,648
Quality-Adjusted Life Years
10.28
8.93
9.72
10.28

• Conclusion Although the long term medical costs
  associated with care and treatment of HBeAg
  negative patients are not completely known, this
  study suggests that TDF will be a more
  cost-effective treatment than LAM, ADV, and ETV.

Deniz H, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 976.
55
New Therapies and Strategies for HBV Treatment

• Mark Sulkowski, MD
• Johns Hopkins School of Medicine
• Baltimore, MD

56
Clevudine (L-FMAU)

• CLV is a pyrimidine nucleoside analog
• No mitochondrial toxicity
• Inhibition of synthesis of dsDNA from ssRNA
• Randomized, placebo controlled trial 30 mg/day
• HBV DNA reduction of 5.10 log10 c/mL at week 24
• Prolonged suppression 24 weeks after dosing
  (-2.02 log)
• Resistance profile similar to other L-nucleosides
• M204I L180M 204I/V A181T
• Phase 3 clinical trials for United States
  registration Approved in Korea (Bukwang
  Pharmaceuticals)

Byung CY, et al. Hepatology 2007451172 1178.
57
CLV vs. LAM Comparison in HBeAg-positive, CHB
Patients

• Randomized, blinded trial (N55)
• CLV 30 mg/d vs. LAM 100 mg/d
• Entry Treatment-naïve, HBV DNA 3 million c/mL
  ALT 1xULN
• At 48 weeks, all analyses favored CLV
• More pts with HBV DNA
• Greater HBV DNA decrease
• CLV 4.7 log (3.3 6.2)
• LAM 3.2 log (0.2 5.7)
• More HBe seroconversion(17 vs. 8)
• Less Resistance (0 vs. 9 patients)
• Conclusion CLV more effective than LAM in
  HBeAg-positive CHB pts

HBV DNA
at Week 48
100
80
72
59
60
Patient Percent
46
40
32
20
0
W32
W48
CLV
LAM
Lau G, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 911.
58
Clevudine Efficacy and Resistance

• 34 treatment naïve pts with CHB (24
  HBeAg)Treated with CLV (30 mg/d) for median 52
  weeks
• Mean HBV DNA 7.3 1.1 log10 c/mL
• Mean ALT 263 234 U/L
• Cirrhosis 10 patients
• Results
• HBeAg-negative 10/10 HBV DNA undetectable at
  week 24
• HBeAg-positive
• 58.3 and 75 undetectable at weeks 24 and 48
• 2 pts with viral breakthrough at weeks48 and 56
  mutation rtM204I detected in both
• Conclusions
• CLV effective in CHB
• rtM204I a common mutation on CLV failure

Kwon SY, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 943.
59
CLV vs. ETV in Treatment-Naïve CHB

• Non-randomized, cohort study of treatment-naïve
  CHB pts (N148)
• CLV 30 mg/day (n39) vs. ETV 0.5 mg/day (n109)
• Longer treatment with ETV (16.6 2.8 mos.)
  compared to CLV (9.9 3.3 mos.) (P
• Similar HBV DNA suppression observed
• Conclusions
• CLV and ETV appear similarly potent at 48 weeks
• Longer F/U needed to assess long-term HBV DNA
  suppression and resistance profiles

HBV DNA
100
80
55.9
60
55.3
Patient Percent
44.4
40
30.8
20
13.5
12.7
0
12 wks
24 wks
48 wks
ETV
CLV
Sul H, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 912.
60
In Vitro Simvastatin is Active Against Drug
Resistant and Wild-type HBV Strains

• In vitro, simvastatin inhibits HBV extracellular
  virion production and intracellular DNA
  intermediate forms
• Study in which cultured HBV-producing HepG2 2.15
  cells treated with 9 consecutive daily doses of
  SIM, LAM or ADV
• Comparable efficacy of SIM, LAM and ADV against
  clinically relevant resistant viruses found
• Clinical studies are needed to test in vivo
  significance and utility of SIM in treatment of
  CHB

