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Roadmap for Management
of Patients with
Chronic Hepatitis B (CHB)
Prof. Xinxin Zhang
Rui Jin Hospital
Jiao Tong University
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2
Contents
Introduction
Presentation Objectives
Data Review: Associations of HBV DNA with Outcomes
i. Natural history studies
ii. Impact of treatment
Key role of HBV DNA in On-Treatment Management
i. Timing and magnitude of HBV DNA suppression
On-Treatment Roadmap Concept
Summary and Conclusions
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Introduction
Treatment challenges highlight need for new management approach
 Treating hepatitis B virus (HBV) infection continues to be a
challenge for physicians due to
– Complications arising from chronic HBV (CHB)
– The increasing number of available therapeutic options
 Treatment guidelines recognize the importance of monitoring and
evaluation of treatment response; however, a standard
on-treatment management approach does not exist
 To establish a new treatment paradigm, we should ask
– Does long-term suppression of HBV replication achieve the goals of
treatment in CHB?
– Can the degree of on-treatment viral suppression predict outcomes?
– Does profound, early viral suppression at week 24 predict clinical
outcomes?
– Can a Roadmap concept help achieve the goals of treatment in CHB?
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Presentation Objectives
 To explore the association between persistent viraemia and
hepatitis disease progression
 To assess the relationship between the degree of viral
suppression and clinical outcome
 To assess the role of early and effective viral load reduction and
the association with clinical outcomes*
 To review an on-treatment management strategy – the roadmap
concept – that may offer a valuable opportunity for enhanced
treatment response
* For
safety information on the products referred to, please refer to the Product Information.
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Data Review: Associations of
HBV DNA with Outcomes
i. Natural history studies
Correlation Between HBV DNA and Histologic
Activity Index (HAI) in Untreated Patients
HAI at baseline
12
10
8
6
4
r=0.78; P=0.0001
2
0
0
2
4
6
8
10
12
Baseline HBV DNA level, log10 copies/mL

Review of 26 prospective clinical trials found a statistically significant
correlation between viral load level and histological grading
Mommeja-Marin et al 2003
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Cirrhosis: Association with Baseline HBV DNA
Taiwan natural history study
Cumulative incidence of cirrhosis, %
40
Multivariate adjusted
hazard ratio
HBV DNA at entry, copies/mL:
>1,000,000
10,000–999,999
1000–9999
300–999
P<0.001 (log-rank test)
<300
30
6.5
20
5.6
10
2.5
1.4
1.0
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Year of follow-up
Iloeje et al 2006
8
Hepatocellular Carcinoma (HCC)
Association with baseline HBV DNA: Taiwan natural history study
Cumulative incidence of HCC, %
20
HBsAg-positive, untreated participants (n=3,653)
14.9
15
12.2
10
5
3.6
1.3
1.4
<300
300–103
0
103–104
104–106
>106
HBV DNA at baseline, copies/mL
Chen et al 2006
Evidence for Association Between HBV DNA
and Clinical Outcomes
 Natural history studies demonstrate
– Lower HBV DNA levels are associated with better underlying
histology
– High HBV DNA may be an independent predictor for cirrhosis
and HCC
– Sustained suppression of HBV may reduce long-term risk of
cirrhosis and HCC
 Hypothesis needs to be proven prospectively
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Data Review: Associations of
HBV DNA with Outcomes
ii. Impact of treatment
Correlation Between HBV DNA and Histologic
Activity Index (HAI) in Treated Patients
HAI improvement from baseline
5
4
3
2
r=0.96; P<0.000003
1
0
–1
1
2
3
4
5
–2
Median HBV DNA level decrease from baseline, log10 copies/mL
 Consistent relationship in treated and untreated patients
 HBV DNA could be used as a marker of efficacy
Mommeja-Marin et al 2003
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Viral Suppression at Week 72 is Associated with
Histologic Improvement
Patients with histological response at week 72, %
100
HBeAg-negative patients (n=537) treated with lamivudine,
peg-interferon alfa-2a, or both combined for 48 weeks
80
P<0.001
60
56
40
32
20
0
116/208
105/329
<20,000
≥20,000
HBV DNA at week 72, copies/mL
Marcellin et al 2004
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Viral Suppression Significantly
Impacts Disease Progression
Patients with disease progression, %
HBeAg-positive patients (n=651) treated
with lamivudine or placebo
25
20
Placebo
Lamivudine – YMDDm
Lamivudine – Wild type
15
21%
13%
10
5%
5
0
0
6
12
18
24
30
36
Months
Liaw 2005
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Viral Suppression Improves Outcomes
Studies reporting associations with outcomes
Outcome
Citation(s)
