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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Anna S.F. Lok, MDProfessor of Internal Medicine and Director of Clinical HepatologyUniversity of Michigan, Ann ArborAnn Arbor, Michigan
Hepatitis B Virus Resistance:
An Overview by a Clinician for a Clinical Audience
clinicaloptions.com/hep
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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
What Causes Antiviral-Resistant HBV Mutants to Become Dominant?
Antiviral Therapy
SS
S
SS
S SS
SR
R
R RR R R
Survival of the fittest: selection of virus with survival advantage in the presence of antiviral therapy
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Factors Associated With Antiviral Resistance
VIRUSDRUG
HOST
Daily production Replication fidelity Preexistent mutations
Potency Structure Genetic barrier to resistance
Prior therapy Compliance Immune status Pharmacogenetics Body size
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Better Viral Suppression Reduces the Risk of Genotypic Resistance
Yuen MF, et al. Hepatology. 2001;34:785-791 Locarnini S, et al. J Hepatol. 2005;42(suppl.2):17.
LAMResistance (median 29 mos)
vs Week 24 HBV DNA
ADVResistance at Week 144
vs Week 48 HBV DNA
% R
esis
tan
ce
8%13%
32%
64%
4%
26%
67%
Week 24 HBV DNA (log10 c/mL)N = 159 HBeAg-positive patients
< ND 3-6 >6< ND > 4< 4< 3
Week 48 HBV DNA (log10 c/mL) N = 114, primarily HBeAg-negative
patients
clinicaloptions.com/hep
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
Entecavir 169 or 202 184 or 250
M204V/I + 1 ETV-RM204V/I + 2 ETV-R
~ 1 2-10
10-250 > 500
ETV-R, entecavir resistance mutation.
clinicaloptions.com/hep
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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Manifestations of Antiviral Resistance
HB
V D
NA
(lo
g1
0 IU
/mL
)
AL
T (
U/L
)
BiochemicalbreakthroughULN
Viralbreakthrough
0 1 2 3
Years
Antiviral Treatment
0
2
4
6
8
Hepatitis flare
Viral rebound
Genotypicresistance
-1
clinicaloptions.com/hep
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
clinicaloptions.com/hep
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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Selection of LAM-Resistant Mutations Limits Future Treatment Options
L18
0M
A18
1V/T
T18
4G/S
/A/C
S20
2G
M20
4V/1
N23
6T
M25
0V
LAM
FTC
LdT
ADV
ETV
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Multirug-Resistant HBV Responds Poorly to Combination Therapy
Brunelle MN, et al. Hepatology. 2005;41:1391-1398.
HBV LAMFold Δ
ADVFold Δ
LAM + ADVFold 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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
5 samples with single drug resistant mutations
11 samples with MDR mutations
Multidrug-Resistant HBV Mutants
15 samples from 6 patients
Direct sequencing
Clonal analysis215 clones
Mutations to > 1 drug on the same
genome in 183 clones
Mutations to only 1 drug in 31 clones
Wild-type HBV DNA in
1 clone
Mutations to > 1 drug on the same
genome in 5 clones
Mutations to only 1 drug in 89 clones
94 clones
Yim HJ, et al. Hepatology. 2006. In press.
clinicaloptions.com/hep
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 multidrug-resistant HBV
clinicaloptions.com/hep
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
clinicaloptions.com/hep
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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Rescue Therapy for Antiviral-Resistant 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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
The Changing Face of Antiviral Therapy
Robert P. Perrillo, MDDirector, Academic AffairsSection of Gastroenterology and HepatologyOchsner Clinic FoundationNew Orleans, Louisiana
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBeAg Seroconversion vs Level of HBV DNA Suppression
Lau GK, et al. N Engl J Med. 2005;352:2682-2695.
On treatment Follow-up
Mea
n H
BV
DN
A (
log
10 c
op
ies/
mL
)
2
4
6
8
10
12
0 6 12 18 24 30 36 42 48 54 60 66 72
-4.48
-5.81
-7.18*
PEG-2a + placebo
HBeAg seroconversionEOF = 32%*
HBeAg seroconversionEOF = 27%*
PEG-2a + LAM
LAM
HBeAg seroconversionEOF = 19%
Weeks
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
On-Treatment ALT Maximums and HBeAg Seroconversion at Week 72
Piratvisuth T, et al. EASL 2005.