SIM EC50 (uM)
LAM EC50 (uM)
ADV EC50 (uM)
WT
8.2
0.2
1.5
M204V
9
100
1.8
N236T
9.3
0.6
8.1
Bader T, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 877.
61
In Vitro Interferon Gamma Anti-HBV Activity With
and Without LAM or ADV

• IFN-? 1b is a type 2 IFN which binds to a unique
  cell surface receptor
• In vitro model, HepG2 2.2.15 cells transfected
  with wild type HBV
• Txd with IFN-? 1b or peginterferon a-2a 2 days
  after plating or LAM or ADV 3 days after plating
• IFN-? 1b also combined with peginterferon a-2a,
  Lam or ADV
• All showed potent antiviral activity
• LAM and ADV activity increased in presence of
  IFN-? 1b
• Models support in vivo testing of IFN-? 1b alone
  or in combination with nucleos(t)ide analogs in
  CHB

IFN gamma
IFN alfa-2a
LAM
ADV
EC50
20 pg/mL
90 pg/mL
540 nM
620 nM
IFN-? 1b
_
_
? 6-fold
? 15-fold
Increased Potency
Blatt L, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 898.
62
Combination Therapy EASL Clinical Practice
Guidelines Management of CHB

• As of yet, no data to support de novo combination
  therapy in Tx-naïve patients receiving first line
  nucleos(t)ide analogs (ETV or TDF)
• Some experts recommend de novo combination
  therapy to prevent resistance in high-risk
  patients (e.g., high HBV DNA level) or persons in
  whom resistance is life threatening (e.g.,
  cirrhosis, transplant)
• TDF either LAM or FTC may be considered in such
  patients
• Combination therapy (add-on) is recommended for
  patients with treatment failure
• Agents that do not share cross-resistance

EASL Clinical Practice Guidelines Management of
CHB. Hepatology (2008)
63
4 Year Follow-up of Add-on ADV to
LAM-resistant Patients

• LAM-resistant pts treated with add-on ADV (10
  mg/d) LAM (100 mg/d) for mean of 55 mos.
  (n145)
• 73 Cirrhotic 92 HBeAg-negative
• Results
• Overall, 81 HBV DNA undetectable with continued
  improvement through 5 years of Tx
• 84 ALT normalization
• 3 developed new rtA181T (2 became undetectable)
  no rtN236T observed
• 23 pts with increase serum Cr 0.5 mg managed
  with ADV dose adjustment (10 mg QOD) with
  stabilization or improvement
• ConclusionIn patients with LAM-resistant HBV,
  ADV add on to LAM is an effective and safe Tx
  strategy

88
86
100
78
68
58
50
HBV DNA
of Tx
undetectable by Year
0
1
2
3
4
5
Year
Lmpertico P, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 906.
64
5 Year Add-on ADV toLAM Resistant Patients

• Prospective single center cohort (n41)
• HBeAg-negative CHB with LAM resistance
• Median HBV DNA 6 million c/mL
• ADV (10 mg/d) LAM (100 mg/d)
• Results
• Significant HBV decline through 5 years of Tx
• ALT normalization in 93 at 5 years of Tx
• No ADV resistance observed
• Conclusion ADV LAM is effective in
  HBeAg-negative CHB with LAM resistance

95
93
93
92
100
86
86
88
85
81
68
80
60
Patient Percent
HBV DNA ?250 c/mL
40
ALT Normalization
20
0
Year 1
Year 2
Year 3
Year 4
Year 5
Hadziyannis S, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 924.
65
De novo ADV LAM Compared to Add-on ADV to LAM

• Retrospective, single center cohort study (n201)
• Pts receiving ADV LAM for median 17 months
  (range 3 48)
• De novo (n151)
• HBeAg 38 Cirrhosis 38 Mean HBV DNA 4.9 log
• Add-on (n50)
• HBeAg 68 Cirrhosis 80 Mean HBV DNA 4.0 log
• De novo strategy more effective
• Greater virologic suppression
• 3 add-on pts acquired ADV-R in setting of prior
  LAM-R

HBV DNA Suppression
3
6
12
18
0
-1
HBV DNA c/mL
-2
-3
10
-4
Log
-5
Months
de novo
add on
Carey I, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 930.
66
CLV compared to LAM as add-on in Patients with
ADV Failure

