Transcript Clinical Care Options for Hepatitis Symposium:

4th Annual Clinical Care Options
for Hepatitis Symposium:
HBV Highlights
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Hepatitis B Virus Resistance:
An Overview by a Clinician
for a Clinical Audience
Anna S.F. Lok, MD
Professor of Internal Medicine and
Director of Clinical Hepatology
University of Michigan, Ann Arbor
Ann Arbor, Michigan
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Why Do Antiviral-Resistant HBV
Mutants Arise?
 High rate of virion production: 1012-13 virions per day
 High rate of spontaneous mutations—lack of proofreading
capacity of HBV reverse transcriptase: 10-5
substitution/base/cycle
 All possible single base changes can be produced each
day
 Antiviral resistant mutations may be present prior to
therapy
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
What Causes Antiviral-Resistant HBV
Mutants to Become Dominant?
 Survival of the fittest: selection of virus with survival
advantage in the presence of antiviral therapy
S
S
S
S
R
S
S
R
R
S
S
R
R
R
S
R
Antiviral Therapy
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Factors Associated With Antiviral
Resistance
DRUG
VIRUS
 Daily production
 Replication fidelity
 Preexistent mutations
 Potency
 Structure
 Genetic barrier to
resistance
HOST
 Prior therapy
 Compliance
 Immune status
 Pharmacogenetics
 Body size
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
% Resistance
Better Viral Suppression Reduces the
Risk of Genotypic Resistance
LAM
ADV
Resistance (median 29 mos)
vs Week 24 HBV DNA
64%
Resistance at Week 144
vs Week 48 HBV DNA
67%
32%
26%
8%
< ND
13%
4%
<3
<4
>4
Week 24 HBV DNA (log10 c/mL)
N = 159 HBeAg-positive patients
Yuen MF, et al. Hepatology. 2001;34:785-791
Locarnini S, et al. J Hepatol. 2005;42(suppl.2):17.
< ND
3-6
>6
Week 48 HBV DNA (log10 c/mL)
N = 114, primarily HBeAg-negative
patients
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Genetic Barriers to Antiviral
Resistance
 No. of amino acid changes required to confer resistance
 Decrease in susceptibility (increase in IC50) caused by the
mutations
Nucleos(t)ide Analogue
Mutation
Fold Decrease in Susceptibility
LAM
M204V/I
> 1000
ADV
A181V or N236T
3-15
169 or 202
184 or 250
M204V/I + 1 ETV-R
M204V/I + 2 ETV-R
~1
2-10
10-250
> 500
Entecavir
ETV-R, entecavir resistance mutation.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Nomenclature for Antiviral Resistance
 Virological breakthrough—consistent increase in serum
HBV DNA by > 1 log above nadir while on treatment, after
achieving initial response
 Biochemical breakthrough—consistent increase in serum
ALT while on treatment, after achieving initial response
 Genotypic resistance—detection of HBV polymerase
mutation(s) that has been shown to decrease susceptibility
to treatment
 Phenotypic resistance—in vitro confirmation that the
mutation decreases susceptibility to treatment
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Manifestations of Antiviral Resistance
HBV DNA (log10 IU/mL)
ALT (U/L)
Antiviral Treatment
8
Viral
rebound
6
Viral
breakthrough
Hepatitis flare
4
Biochemical
breakthrough
ULN
Genotypic
resistance
2
0
-1
0
1
2
3
Years
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Indicators of Antiviral-Resistant HBV
 Detection of antiviral resistant mutations
 Viral breakthrough—> 1 log increase in serum HBV DNA
 Viral rebound—serum HBV DNA exceeds pretreatment
value or defined cutoff (eg, > 5 log)
 Biochemical breakthrough—abnormal ALT
 Hepatitis flares, hepatic decompensation
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Consequences of Antiviral-Resistant
HBV
 Loss of initial virologic, biochemical, and histologic
response
 Virologic and biochemical breakthrough
 Hepatitis flares, hepatic decompensation, and death
 Increased risk of HBV recurrence postliver transplant
 Limit future treatment options
 Transmission to treatment-naive persons → public health
problem
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
M250V
N236T
M204V/1
S202G
T184G/S/A/C
A181V/T
L180M
Selection of LAM-Resistant Mutations
Limits Future Treatment Options
LAM
FTC
LdT
ADV
ETV
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Multirug-Resistant HBV Responds
Poorly to Combination Therapy
HBV
LAM
Fold Δ
ADV
Fold Δ
LAM + ADV
Fold Δ
WT
1.0
1.0
1.0
N236T
1.1
3.2
1.6
L180M + M204V
> 40.0
1.0
11.0
L180M + M204V + N236T
> 40.0
6.3
58.8
Brunelle MN, et al. Hepatology. 2005;41:1391-1398.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Multidrug-Resistant HBV Mutants
15 samples from 6 patients
Direct sequencing
11 samples with MDR
mutations
215 clones
Mutations to
> 1 drug on
the same
genome in
183 clones
Mutations to
only 1 drug
in 31 clones
Yim HJ, et al. Hepatology. 2006. In press.