Patients With
HBeAg Seroconversion Rates in
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%)
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
On-Treatment Flares (3 x BSL) With PEG-IFN α-2b According to Genotype
Flink HJ, et al. Gut. 2005;54:1604-1609.
015304560
75
An = 19
Per
cen
t
33%
74%
43%
Bn = 7
Cn = 11
Dn = 26
P = .046
On-treatment flares
010203040
50
An = 19
18%
47%
28%19%
Bn = 7
C n = 11
D n = 26
P =.05
Treatment response after flare
27%
NB: Only host-induced flare and height of ALT during flare predicted
response
All HBsAg seroconverters had
host-induced flare
Per
cen
t
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBsAg Seroconversion: PEG-IFN in HBeAg(+) Patients According to Genotype
1. Flink HJ, et al. Am J Gastro. 2006;101:297-303. 2. Hadziyannis S, et al. EASL 2005.
PEG-IFN α-2b[1]
0
3
6
9
12
15
A n = 90
3%
9%
2%
Bn = 23
C n = 39
D n = 103
1814%
Pat
ien
ts (
%)
21
24
PEG-IFN α-2a[2]
0
3
6
9
12
15
A n = 23
2%0% 0%
Bn = 76
C n = 162
D n = 9
18
22%
Pat
ien
ts (
%)
21
24
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
6-Month and 2-Year Posttreatment Responses in HBeAg-Negative CHB
1. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. 2. Marcellin P, et al. EASL 2006.
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]
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Tenofovir vs Adefovir in LAM-Resistant CHB
van Bömmel F, et al. Hepatology. 2004;40:1421-1425.
*P < .001 vs ADV
Week 24 Week 36 Week 480
-7Mean change in log10 HBV DNA (PCR)
Tenofovir 300 mg/day for 72-130 weeks (n = 35)
Adefovir 10 mg/day for 60-80 weeks (n = 18)
% HBV DNA < 400 copies/mL at Week 48
100% of tenofovir patients
44% of adefovir group-5.2*
-2.6
-5.4*
-3.0
-5.5*
-2.8
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Virologic Response to Entecavir vs LAM: Week 48 vs 96Parameter 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.
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Entecavir vs Lamivudine in LAM-Refractory, HBeAg+ CHB
Sherman M, et al. Hepatology. 2004;40:1465-1473.
Pat
ien
ts (
%)
HistologicImprovement
100
0Composite Endpoint†
*55
*55
28
4
0
-0.48
-5.14*-6
HBV DNA Mean Change From Baseline
(log10 copies/mL)
Entecavir 1.0 mg QD (n = 141)
LAM 100 mg QD (n = 145)
†ALT < 1.25 x ULN, ALT < 1.25 x ULN, HBV DNA < 0.7 MEq/mLHBV DNA < 0.7 MEq/mL
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Combination LAM + ADV: Efficacy Outcomes at Week 104
*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
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
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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
Lai, et al. Gastroenterology. 2005
LdT + LAM LdTLAM
% with HBeAg loss * 28 % 33% 17%
% HBeAg sero 22% 31% 15%
% Patients HBV DNA negative 32% 61%* 49% by PCR
N 18 42 41
*P < .05 compared to LAM
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Hepatitis B: Histology and Normal ALTin 452 Chinese Patients
Yang et al. Chinese J Dig Dis. 2002;3:150.
Pa
tie
nts
(%
)
100
0
40 42
7580
34
4652
73
Grade 2 or More Stage 2 or More
Normal ALT,HBeAg positive
Normal ALT,HBeAg negative
Normal ALT,HBeAg negative
Normal ALT,HBeAg positive
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Risk of Cirrhosis or HCC According to Baseline HBV DNA
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.