Improved clinical outcomes after response
to interferon alfa (HBeAg+ or HBeAg-)
– Niederau et al 1996
– Papatheodoridis et al 2001
– van Zonneveld et al 2004
– Lin et al 2005
Improved clinical outcomes with lamivudine
long-term viral suppression
– DiMarco et al 2004
– Liaw et al 2004
– Papatheodoridis et al 2005
Decreased clinical events, improved Child-Pugh
scores, decreased HCC in patients with
advanced liver disease treated with lamivudine
– Liaw et al 2004
Improved virological, biochemical, and clinical
parameters in lamivudine-resistant patients with
decompensated cirrhosis treated with adefovir
– Schiff et al 2004
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Key Role of HBV DNA in
On-Treatment Management
i. Timing and magnitude of HBV
DNA suppression
Rapid and Profound HBV Suppression:
a Critical Goal of Therapy
Primary goal of treatment
Outcomes
 Sustained suppression of
HBV replication to the lowest
possible level
 Delay in progression to
cirrhosis and HCC
 Improved survival
 Reduced resistance
 Increased seroconversion
 Improved liver histology
 Normalised alanine
aminotransferase (ALT) levels
Fontana 2003; Gauthier et al 1999; Keeffe et al 2006; Liaw et al 2004;
Liaw et al 2005; Mommeja-Marin et al 2003; Niederau et al 1996; Yuen et al 2001
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Viral Suppression with Peg-Interferon alfa-2a
Association with subsequent HBV DNA response
Patients with HBV DNA <20,000 copies/mL at 72 weeks (%)
100
HBeAg-negative patients (n=176) treated with
peg-interferon alfa-2a for 48 weeks
80
61
P<0.001
60
40
31
20
0
<400
≥400
Serum HBV DNA level at 12 weeks, copies/mL
Farci et al 2005
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Profound, Early Viral Suppression
Week 24 viral load and 2-year outcomes† with telbivudine and lamivudine
HBeAg-positive (n=921)
HBeAg-negative (n=446)
PCR-negative at 2 years, %
100
100
82
80
73
80
61 60
Telbivudine
Lamivudine
88
78
68
60
60
63
60
40
40
40
28
25
20
20
0
7
203 146
≤QL
57
63
300–
3 log
83
79
3–4 log
107 165
>4 log
20
20
5
0
178 157
18
≤QL
20
300–
3 log
16 24
3–4 log
10
20
>4 log
HBV DNA at week 24, copies/mL
QL=quantification limit (polymerase chain reaction (PCR)-undetectable at <300 copies/mL
by COBAS® Amplicor™) †Preliminary data from locked database
Di Bisceglie et al 2006
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Profound, Early Viral Suppression
Week 24 viral load and 1-year outcomes with entecavir
HBeAg-positive
HBeAg-negative
PCR-negative at week 48, %
100
96
100
97
95
84
82
80
80
60
60
40
40
40
40
25
20
20
0
153/195
28/34
47/118
6/15
≤400
400–
3 log
3–5 log
>5 log
0
240/247
≤400
20/21
400–
3 log
32/38
3–5 log
1/4
>5 log
HBV DNA at week 24, copies/mL
BMS Entecavir AVDAC Briefing Document 2005
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Magnitude of Viral Response to Lamivudine
Association with higher rates of HBeAg seroconversion
Median HBV DNA, log10 copies/mL
10
Median <104 (n=12)
Median >104 (n=11)
8
6
HBeAg seroconversion
occurred only in this group
4
2
Baseline
8
16
24
32
40
48
56
64
72
Weeks
Potential assessment of early virological
response to predict outcome
Gauthier et al 1999
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Early Viral Suppression with Telbivudine
Association with 2-year HBeAg seroconversion†
Seroconversion at 2 years, %
50
HBeAg-positive patients
46
39
40
30
21
20
10
6
n=183
n=54
n=81
n=107
<QL
QL–3
3–4
>4
0
Serum HBV DNA level at 24 weeks, log10 copies/mL
†Preliminary
data from locked database
Han et al 2007
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Early Viral Suppression with Entecavir
Association with 1-year HBeAg seroconversion†
Seroconversion at 48 weeks, %
HBeAg-positive patients
50
40
30
30
24
20
12
13
10
47/159
8/34
14/117
2/15
<400
400–3 log
3–5 log
>5 log
0
HBV DNA at 24 weeks, copies/mL
BMS Entecavir AVDAC Briefing Document 2005
Profound, Early Viral Suppression Correlates
with Lower Risk of Resistance
Patients with lamivudine resistance , %
100
80
HBeAg-positive
patients (n=159), median
30 months follow up
64
60
20
0
Patients with ADV resistance at week 192, %
100
80
HBeAg-negative
patients (n=125)
60
40
32
8
1/12
<200
3/23
20
13/41
49
40
13
76/118
<3 log <4 log >4 log
HBV DNA level at week 24,
copies/mL
23
6
0
<3 log
>3 log
HBV DNA level at week 48,
copies/mL
Hadziyannis et al 2006; Yuen et al 2001
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Early Viral Suppression with Telbivudine
Association with resistance†
Patients with telbivudine resistance week 92, %
100
80
HBeAg-negative patients
60
60
40
20
n=178
20
12
2
n=18
≤300
300–3 log10
n=16
n=10
0
3 log10–4 log10
>5 log10
HBV DNA level at week 24, copies/mL
†Preliminary
analysis of patients with viral rebound at week 92
Di Bisceglie et al 2006
Early Viral Suppression Can Be a Signpost for
Future Therapeutic Response
HBeAg-positive
Reduce
serum
HBV DNA
Normal ALT
PCR
negative
HBeAg
loss
Signpost
Start
Rx.