5 samples with single drug
resistant mutations
Clonal analysis
Wild-type
HBV DNA in
1 clone
94 clones
Mutations to
> 1 drug on
the same
genome in
5 clones
Mutations to
only 1 drug
in 89 clones
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Multidrug-Resistant HBV Mutants
(cont’d)
 Mutations to both therapies locate in same HBV genome
in 85% clones analyzed
 Progressive evolution from
– All clones with LAM-R mutations →
– Mixtures of clones with multidrug R mutations and clones
with LAM-R mutations →
– All clones with multidrug-resistant mutations
 Combination therapy directed against mutants to each
treatment may not be adequate in suppressing multidrugresistant HBV
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Prevention of Antiviral-Resistant HBV
 Judicious use of antiviral treatment—avoid
futile/unnecessary treatment
 Initiate treatment with combination therapy—what agents
to combine?
 Use potent agent that has high genetic barrier to
resistance
 Monitor viral response—switch therapy if response
suboptimal
 Avoid sequential monotherapy
 Avoid cross-resistant drugs
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Management of Patients With
Antiviral-Resistant HBV
 Close monitoring for viral rebound, hepatitis flare, and
decompensation
 Strategies
– Stop treatment and observe if patient did not warrant
treatment initially (immune tolerant patient, inactive carriers)
– Continue current treatment temporarily and observe if HBV
DNA level is low, ALT is normal, and no cirrhosis or immune
suppression
– Implement rescue therapy immediately if viral rebound or
hepatitis flare and in all patients with cirrhosis or immune
suppression
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Rescue Therapy for AntiviralResistant HBV
 Lamivudine-R
– Add adefovir/tenofovir
– Switch to emtricitabine + tenofovir or switch to entecavir (risk of
subsequent entecavir-R)
 Adefovir-R*
– Add lamivudine or switch to emtricitabine + tenofovir
– Switch to entecavir (if no prior LAM-R)
 Entecavir-R*
– Add or switch to adefovir or tenofovir
 Multidrug R → ???
*Limited in vivo data
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
The Changing Face
of Antiviral Therapy
Robert P. Perrillo, MD
Director, Academic Affairs
Section of Gastroenterology and Hepatology
Ochsner Clinic Foundation
New Orleans, Louisiana
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBeAg Seroconversion vs Level of
HBV DNA Suppression
Mean HBV DNA (log10 copies/mL)
12
On treatment
Follow-up
10
8
6
-4.48
-5.81
4
-7.18*
2
0
6
PEG-2a + placebo
HBeAg seroconversion
EOF = 32%*
LAM
HBeAg seroconversion
EOF = 19%
PEG-2a + LAM
HBeAg seroconversion
EOF = 27%*
12 18 24 30 36 42 48 54 60 66 72
Weeks
Lau GK, et al. N Engl J Med. 2005;352:2682-2695.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
On-Treatment ALT Maximums and
HBeAg Seroconversion at Week 72
HBeAg Seroconversion Rates in
Patients With
PEG/PLC
PEG/LAM
LAM
ALT > 5 x bALT
6/14 (43%)
6/16/ (38%)
3/12 (25%)
> 10 x ULN
20/48 (42%)
12/35 (34%)
3/31 (10%)
> 5 - < 10 x ULN
28/74 (38%)
27/86 (31%)
16/64 (25%)
≤ 5 x ULN
39/149 (26%)
35/150 (23%)
33/177 (19%)
Piratvisuth T, et al. EASL 2005.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
On-Treatment Flares (3 x BSL) With
PEG-IFN α-2b According to Genotype
P = .046
60
45
30
15
0
74%
NB: Only host-induced flare and
height of ALT during flare predicted
response
43%
33%
27%
P =.05
A
B
C
D
n = 19 n = 7 n = 11 n = 26
On-treatment flares
All HBsAg seroconverters had
host-induced flare
50
Percent
Percent
75
40
30
20
10
0
47%
28%
18% 19%
A
B
C
D
n = 19 n = 7 n = 11 n = 26
Treatment response after flare
Flink HJ, et al. Gut. 2005;54:1604-1609.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBsAg Seroconversion: PEG-IFN in
HBeAg(+) Patients According to Genotype
PEG-IFN α-2a[2]
24
24
21
21
18
18
15
Patients (%)
Patients (%)
PEG-IFN α-2b[1]
