Title: 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
2Accreditation 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.
3Faculty CME Course Director
S. Martin Cohen, MD Associate Professor of
Medicine Director, Section of Hepatology Rush
University Medical Center Chicago, Illinois
4Faculty 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
5Disclosure 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
6Disclosure 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
7Disclosure 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
8Disclosure 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
9Learning 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
1059th American Association for the Study of Liver
Diseases Meeting (59th AASLD)
- San Francisco, CA
- October 31-November 4, 2008
11Epidemiology and Natural History of HBV Infection
- Douglas Dieterich, MD
- Mount Sinai School of Medicine
- New York, NY
12Estimated Prevalence of Chronic Hepatitis B in
Foreign-Born Persons Living in the United States
- Centers for Disease Control (CDC) estimates that
lt0.5 of the U.S. population (800,0001.4
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.
13Total 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.
14Published 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.
15Published 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.
16Percent 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.
17Study 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.
18New 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.
19Study 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.
20Evaluation 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 gtULN
- Intermittent ALT elevation, 1 NRALT (IE ALT)
- Persistent ALT elevation, all ALT values gtULN (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.
21Patient 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)
lt0.001
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
lt0.001
Baseline ALT (U/L) mean SD range
44.6 31.6 6-223
144.2 127.0 36-1459
lt0.001
Intermittent ALT elevation, 1 NRALT
Persistent ALT elevation, all ALT values gt
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.
22Liver 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
Plt0.00
1
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.
23Normal 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
2
0
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.
24Results 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.
25Patients 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.
26Study 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 gt2 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.
27Age 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 lt40 years of age
- 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 (Plt0.0001)
- 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.
28Perinatal 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 gt8 log10 c/mL and
HBeAg - Transmission rate 7.2 HBV DNA gt8 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 gt8 log10 c/mL
Wiseman E, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 827.
29High 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, Plt0.0001)
- Higher BMI (27 vs. 24, Plt0.00057)
- 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.
30Predictors 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
lt0.0001
Mean Age (Years)
39.6
35.0
lt0.0001
Male ()
69.0
68.5
0.89
Caucasian/African/Asian ()
22.1/52.4/25.5
30.0/20.5/49.5
lt0.0001
Alcohol 0/50/gt50 g/day ()
83.2/11.5/5.3
80.6/15.3/4.1
0.27
HBV DNA lt4/4-lt6/6 log10 c/mL ()
47.8/20.9/19.0
3.0/7.0/84.5
lt0.0001
Median ALT (IU/L)
32
62.5
0.09
Anti-HBV Tx ()
46.7
81.0
lt0.0001
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.
31Factors Associated withComplications of HBV
1.00
ALT lt2xULN
1.00
HBV DNA lt4 log
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
lt35 years of age
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.
32Multivariate 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
lt0.0001
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 gt4 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.
33Therapeutic Strategies for HBV Treatment
- Paul Kwo, MD
- University of Indiana
- Indianapolis, IN
34Tenofovir 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.
35Tenofovir 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
Plt0.00
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
lt
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.
36Study 102 Two Year Tenofovir Treatment and
Adefovir Switch Data in HBeAg-Negative Patients
with CHB
- Randomized, Double-Blind, Comparison of TDF vs.
ADV for HBeAg(-) Chronic Hepatitis B - HBV DNA gt105 c/mL and ALT 2x and lt10xULN
- Knodell Necroinflammatory score 3
- LAM Experienced or Naïve
8 Years
5 Years
2 Years
1 Year
Open-label
Double Blind
Tenofovir 300 mg (n250)
TDF 300 mg
RANDOMIZATION 21
Adefovir 10 mg (n125)
TDF 300 mg
Week 240Liver Biopsy
Week 48 Liver Biopsy
Pre-treatment Liver Biopsy
Week 96
End of Study
Week 72 HBV DNA 400 copies/mL option to add
emtricitabine (FTC) to TDF in a fixed dose tablet
- Week 48 Phase 3 data showed TDF superior to ADV
- 93 of TDF-treated patients had HBV DNA lt400
copies/mL - 96 week data presented
Marcellin P, et al. 59th AASLD San Francisco,
CA October 31-November 4, 2008 Abst. 146.
