1

Roadmap for Management of Patients with

Chronic Hepatitis B (CHB)

Prof. Xinxin ZhangRui Jin Hospital

Jiao Tong University

2

Introduction

Presentation Objectives

Data Review: Associations of HBV DNA with Outcomesi. Natural history studiesii. Impact of treatment

Key role of HBV DNA in On-Treatment Managementi. Timing and magnitude of HBV DNA suppression

On-Treatment Roadmap Concept

Summary and Conclusions

Contents

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IntroductionTreatment 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

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Correlation Between HBV DNA and Histologic Activity Index (HAI) in Untreated Patients

Review of 26 prospective clinical trials found a statistically significant correlation between viral load level and histological grading

2 4 6 8 10 1200

2

4

6

8

10

12

Baseline HBV DNA level, log10 copies/mL

r=0.78; P=0.0001

HAI at baseline

Mommeja-Marin et al 2003

7

2.51.4

1.0

5.6

6.5

P<0.001 (log-rank test)

Multivariate adjusted hazard ratio

0

10

20

30

40

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Year of follow-up

Cumulative incidence of cirrhosis, %

>1,000,000

10,000–999,999

1000–9999

300–999

<300

HBV DNA at entry, copies/mL:

Cirrhosis: Association with Baseline HBV DNA Taiwan natural history study

Iloeje et al 2006

8

1.3 1.4

3.6

12.2

14.9

0

5

10

15

20

Hepatocellular Carcinoma (HCC)Association with baseline HBV DNA: Taiwan natural history study

Cumulative incidence of HCC, %

HBV DNA at baseline, copies/mL

HBsAg-positive, untreated participants (n=3,653)

Chen et al 2006

<300 300–103 103–104 104–106 >106

9

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

10

Data Review: Associations of HBV DNA with Outcomes

ii. Impact of treatment

11

Consistent relationship in treated and untreated patients HBV DNA could be used as a marker of efficacy

Median HBV DNA level decrease from baseline, log10 copies/mL

HAI improvement from baseline

r=0.96; P<0.000003

1 2 3 4 5

–2

–1

0

1

2

3

4

5

Mommeja-Marin et al 2003

Correlation Between HBV DNA and Histologic Activity Index (HAI) in Treated Patients

12

56

32

0

20

40

60

80

100

<20,000 ≥20,000

P<0.001

HBV DNA at week 72, copies/mL

HBeAg-negative patients (n=537) treated with lamivudine, peg-interferon alfa-2a, or both combined for 48 weeks

Patients with histological response at week 72, %

Marcellin et al 2004

Viral Suppression at Week 72 is Associated with Histologic Improvement

105/329116/208

13

Months

0

5

10

15

20

25

0 6 12 18 24 30 36

13%

21%

5%

Liaw 2005

Patients with disease progression, %

Viral Suppression Significantly Impacts Disease Progression

Lamivudine – Wild typeLamivudine – YMDDmPlacebo

HBeAg-positive patients (n=651) treated with lamivudine or placebo

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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

16

Rapid and Profound HBV Suppression: a Critical Goal of Therapy

Outcomes

Primary goal of treatment

Delay in progression to cirrhosis and HCC

Improved survival Reduced resistance Increased seroconversion Improved liver histology Normalised alanine

aminotransferase (ALT) levels

Sustained suppression of HBV replication to the lowest possible level

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

17

Patients with HBV DNA <20,000 copies/mL at 72 weeks (%)

31

61

0

20

40

60

80

100

<400 ≥400

Serum HBV DNA level at 12 weeks, copies/mL

HBeAg-negative patients (n=176) treated with peg-interferon alfa-2a for 48 weeks

P<0.001

Farci et al 2005

Viral Suppression with Peg-Interferon alfa-2a Association with subsequent HBV DNA response

18

73

60

28

7

82

61

40

20

0

20

40

60

80

100

Profound, Early Viral Suppression Week 24 viral load and 2-year outcomes† with telbivudine and lamivudine

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

HBV DNA at week 24, copies/mL

PCR-negative at 2 years, %

HBeAg-positive (n=921) HBeAg-negative (n=446)

≤QL 300–3 log

3–4 log >4 log ≤QL 300–3 log

3–4 log >4 log

TelbivudineLamivudine

203 146 57 63 83 79 107 165

6860

25

5

8878

63

20

0

20

40

60

80

100

178 157 18 20 16 24 10 20

19

97 95

84

25

0

20

40

60

80

10096

82

40 40

0

20

40

60

80

100

Profound, Early Viral Suppression Week 24 viral load and 1-year outcomes with entecavir

HBV DNA at week 24, copies/mL

PCR-negative at week 48, %

HBeAg-positive HBeAg-negative

≤400 400–3 log

3–5 log >5 log ≤400 400–3 log

3–5 log >5 log

153/195 28/34 47/118 6/15 240/247 20/21 32/38 1/4

BMS Entecavir AVDAC Briefing Document 2005

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HBeAg seroconversion occurred only in this group4

6

8

10

2

Baseline 8 16 24 32 40 48 56 64 72

Weeks

Median HBV DNA, log10 copies/mL

Median >104 (n=11)Median <104 (n=12)

Potential assessment of early virological response to predict outcome Gauthier et al 1999