14%
12
9
6
3
9%
3%
2%
15
12
9
6
3
0
0
B
C
D
A
n = 90 n = 23 n = 39 n = 103
1. Flink HJ, et al. Am J Gastro. 2006;101:297-303.
2. Hadziyannis S, et al. EASL 2005.
22%
2%
0%
0%
A
B
C
D
n = 23 n = 76 n = 162 n = 9
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
6-Month and 2-Year Posttreatment
Responses in HBeAg-Negative CHB
6 Months
Posttreatment, %
(n = 177)
2 Years
Posttreatment, %
(n = 116)
ALT normal
59[1]
66[2]
HBV DNA < 20,000 copies/mL
43[1]
48[2]
HBV DNA < 400 copies
19[1]
23[2]
HBsAg loss
4[1]
9[2]
1. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.
2. Marcellin P, et al. EASL 2006.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Tenofovir vs Adefovir in LAMResistant CHB
Week 24
Week 36
Week 48
0
Tenofovir 300 mg/day for
72-130 weeks (n = 35)
Adefovir 10 mg/day for 6080 weeks (n = 18)
-2.6
-2.8
-3.0
% HBV DNA < 400 copies/mL
at Week 48
-5.2*
-5.4*
-5.5*
*P < .001 vs ADV
 100% of tenofovir patients
 44% of adefovir group
-7
Mean change in log10 HBV DNA (PCR)
van Bömmel F, et al. Hepatology. 2004;40:1421-1425.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Virologic Response to Entecavir
vs LAM: Week 48 vs 96
Parameter
Entecavir, %
(n = 354)
LAM, %
(n = 355)
HBV DNA(-)
 At Week 48*
67
36*
 At Week 96
80
39
HBeAg seroconversion
 At Week 48
21
18
 At Week 96
31
25
Chang TT, et al. N Engl J Med. 2006;354:1001-1010.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Entecavir vs Lamivudine in
LAM-Refractory, HBeAg+ CHB
Entecavir 1.0 mg QD (n = 141)
100
LAM 100 mg QD (n = 145)
0
Patients (%)
*
55
-0.48
*
55
28
4
0
†ALT
-6
Histologic
Improvement
Composite
Endpoint†
< 1.25 x ULN, HBV DNA < 0.7 MEq/mL
Sherman M, et al. Hepatology. 2004;40:1465-1473.
-5.14
*
HBV DNA Mean Change
From Baseline
(log10 copies/mL)
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Combination LAM + ADV:
Efficacy Outcomes at Week 104
LAM + PLAC, %
(n = 57)
LAM + ADV, %
(n = 54)
HBeAg seroconversion
20
13
HBeAg loss
24
19
Sustained virologic breakthrough*
40
17
HBV DNA negative by PCR†
14
26
ALT normalization
41
47
*Defined as  1 log increase over lowest prior value on 2 or more successive visits
(at least one value > 104) and same criteria at last visit
†Roche, Cobas, LLOD 200 copies
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Virologic Response at Week 52 to LdT,
LAM, or Combination Therapy
LAM
N
18
LdT
LdT + LAM
42
41
% with HBeAg
loss *
28 %
33%
17%
% HBeAg sero
22%
31%
15%
% Patients
HBV DNA negative
by PCR
32%
61%*
49%
*P < .05 compared to LAM
Lai, et al. Gastroenterology. 2005
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Hepatitis B: Histology and Normal ALT
in 452 Chinese Patients
Normal ALT,
HBeAg positive
100
Patients (%)
75
40
80
73
46
42
52
34
Normal ALT,
HBeAg negative
Normal ALT,
HBeAg positive
Normal ALT,
HBeAg negative
0
Grade 2 or More
Yang et al. Chinese J Dig Dis. 2002;3:150.