Population Outcome Variable HBV DNA Relative Risk
3754 AsianAmericans[1]
HCC < 105
> 105
4.18.5
1520 Chinese[2] Mild/mod CHBCirrhosis/HCC
< 105 vs > 105 1.4, 1.01.9, 2.5
3851 Taiwanese[3] Cirrhosis ≤103 vs 104 vs ≥ 105
E (-) 1.0, 1.9, 4.9E (+) 2.6, 6.2, 8.6
3582 Taiwanese[4] Cirrhosis ≥ 104 to < 105
≥ 105 to < 106
≥ 106
2.55.66.5
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
New Drugs for the Treatment of Chronic Hepatitis B
Patrick Marcellin, MD, PhDProfessor of MedicineService d’HepatologieINSERM CRB3Hôpital BeaujonUniversity of ParisClichy, 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
Shiffman M, et al. AASLD 2004. Abstract 22.
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 -- --
clinicaloptions.com/hep
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
Lau G, et al. AASLD 2004. Abstract 245.
Median Change in HBV DNA
Adefovir, log10 copies/mL
(n = 14)
Adefovir + Emtricitabine, log10 copies/mL
(n = 24)P Value
Week 24 -3.19 -5.08 --
Week 48 -3.40 -5.44 .03
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
GLOBE: Year 1 Results of Telbivudine for Chronic Hepatitis B
Lai C, et al. AASLD 2005. Abstract LB01.
Summary of Year 1 Results With Telbivudine
Outcome HBeAg-Positive Patients, % HBeAg-Negative Patients, %
LdT(n = 458)
LAM(n = 463)
LdT(n = 222)
LAM(n = 224)
Undetectable HBV DNA Week 52 Week 76
75*75* (n = 163)
6758 (n = 165)
88*84* (n = 68)
7167 (n = 67)
Virologic breakthrough by Week 48 3* 10 2* 9
Normalized ALT Week 52 Week 76
7778* (n = 163)
7568 (n = 165)
7476 (n = 68)
7964 (n = 67)
Fibrosis decline by Week 52 68 61 59 46
HBeAg seroconversion by Week 76 41* (n = 100) 26 (n = 93) N/A N/A
*P < .05 vs LAM
GLOBE trial: phase III international study (N = 1367)
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
GLOBE: Early HBV DNA Levels and Year 1 Outcomes With Telbivudine
Lai C, et al. AASLD 2005. Abstract 92.
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
9194
6967
3040
510
Normal ALT levels HBeAg positive HBeAg negative
8881
8968
7960
5341
Virologic breakthrough HBeAg positive HBeAg negative
10
47
917
1444
HBeAg seroconversion 41 26 13 4
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
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
HBV DNA Undetectability at 1 Year by Genotype
Thongsawat S, et al. EASL 2006. Abstract 110.
HBeAg Positive
5765
47
9080
94
40 4335
8074
63
0102030405060708090
100
B C Other B C Other
LdTLAM
HB
V D
NA
Un
det
ecta
ble
(%
)
HBeAg Negative
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
018 Trial: LdT vs ADV in HBeAg+ CHB Patients Results at 24 Weeks
Chan HL, et al. EASL 2006. Abstract 52.
Ser
um
HB
V D
NA
Mea
n L
og
¹º C
han
ge
Fro
m
Bas
elin
e ±
SE
0
-1
-2
-3
-4
-5
-6
-7
Weeks
Adefovir (n = 89)
Telbivudine (n = 44)
PCR Negative at 6 MonthsTelbivudine: 38.6%Adefovir: 12.4%
P < .01
-6.3
-4.97
HBeAg Loss at 6 MonthsTelbivudine: 16%Adefovir: 10%
0 4 8 12 16 20 24
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Tenofovir vs Adefovir in LAM-Refractory 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
More patients receiving tenofovir exhibited HBeAg and HBsAg loss vs adefovir after up to 2 years
van Bömmel F, et al. AASLD 2005. Abstract 184.