• Open-label, non-randomized cohort followed for
  12 months evaluating adding CLV (30 mg/d) or LAM
  (100 mg/d) to ADV after viral failure
• 450 LAM-resistant CHB pts treated with ADV
• 29 with viral breakthrough on ADV after median 60
  months
• 6 with ADV resistant variants rtA181VT or
  rtN236T
• CLV added (n12) LAM added (n17)
• Similar outcomes regarding effectiveness, safety
  and tolerability
• No additional resistance mutations observed

CLV ADV (n12)
LAM ADV (n17)
p value
Baseline HBV DNA (median log10 c/mL)
6.43
6.13
NR
HBV DNA ? at wk 24 (median log10 c/mL)
- 2.97
- 2.27
0.28
HBV DNA undetectable at wk 24
50
29
0.22
Park NH, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 961.
67
Switch to ADV ETV in Patients Failing ADV LAM

• Observational, open-label, cohort study of
  switching ETV (1 mg/d) for LAM in pts failing
  ADV LAM (n13)
• Failure after ADV LAM combination (n9) or
  sequential (n4)
• Baseline HBV DNA 2 x 105 c/mL (range 9 x 103 4
  x 107)
• Results (Median of 10 mos.)
• Median ? 3 log10 c/mL (range 1.6 4.3)
• 10/13 with HBV DNA
• 2/3 without full suppression had rtA181T variant
• Significant reduction in ALT (median 0.72 ULN,
  P0.034)
• No significant adverse events
• Further research on nucleotide analog (ADV or
  TDF) ETV is warranted

Schollmeyer J, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 925.
68
ETV TDF in Patients withMulti-drug Resistant
CHB

• Open-label, single center, cohort study
• 12 treatment-experienced patients with
  CHB-related cirrhosis
• 11/12 with genotypic resistance to LAM ADV
• 7/12 received LAM ADV at time of switch
• HBV DNA level 5 x 106 c/mL (7 x 104 7 x 109)
• TDF (245 mg/d) ETV (1 mg/d) for median 6 months
  
• No AEs or decompensation observed
• Median ? HBV DNA 4.6 log10 c/mL (1.7 7.8)
• 9/12 with HBV DNA
• Further research is needed to test TDF ETV
  combination

Schollmeyer J, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 985.
69
De Novo TDF LAM or FTC is Associated with
Early Virologic Response in HIV/HBV Co-infected
Patients

• Retrospective study comparing de novo vs. add-on
  therapy for HBV in HIVHBV co-infected patients
• Group 1 TDF plus either LAM or FTC (n15)
• Never received or no LAM in 4 years
• Group 2 LAM initially with add on TDF (n46)
• Results
• More Group 1 achieved HBV DNA
• 14 pts in Group 2 had HBV DNA decrease 6 mos.
• 7 considered noncompliant
• 7 had HBV clearance at median of 20 mos.
• LAM baseline resistance higher in Group 2 (46
  vs. 11, P0.026)
• Conclusion De novo therapy leads to an earlier
  virologic response than add-on therapy

Percent
100
100
77
80
60
Patient Percent
40
20
0
Group 1
Group 2
Lada O, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 922.
70
Treatment of CHB in HIV/HBV co-infected Patients
with TDF Containing HAART

• HIV/HBV co-infected patients naïve to
  antiretroviral therapy (n47)
• Median CD4 count 42 cells/mm3
• Median HBV DNA 8 log10 IU/mL
• 34/47 (64) HBeAg-positive
• Treated with combination HAART containing TDF
  alone (n11) or TDF FTC or LAM (n36)
• Median follow-up 27 months
• Median TDF exposure 25 months

Matthews G, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 907.
71
High Rate of HIV and HBV Suppression with TDF
Containing HAART

• HIV Responses
• All HIV RNA
• Median CD4 count 342 cells/mm3 after Tx
• HBV Responses
• HBV DNA
• 72
• 94
• No patient 1000 IU/mL
• HBeAg Loss 36
• HBeAb seroconversion 33
• HBsAg loss, 6
• Conclusion TDF containing ART with and without
  FTC or LAM was very effective in controlling HIV
  and HBV in HIV/HBV co-infected patients with
  advanced HIV disease