Stage 2 or More
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Risk of Cirrhosis or HCC According
to Baseline HBV DNA
Population
3754 Asian
Americans[1]
1520
Chinese[2]
3851
Taiwanese[3]
3582 Taiwanese[4]
Outcome Variable
HBV DNA
Relative Risk
HCC
< 105
> 105
4.1
8.5
Mild/mod CHB
Cirrhosis/HCC
< 105 vs > 105
1.4, 1.0
1.9, 2.5
Cirrhosis
≤103 vs 104
vs ≥ 105
E (-) 1.0, 1.9, 4.9
E (+) 2.6, 6.2, 8.6
Cirrhosis
≥ 104 to < 105
≥ 105 to < 106
≥ 106
2.5
5.6
6.5
1. Evans AA. AASLD 2004. Abstract 1013. 2.Chen G. AASLD 2004. Abstract 996.
3. Chen G. EASL 2005. Abstract 476. 4.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
New Drugs for the Treatment
of Chronic Hepatitis B
Patrick Marcellin, MD, PhD
Professor of Medicine
Service d’Hepatologie
INSERM CRB3
Hôpital Beaujon
University of Paris
Clichy, France
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Emtricitabine Monotherapy in
Chronic Hepatitis B
 Emtricitabine is approved for treatment of HIV
 FTCB 301: double-blind, placebo-controlled, phase III trial
 248 patients randomized to receive:
– Emtricitabine (200 mg/day) or placebo for 48 wks
48-Week Results
Emtricitabine, % (n = 167)
Placebo, % (n = 81)
P Value
Histologic response
62.0
25.0
< .001
Improvement in fibrosis
21.0
7.0
< .009
Normal ALT
65.0
25.0
< .001
Undetectable HBV DNA
56.0
7.0
< .001
HBeAg seroconversion
12.1
12.0
NS
YMDD resistance
12.6
--
--
Shiffman M, et al. AASLD 2004. Abstract 22.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Emtricitabine Plus Adefovir
 Emtricitabine resistance limits its use as monotherapy
– Combination therapy may resolve this issue
 FTC-201: double-blind, placebo-controlled, phase II study
– 30 HBeAg-positive nucleoside-naive patients
– Randomized to adefovir + emtricitabine or adefovir alone
Median Change in
HBV DNA
Adefovir, log10
copies/mL
(n = 14)
Adefovir + Emtricitabine,
P Value
log10 copies/mL
(n = 24)
Week 24
-3.19
-5.08
--
Week 48
-3.40
-5.44
.03
Lau G, et al. AASLD 2004. Abstract 245.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
GLOBE: Year 1 Results of Telbivudine
for Chronic Hepatitis B
 GLOBE trial: phase III international study (N = 1367)
Summary of Year 1 Results With Telbivudine
Outcome
Undetectable HBV DNA
 Week 52
 Week 76
Virologic breakthrough by Week 48
Normalized ALT
 Week 52
 Week 76
Fibrosis decline by Week 52
HBeAg seroconversion by Week 76
HBeAg-Positive Patients, %
HBeAg-Negative Patients, %
LdT
(n = 458)
LAM
(n = 463)
LdT
(n = 222)
LAM
(n = 224)
75*
75* (n = 163)
67
58 (n = 165)
88*
84* (n = 68)
71
67 (n = 67)
3*
10
2*
9
77
78* (n = 163)
75
68 (n = 165)
74
76 (n = 68)
79
64 (n = 67)
68
61
59
46
41* (n = 100)
26 (n = 93)
N/A
N/A
*P < .05 vs LAM
Lai C, et al. AASLD 2005. Abstract LB01.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
GLOBE: Early HBV DNA Levels and
Year 1 Outcomes With Telbivudine
 Year 1 outcomes linked to viral load at Weeks 12 and 24
– 93% of individuals with HBV DNA > 3 log10 copies/mL at
Week 24 failed to seroconvert by Year 1
Week 24 HBV DNA Levels, copies/mL
Week 52 Outcome
Undetectable
300 to < 3 log10
3-4 log10
> 4 log10
HBV DNA negative
 HBeAg positive
 HBeAg negative
91
94
69
67
30
40
5
10
Normal ALT levels
 HBeAg positive
 HBeAg negative
88
81
89
68
79
60
53
41
Virologic breakthrough
 HBeAg positive
 HBeAg negative
1
0
4
7
9
17
14
44
HBeAg seroconversion
41
26
13
4
Lai C, et al. AASLD 2005. Abstract 92.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBV DNA Undetectability at 1 Year
by Genotype
100
90
80
70
60
50
40
30
20
10
0
94
90
80
74
80
65
63
57
40
B
43
LdT
LAM
47
35
C
Other
HBeAg Positive
Thongsawat S, et al. EASL 2006. Abstract 110.