Anti-HBeAg
seroconversion
HBsAg loss
Goals of HBV therapy
a) Prevent cirrhosis,
liver failure and HCC
b) Improve survival
HBeAg-negative
Reduce
serum
HBV DNA
PCR
negative
Normal ALT
Signpost
Liver inflammation and fibrosis
HBsAg loss
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On-Treatment Roadmap
Concept
Potential Foundation for Building a CHB
Therapeutic Roadmap
On-treatnent early virological response monitoring
 Can help to identify suboptimal responders
 Provides opportunities to modify treatment to
enhance antiviral efficacy
 Can help support individualised treatment maps
 Has the potential to improve long-term outcomes
Response markers act as signposts
for clinical management
Additional
interventions
required
Chosen therapy
is effective and
well tolerated
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Proposed New Treatment Algorithm for CHB
Recent expert panel and Roadmap publication
??
Unresolved questions
What
When
What
Which
Is the best on-treatment marker?
Is the best timing for decision points?
Cut-off level for on-treatment decisions?
Type of initial/add-on therapy?
Expert panel convened to
evaluate evidence and develop
treatment recommendations

Report of an International Workshop: Roadmap
for Management of Patients Receiving Oral
Therapy for Chronic Hepatitis B
Keeffe EB et al.
Clinical Gastroenterology and Hepatology 2007
Keeffe et al 2007
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Roadmap Concept
Management algorithm according to 12-week virologic response
Start treatment
Week 12: assessment for
primary non-response
≥1 log 10 copies/mL
decrease from baseline:
primary response
Continue
<1log10 copies/mL
decrease from baseline:
primary failure
Non-compliant
Compliant
Counsel
Change Tx
Keeffe et al 2007
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Roadmap Concept
On-treatment responses
Start treatment
Week 12: assessment for
primary non-response
Week 24: early predictors
of efficacy
Complete response
PCR negative†
†Defined
as <300 copies/mL
Partial response
Inadequate response
≥60–<2000 IU/mL or
≥300–<10,000 copies/mL
>2000 IU/mL or
≥10,000 copies/mL
Keeffe et al 2007
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Roadmap Concept
Management algorithm for complete response at 24 weeks
Week 24: early predictors
of efficacy
Complete response

PCR negative†


Continue
Monitor 6-monthly
†Defined
as <300 copies/mL
Definition of complete response:
PCR negative (≤300 copies/mL)
Interval for monitoring can be prolonged to
every 6 months
In patients with more advanced disease,
monitoring every 3 months or more
frequently
Keeffe et al 2007
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Roadmap Concept
Management algorithm for partial response at 24 weeks
Week 24: early predictors
of efficacy
Partial response
≥60–<2000 IU/mL or
≥300–<10,000 copies/mL
Add another drug
without crossresistance or continue
Monitor 3-monthly
Keeffe et al 2007
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Roadmap Concept
Management algorithm for inadequate response at 24 weeks
Week 24: early predictors
of efficacy
Inadequate response
≥2000 IU/mL or
≥10,000 copies/mL
Adapt regimen
Complete response
†Defined
as <300 copies/mL
Partial response
Inadequate response
Keeffe et al 2007
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HBV Roadmap Proposal: Monitoring
 Monitor every 3 months
 If patient achieves complete response by 48 weeks, follow
monitoring recommendation (6-monthly)
 If patient shows continuous decline up to 48 weeks, but still has
higher viral load than a complete responder, continue to monitor
every 3 months
 If patient shows an increase or ‘plateauing’ of viral level, they
should be treated based on roadmap recommendation for
inadequate or non-responder
 In patients with more advanced disease, more frequent
monitoring may be indicated
Keeffe et al 2007
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Summary and Conclusions
Importance of early monitoring of virologic response to therapy
 Early and sustained viral suppression has been
associated with prevention of disease progression
 HBV DNA is a critical signpost in the on-treatment
management of CHB
 On-treatment management offers opportunities to
optimise treatment response
– Essential to identify suboptimal responses
– Modify management to enhance antiviral efficacy
– Potential to improve long-term outcomes
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How should the roadmap be applied to
telbivudine?