Matthews G, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 907.
72
PegIFN alfa-2a With or WithoutRibavirin for CHB

• RBV inhibits viral replication and modulates
  immune response
• Role in CHB unknown
• Multicenter, randomized clinical trial in
  HBeAg-negative CHB patients (N133)
• Male, 74 mean age, 42.2 yrs HBV genotype D 80
• PegIFN alfa-2a 180 mcg weekly either placebo
  orRBV 1000 1200 mg/d for 48 weeks

Janssen H, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 991.
73
RBV Does Not Improve Response Compared with
PegIFN Alone for HBeAg-negative CHB
Week 48 End of treatment
Week 72 End of follow-up
PegIFN Placebo (n69)
PegIFN RBV (n64)
PegIFN Placebo (n69)
PegIFN RBV (n64)
HBV DNA 67
55
20
19
HBV DNA 52
28
9
6
ALT normal
41
53
41
52

• Conclusion No benefit to adding RBV to PegIFN
  Tx of HBeAg-negative CHB

Janssen H, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 991.
74
Resistance Issues with HBV Treatment

• Yves Benhamou, MD
• Groupe Hospitalier Pitie-Salpetriere
• Paris, France

75
HBV Resistance ToNucleos(t)ide Analogues

• As anti-HBV therapy may be indefinite for the
  large majority of the patients, treatment and
  prevention of long term resistance is a major
  issue
• Pre-existing resistance may be important to
  recognize in order to tailor first line anti-HBV
  therapy
• The resistance profile of TDF, the latest
  approved drug for treatment of CHB, was
  particularly studied and discussed at this meeting

76
Most Common HBVCross-Resistance Mutations
Lamivudine
Telbivudine
Entecavir
Adefovir
Tenofovir
Wild-type
S
S
S
S
S
M204l
R
R
I/R
S
S
L180M M204V
R
R
I
S
S
A181 T/V
I
S
S
R
S
N236T
S
S
S
R
I
I169T V173L M250V
R
R
R
S
S
T184G S202lI/G
R
R
R
S
S
( L180M M204I/V)
Durantel, et al. Hepatology (2004) Brunelle, et
al. Hepatology (2005) Yang, et al. Antiviral
Therapy (2005) Villet, et al. Gastroenterology
(2006) Delaney, et al. AAC (2006) Villet, et
al. J Hepatol (2007) Brunelle, et al. AAC
(2007) Qi, et al. Antiviral therapy (2007)
Tenney, et al. AAC (2004 2007) Villet, et al.
J Hepatol (2008).
77
Rates of HBV Resistance Over Time in
HBeAg-Positive, Treatment-Naïve Patients
70
60
50
40
Patients with Resistance ()
year 5
30
year 4
20
year 3
year 2
10
year 1
0
Lamivudine
Adefovir
Entecavir
Telbivudine
Tenofovir
Marcellin P, et al. J Hepatology 200542
(suppl2)31-2 Lai CL, et al. Hepatology
200644(suppl)222A Colonno R, et al. Hepatology
200644 (suppl)229A Shiffman ML, et al.
Hepatology 200440(suppl)172A Chung YH, et al.
Hepatology 2006 44(suppl)698A Heathcote J, et
al. Hepatology 200746 (suppl 1)861.
78
Rates of HBV Resistance Over Time in
HBeAg-Negative Treatment-Naïve Patients
80
60
40
Patients with Resistance ()
5
4
20
3
Years
2
1
0
LAM
TDF
ETV
ADV
LdT
CLV
FTC
Marcellin P, et al. J Hepatology 200542
(suppl2)31-2 Lai CL, et al. Hepatology
200644(suppl)222A Colonno R, et al. Hepatology
200644 (suppl)229A Shiffman ML, et al.
Hepatology 200440(suppl)172A Chung YH, et al.
Hepatology 2006 44(suppl)698A Heathcote J, et
al. Hepatology 200746 (suppl 1)861.
79
Pre-Existing AntiviralResistance Mutations

• Pre-existing HBV antiviral resistanc