B
C
Other
HBeAg Negative
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
018 Trial: LdT vs ADV in HBeAg+ CHB
Patients Results at 24 Weeks
Serum HBV DNA
Mean Log¹º Change From
Baseline ± SE
0
PCR Negative at 6 Months
Telbivudine: 38.6%
Adefovir: 12.4%
-1
-2
HBeAg Loss at 6 Months
Telbivudine: 16%
Adefovir: 10%
P < .01
-3
Adefovir (n = 89)
-4
-4.97
-5
-6.3
-6
Telbivudine (n = 44)
-7
0
4
Chan HL, et al. EASL 2006. Abstract 52.
8
12
Weeks
16
20
24
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Tenofovir vs Adefovir in LAMRefractory Patients
 Retrospective analysis: LAM-refractory patients switched to tenofovir
300 mg/day (n = 38) or adefovir 10 mg/day (n = 68)
 More tenofovir patients with undetectable HBV DNA at M6
Undetectable HBV DNA
Month 12
Month 18
Month 24
Tenofovir 300 mg/day, %
(n = 38)
94
100
100
Adefovir 10 mg/day, %
(n = 68)
32
35
49
 More patients receiving tenofovir exhibited HBeAg and HBsAg loss vs
adefovir after up to 2 years
Outcome
HBeAg loss
HBsAg loss
van Bömmel F, et al. AASLD 2005. Abstract 184.
Tenofovir 300 mg/day, %
(n = 38)
49
19
Adefovir 10 mg/day, %
(n = 68)
13
6
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Tenofovir Use in Patients With
Incomplete Response to Adefovir
 Retrospective analysis (N = 20) of tenofovir in patients with
chronic hepatitis B who had suboptimal response to adefovir
– Lamivudine experienced prior to adefovir treatment
– Mean change from baseline in HBV DNA -0.4 log10 copies/mL (range: -4.2
to +3.4) during the adefovir treatment phase
 At tenofovir initiation, the mean HBV DNA was 6.6 log10
copies/mL
– Mean changes from baseline in HBV DNA
– -3.2 log10 copies/mL (range: -1.4 to -5.7) at 3 months
– -3.8 log10 copies/mL (range: -1.4 to -6.7) at 6 months
– 18 of 20 (90%) patients achieved HBV DNA < 400 copies/mL after a mean
of 4 months (range: 1-9)
– 3 patients lost HBeAg after 3-5 months
van Bömmel F, et al. AASLD 2005. Abstract 1000.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
12-Week Treatment With Clevudine
0
10 mg
Change From Baseline in
Log10 Serum HBV DNA
-0.5
30 mg
-1.0
Treatment
period
-1.5
50 mg
-2.0
-2.5
-3.0
-3.5
-4.0
-4.5
0
2
4
Marcellin P, et al. AASLD 2004.