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Conclusion from
Report of an International Workshop: Roadmap for Management
of Patients Receiving Oral Therapy for Chronic Hepatitis B
Early monitoring of the virologic response to therapy in chronic
hepatitis B treated with oral nucleos(t)ides is essential…
Use of this roadmap should permit improved individualized ontreatment management designed to enhance long-term patient
outcomes
1.Keeffe
EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane E, Jacobson IM, Lim SG,
Naoumov NN, Marcellin P, Piratvisuth T, Zoulim F. Clin Gastroenterol Hepatol. In press.
37
How May the HBV Treatment Roadmap be
Applied to Telbivudine Treatment?
38
Start Telbivudine
Assessment of Primary Response at week 12
Early Virologic Response Efficacy at Week 24
PCR Negative
(<300 copies/mL)
HBV DNA
300 copies/mL
to 10，000 copies/mL
HBV DNA
> 10，000 copies/mL
Maintain Telbivudine
Adapted form: Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane E, Jacobson IM, Lim SG,
Naoumov NN, Marcellin P, Piratvisuth T, Zoulim F. Clin Gastroenterol Hepatol. In press.
38
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Viral Load Achieved by Week 24:
Telbivudine vs. Lamivudine
HBeAg Positive
HBeAg Negative
100%
100%
36%
80%
18%
60%
17%
13%
40%
20%
14%
45%*
% of patients PCR non-detectable
% of patients PCR non-detectable
24%
5%
7%
9%
8%
11%
80%
9%
60%
40%
80%*
71%
20%
32%
0%
0%
Telbivudine, n=450
Lamivudine, n=453
<QL
QL-3 Log
Telbivudine, n=222
3-4 Log
Lamivudine, n=221
>4 Log
* P < 0.05
Di Bisceglie A, et al. Presented at AASLD 2006
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Telbivudine Is A Good Option for Therapy for
HBeAg-Positive Patients
Baseline
ALT ≥ 2 x ULN
N=558
49%
of Telbivudine Treated Patients
Achieve PCR Negativity (≤300 copies/mL)
at Week 24
86%
49%
85%
2%
PCR Negative
Week 104
Seroconversion
Week 104
ALT Normalization
Week 104
Resistance
Week 92
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Telbivudine Is A Good Option for Therapy for
HBeAg-Negative Patients
All telbivudine-treated
HBeAg-Negative Patients
N=588
80%
of Telbivudine Treated Patients
Achieve PCR Negativity (≤300 copies/mL)
at Week 24
88%
PCR Negative
Week 104
N=78/86
49%
Seroconversion
Week 104
2%
Resistance at
92 weeks
41
How May the HBV Treatment Roadmap be
Applied to Telbivudine Treatment?
42
Start Telbivudine
Early Virologic Response Efficacy at Week 24
HBV DNA
PCR Negative
(<300 copies/mL)
HBV DNA
≥300–<10,000 copies/mL
HBV DNA
> 10，000 copies/mL
Maintain Telbivudine Week 52 - Monitor HBV DNA closely
If PCR Negative
Maintain Telbivudine Monotherapy
If PCR Positive revise
treatment strategy
Adapted form: Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane E, Jacobson IM, Lim SG,
Naoumov NN, Marcellin P, Piratvisuth T, Zoulim F. Clin Gastroenterol Hepatol. In press.
42
How May the HBV Treatment Roadmap be
Applied to Telbivudine Treatment?
43
Start Telbivudine
Assessment of Primary Response at week 12
Early Virologic Response Efficacy at Week 24
PCR Negative
(<300 copies/mL)
HBV DNA
≥300–<10,000 copies/mL
HBV DNA
> 10,000 copies/mL
Revise treatment
strategy
Adapted form: Keeffe EB, Zeuzem S, Koff RS, Dieterich DT, Esteban-Mur R, Gane E, Jacobson IM, Lim SG,
Naoumov NN, Marcellin P, Piratvisuth T, Zoulim F. Clin Gastroenterol Hepatol. In press.
43
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