37Study 102 Patients with HBV DNA lt400 copies/mL
On treatment analysis
ITT analysis
99
P0.166
100
100
100
100
91
P0.672
100
90
90
89
80
80
LAM Exp. 97 100
LAM Exp. 93 96
70
70
60
60
Percentage ()
Percentage ()
50
50
50
50
40
40
30
30
20
20
20
20
10
10
Randomized Double Blind
Open Label
Randomized Double Blind
Open Label
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
250 125
234 122
245 125
243 124
248 120
247 123
242 123
243 122
TDF-TDF n ADV-TDF n
250 125
214 109
242 123
239 121
242 117
241 117
226 110
224 109
TDF-TDF n ADV-TDF n
- TDF demonstrated durable, potent antiviral
activity through Week 96 - 99 of patients on therapy had HBV DNA lt400
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.
38Long 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.
39Reduction 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.
40HBV 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 lt20,000 c/mL
- In HBeAg, HBeAg seroconversion
Erhardt A, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 883.
41HBV 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 gt5 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.
42ETV-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.
43Results 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
Plt0.0001, P0.0002, P0.043 (all compared to
baseline)
Katano Y, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 889.
44Studies 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 lt0.7 MEq/mL by bDNA and
HBeAg loss
Virologic Responders VRHBV DNA lt0.7 MEq/mL by
bDNA and HBeAg()
Han S, et al. 59th AASLD San Francisco, CA
October 31-November 4, 2008 Abst. 893.
45Studies 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.
46Studies ETV-022/-901 Proportion with HBV DNA
lt300 c/mL Through 5 Years
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 lt300 copies/mL
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.
47Studies 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.
48Studies 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.
49Distribution 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.
50Continued 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 lt300 copies/mL)
66/86 (76.7)
Maintained PCR Negativity (HBV DNA lt300 copies/mL)
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 lt5 log10
copies/mL
88/88 (100.0)
Maintained HBeAg seroconversion and HBV DNA lt3
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.
51Cost-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.
52Results 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.
53New Therapies and Strategies for HBV Treatment
- Mark Sulkowski, MD
- Johns Hopkins School of Medicine
- Baltimore, MD
54Clevudine (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.
55CLV 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 gt 3 million c/mL
ALT gt 1xULN - At 48 weeks, all analyses favored CLV
- More pts with HBV DNA lt300 c/mL
- 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 lt300 c/mL
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.
56Clevudine 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.
57CLV 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.) (Plt0.001) - 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 lt140 c/mL
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.
58In 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
gt100
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.
59In 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.
60Combination 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)
614 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 gt0.5 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.
625 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.
63De 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.
64CLV 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.
65Switch 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 lt400 c/mL
- 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.
66ETV 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 lt400 c/mL
- 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.
67De 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 lt3 log at 6 mos.
- 14 pts in Group 2 had HBV DNA decrease lt1 log at
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 lt3 log10 IU/mL at 6 mos.
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.
68Treatment 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.
69High Rate of HIV and HBV Suppression with TDF
Containing HAART
- HIV Responses
- All HIV RNA lt50 c/mL
- Median CD4 count 342 cells/mm3 after Tx
- HBV Responses
- HBV DNA
- 72 lt20 IU/mL
- 94 lt400 IU/mL
- No patient gt1000 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.
70PegIFN 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.
71RBV 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 lt10,000 c/mL
67
55
20
19
HBV DNA lt400 c/mL
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.
72Resistance Issues with HBV Treatment
- Yves Benhamou, MD
- Groupe Hospitalier Pitie-Salpetriere
- Paris, France
73HBV 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
74Most 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).
75Rates 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.
76Rates 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
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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.
77Pre-Existing AntiviralResistance Mutations
- Pre-existing HBV antiviral resistance (AVR)
mutations in treatment-naïve, CHB patients is
believed to occur at low frequency - Lamivudine 10
- Entecavir 1-2
- Pre-existing AVR may significantly compromise
anti-viral efficacy in the treatment of CHB