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Weeks
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Clevudine in HBeAg-Positive Patients
 Multicenter, randomized, phase III trial
– Patients received 24 weeks of clevudine 30 mg/day (n = 243) or placebo
(n = 61)
– Follow-up: 24 weeks
Clevudine 30 mg/day
(n = 182)
Placebo
(n = 61)
-5.10*
-2.02*
-0.27
-0.68
HBV DNA undetectable at treatment end, %
59
0
Normalized ALT, %
 End of treatment
 End of follow-up
68*
61*
18
28
HBeAg seroconversion at end of follow-up, %
10
12
Outcome
Change in HBV DNA, log10 copies/mL
 End of treatment
 End of follow-up
*P < .0001 vs placebo
Yoo BC, et al. AASLD 2005. Abstract 186.
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Clevudine in HBeAg-Negative Patients
 Multicenter, randomized, phase III trial
– Patients received 24 weeks of clevudine 30 mg/day (n = 63) or placebo
(n = 23)
– Follow-up: 24 weeks
Outcome
Change in HBV DNA, log10 copies/mL
 End of treatment
 End of follow-up
Undetectable HBV DNA, %
 End of treatment
 End of follow-up
Normal ALT, %
 End of treatment
 End of follow-up
Yoo BC, et al. AASLD 2005. Abstract 183.
Clevudine 30 mg/day
(n = 63)
Placebo
(n = 23)
P Value
-4.25
-3.11
-0.48
-0.66
< .0001
< .0001
92
16
0
0
< .0001
75
71
33
29
.006
.007
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Pradefovir for Chronic Hepatitis B:
Week 48 Analysis
 Phase II randomized, open-label, multicenter trial of ADV-naive
patients (N = 244)
– Patients received adefovir 10 mg/day or pradefovir 5, 10, 20, or 30 mg/day
for 48 weeks
– Genotype C: 67%
– Asian: 100%
– HBeAg positive: 70%
Pradefovir
5
mg/day
(n = 47)
10
mg/day
(n = 49)
20
mg/day
(n = 48)
30
mg/day
(n = 48)
Adefovir
(n = 50)
HBV DNA < 400 copies/mL, %
45
63
56
71
36
ALT normalized
 HBeAg-positive patients, n
 HBeAg-negative patients, n
64
57
64
81
65
65
69
67
64
79
HBeAg seroconversion, %
18
12
10
19
17
Week 48 Outcome
Lee KS, et al. EASL 2006. Abstract 741.
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Mean (SE) Change in HBV DNA
From Baseline (log10 copies/mL)
Pradefovir for Chronic Hepatitis B:
Week 48 Analysis (cont’d)
0
-1
-2
-3
-4.09
-4.19
-4.84
-4.89
-5.54
-4
-5
-6
0
4
12
Lee KS, et al. EASL 2006. Abstract 741
18
24
Week
36
Pradefovir 5 mg (n = 47)
Adefovir 10 mg (n = 50)
Pradefovir 10 mg (n = 49)
Pradefovir 20 mg (n = 48)
Pradefovir 30 mg (n = 48)
48
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Serum HBV DNA Mean
Log10 Reduction From Baseline
Effect of Valtorcitabine on Serum
HBV DNA
1
0
Placebo
600 mg/day
900 mg/day
1200 mg/day
-1
-2
-3
-4
0
1
2
3
4
5
Study Week
Lim SG, et al. EASL 2005.
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
ANA380 (LB80380) in HBeAg-Positive
Patients With LAM Resistance
 Phase II, multicenter, doseescalating study (N = 65)
 5 dose escalation groups
– ANA380 (30, 60, 90, 150, or
240 mg/day) + LAM for 4
weeks followed by 8 weeks
ANA380 monotherapy
Lai CL, et al. EASL 2006.
Reduction in HBV DNA by Week 12
(log10 copies/mL)
 HBeAg-positive Asian
patients
ANA380 Dose
30
60
90
150
240
(n = 13) (n = 14)(n = 14) (n = 12) (n = 12)
0
-1
-2
-3
-2.8
-3.2
-4
-3.9
-3.9
-4.1
-5
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Update on the
Management of HBV
Marc Ghany, MD
Investigator, Liver Diseases Branch
NIDDK, National Institutes of Health
Bethesda, Maryland
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Goals of the 2006 NIH Workshop on
the Management of CHB
 Update definitions of response and endpoints of therapy
using more sensitive PCR-based assays
 Standardize the format in which clinical trials should be
presented
 Identify areas for future research
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Should HBV Genotyping Be Included
in Initial Assessment?