Undetectable HBV DNA Tenofovir 300 mg/day, %(n = 38)
Adefovir 10 mg/day, %(n = 68)
Month 12 94 32
Month 18 100 35
Month 24 100 49
Outcome Tenofovir 300 mg/day, %(n = 38)
Adefovir 10 mg/day, %(n = 68)
HBeAg loss 49 13
HBsAg loss 19 6
clinicaloptions.com/hep
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.
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
12-Week Treatment With Clevudine
Marcellin P, et al. AASLD 2004.
-4.5
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Weeks
Ch
ang
e F
rom
Bas
elin
e in
L
og
10 S
eru
m H
BV
DN
A
Treatmentperiod
10 mg
30 mg
50 mg
clinicaloptions.com/hep
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
Yoo BC, et al. AASLD 2005. Abstract 186.
OutcomeClevudine 30 mg/day
(n = 182)Placebo (n = 61)
Change in HBV DNA, log10 copies/mL End of treatment End of follow-up
-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*
1828
HBeAg seroconversion at end of follow-up, % 10 12*P < .0001 vs placebo
clinicaloptions.com/hep
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
Yoo BC, et al. AASLD 2005. Abstract 183.
OutcomeClevudine 30 mg/day
(n = 63)Placebo (n = 23)
P Value
Change in HBV DNA, log10 copies/mL End of treatment End of follow-up
-4.25-3.11
-0.48-0.66
< .0001< .0001
Undetectable HBV DNA, % End of treatment End of follow-up
9216
00 < .0001
Normal ALT, % End of treatment End of follow-up
7571
3329
.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%
Lee KS, et al. EASL 2006. Abstract 741.
Week 48 Outcome
Pradefovir
Adefovir (n = 50)
5 mg/day(n = 47)
10 mg/day(n = 49)
20 mg/day(n = 48)
30 mg/day(n = 48)
HBV DNA < 400 copies/mL, % 45 63 56 71 36
ALT normalized HBeAg-positive patients, n HBeAg-negative patients, n
6457
6481
6565
6967
6479
HBeAg seroconversion, % 18 12 10 19 17
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Pradefovir for Chronic Hepatitis B: Week 48 Analysis (cont’d)
Lee KS, et al. EASL 2006. Abstract 741
Week
-4.09
-5.54
Pradefovir 5 mg (n = 47)
0 4 12 18 24 36 48
-4.19
-4.89
-4.84
0
-1
-2
-3
-4
-5
-6Mea
n (
SE
) C
han
ge
in H
BV
DN
A
Fro
m B
asel
ine
(lo
g10
co
pie
s/m
L)
Adefovir 10 mg (n = 50)
Pradefovir 10 mg (n = 49)Pradefovir 20 mg (n = 48)
Pradefovir 30 mg (n = 48)
clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Effect of Valtorcitabine on Serum HBV DNA
Lim SG, et al. EASL 2005.
-4
-3
-2
-1
0
1
0 1 2 3 4 5
Study Week
Placebo600 mg/day900 mg/day1200 mg/day
Ser
um
HB
V D
NA
Mea
nL
og
10 R
edu
ctio
n F
rom
Bas
elin
e
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, dose-
escalating study (N = 65)
HBeAg-positive Asian patients
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.
-5
-2.8-3.2
-3.9 -3.9 -4.1-4
-3
-2
-1
0
30(n = 13)
60(n = 14)
90(n = 14)
150(n = 12)
240(n = 12)
Red
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clinicaloptions.com/hep
4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Update on the Management of HBV
Marc Ghany, MDInvestigator, Liver Diseases BranchNIDDK, National Institutes of HealthBethesda, 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
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4th Annual Clinical Care Options for Hepatitis Symposium: HBV Highlights
Who Should Receive Treatment?
HBsAg Positive
HBeAgInactive carrier/mild
chronic hepatitis
Monitor every 3-6 months
Decompensated cirrhosis
Consider antiviral therapy/ refer for
OLT
HBV DNA > 104 IU/mL; elevated ALT
3-6 months
Pos
Consider antiviral therapy
Neg
HBV DNA < 104 IU/mL; ALT normal 3-6 months
Grey zone
Consider Liver biopsy
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
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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
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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
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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
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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