Yes
HBV genotypes may correlate with

Rate of spontaneous HBeAg seroconversion

Severity of liver disease

Development of clinically important mutations

Response to treatment
No

Many of the studies were retrospective, small and cross-sectional

Usually compared 2 major genotypes with each other A vs D, B vs C

Referral bias of studies conducted at tertiary care centers

Assays for genotyping not standardized
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Who Should Receive Treatment?
HBsAg Positive
HBeAg
Inactive carrier/mild
chronic hepatitis
Neg
HBV DNA < 104 IU/mL;
ALT normal
3-6 months
Monitor every
3-6 months
Decompensated
cirrhosis
Pos
Grey
zone
Consider Liver
biopsy
HBV DNA > 104 IU/mL;
elevated ALT
3-6 months
Consider antiviral
therapy
Consider
antiviral
therapy/
refer for
OLT
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Should HBeAg(+) Patients With Normal
ALT but High HBV DNA Receive Therapy?
Yes
 Older patient with higher risk for HCC
 Patients with strong family history of HCC
 Patients requiring cytoreductive chemotherapy
 Patients in third trimester of pregnancy with high viral load
No
 Poor response to therapy
 Risk of developing antiviral resistance
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Definitions of Response
Virological
 Full: decrease in HBV DNA to levels that are undetectable by
sensitive PCR assay, eg, < 60 IU/mL
 Partial: decrease in HBV DNA by at least 2 logs and to less than
20,000 IU/mL
 Primary nonresponse: decrease in HBV DNA by < 2 logs
Serological
 HBeAg seroconversion: loss of HBeAg with gain of anti-HBe
 HBsAg seroconversion: loss of HBsAg with gain of anti-HBs
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Definitions of Response
Biochemical
 Normalization of serum ALT level
Histological
 Decrease in hepatic necroinflammatory score by at least
2 points with no worsening in fibrosis score
Complete response
 Combined biochemical, virological, serological (loss of HBsAg),
and histological
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Timing of Response
On-treatment response
 Initial response: response achieved at any time within the first
12 months of therapy
 End-of-treatment response: response at the end of a defined
course of therapy
 Maintained response: response that persists while on therapy
 Breakthrough: response that is lost while on therapy
Off-treatment response
 Sustained response: response that is maintained for ≥ 6 months
after therapy is stopped
 Relapse: response that is lost after therapy is stopped
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Interferon Therapy
 Pros
–
Finite duration of therapy
–
Durable response
–
No resistance
 Cons
–
Route of administration—injection
–
Frequent side effects
–
Cost
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Ideal Clinical Situation for IFN Therapy
 High ALT (> 5 x ULN) and low HBV DNA level
(< 200,000 IU/mL)
 Younger patient
 Black
 Well-compensated cirrhosis
 No contraindications to use of interferon
 ? Genotype A or B
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Lamivudine
 Pros
– Oral
– Negligible side effects
– Excellent safety profile
– Low cost
 Cons
– High rate of resistance and cross-resistance with other
nucleoside analogues
– Long/indefinite duration of therapy
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Ideal Clinical Situation for
Lamivudine Use
 Short duration of therapy
– Prevention of disease flares/reactivation during
chemotherapy
– Protracted or severe acute hepatitis
 Safety a concern
– During pregnancy
 Cost a concern
– HBeAg-negative CHB in developing countries
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Adefovir
 Pros
– Route of administration: oral
– Low rate of resistance
– Effective against lamivudine resistant virus
 Cons
– Slow response and high rate of primary nonresponse
– ? Renal toxicity with long-term use
– Long/indefinite duration of therapy
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Ideal Clinical Situation for
Adefovir Use
 HBeAg-positive and HBeAg-negative chronic hepatitis B
with low HBV DNA
 Management of lamivudine-resistant chronic hepatitis B
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Entecavir
 Pros
– Route of administration: oral
– Potent with low rate of resistance
– Effective against LAM-R
 Cons
– Long-term safety unknown
– Long/indefinite duration of therapy
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Ideal Clinical Situation for
Entecavir Use
 HBeAg-positive or HBeAg-negative chronic hepatitis B
with high viral load
 Management of lamivudine resistance
 Management of HIV/HBV coinfection in patients who do
not require HAART
clinicaloptions.com/hep