Magnitude of Viral Response to Lamivudine Association with higher rates of HBeAg seroconversion

21

6

21

39

46

0

10

20

30

40

50

<QL QL–3 3–4 >4

n=183 n=54 n=81 n=107

Seroconversion at 2 years, %

Serum HBV DNA level at 24 weeks, log10 copies/mL

Early Viral Suppression with Telbivudine Association with 2-year HBeAg seroconversion†

HBeAg-positive patients

Han et al 2007†Preliminary data from locked database

22

1312

24

30

0

10

20

30

40

50

<400 400–3 log 3–5 log >5 log

47/159 8/34 14/117 2/15

Seroconversion at 48 weeks, %

HBV DNA at 24 weeks, copies/mL

HBeAg-positive patients

BMS Entecavir AVDAC Briefing Document 2005

Early Viral Suppression with Entecavir Association with 1-year HBeAg seroconversion†

23

64

32

138

0

20

40

60

80

100

<200 <3 log <4 log >4 log

Profound, Early Viral Suppression Correlates with Lower Risk of Resistance

Hadziyannis et al 2006; Yuen et al 2001

Patients with lamivudine resistance , %

HBeAg-positive patients (n=159), median

30 months follow up

HBV DNA level at week 24, copies/mL

1/12 3/23 13/41 76/118

49

6

0

20

40

60

80

100

<3 log >3 log

Patients with ADV resistance at week 192, %

HBeAg-negative patients (n=125)

HBV DNA level at week 48, copies/mL

24

2

1220

60

0

20

40

60

80

100

HBeAg-negative patients

Patients with telbivudine resistance week 92, %

n=178

n=16n=18 n=10

Di Bisceglie et al 2006

Early Viral Suppression with TelbivudineAssociation with resistance†

†Preliminary analysis of patients with viral rebound at week 92

HBV DNA level at week 24, copies/mL

≤300 300–3 log10 3 log10–4 log10 >5 log10

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HBeAg loss

Liver inflammation and fibrosis

HBeAg-positive

HBeAg-negative

Reduce serum HBV DNA

Normal ALT PCR negative

Anti-HBeAg sero-conversion

HBsAg loss

Reduce serum HBV DNA

Normal ALTPCR negative

HBsAg loss

Goals of HBV therapya) Prevent cirrhosis,

liver failure and HCCb) Improve survival

Signpost

Signpost

Early Viral Suppression Can Be a Signpost for Future Therapeutic Response

StartRx.

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On-Treatment Roadmap Concept

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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

Chosen therapy is effective and well tolerated

Additional interventions

required

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Unresolved questionsWhat Is the best on-treatment marker?When Is the best timing for decision points?What Cut-off level for on-treatment decisions?Which 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 BKeeffe EB et al.Clinical Gastroenterology and Hepatology 2007

Proposed New Treatment Algorithm for CHBRecent expert panel and Roadmap publication

Keeffe et al 2007

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Start treatment

≥1 log 10 copies/mLdecrease from baseline:

primary response

Roadmap ConceptManagement algorithm according to 12-week virologic response

Continue

<1log10 copies/mLdecrease from baseline:

primary failure

Non-compliant Compliant

Counsel Change Tx

Week 12: assessment for primary non-response

Keeffe et al 2007

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Start treatment

Roadmap ConceptOn-treatment responses

Complete response PCR negative†

Partial response ≥60–<2000 IU/mL or

≥300–<10,000 copies/mL

Inadequate response >2000 IU/mL or

≥10,000 copies/mL

Week 12: assessment for primary non-response

Week 24: early predictors of efficacy

Keeffe et al 2007†Defined as <300 copies/mL

31

Roadmap ConceptManagement algorithm for complete response at 24 weeks

Complete response PCR negative†

ContinueMonitor 6-monthly

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

Week 24: early predictors of efficacy

Keeffe et al 2007†Defined as <300 copies/mL

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Roadmap ConceptManagement algorithm for partial response at 24 weeks

Week 24: early predictors of efficacy

Keeffe et al 2007

Partial response≥60–<2000 IU/mL or

≥300–<10,000 copies/mL

Add another drugwithout cross-

resistance or continueMonitor 3-monthly

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Inadequate response≥2000 IU/mL or

≥10,000 copies/mL

Adapt regimen

Complete response Partial response Inadequate response

Roadmap ConceptManagement algorithm for inadequate response at 24 weeks

Week 24: early predictors of efficacy

Keeffe et al 2007†Defined as <300 copies/mL

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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 ConclusionsImportance 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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37Conclusion fromReport 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 on-treatment 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.

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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.

Start Telbivudine

Early Virologic Response Efficacy at Week 24

PCR NegativePCR Negative (<300 copies/mL)(<300 copies/mL)

HBV DNAHBV DNA300 copies/mL300 copies/mL

to 10to 10 ，， 000 copies/mL000 copies/mL

HBV DNAHBV DNA

> 10> 10 ，， 000 copies/mL000 copies/mL

Assessment of Primary Response at week 12

Maintain TelbivudineMaintain Telbivudine

How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?

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39Viral Load Achieved by Week 24:

Telbivudine vs. Lamivudine

13%

14%

18%

17%

24%

36%

32%

45%

0%

20%

40%

60%

80%

100%

Telbivudine, n=450 Lamivudine, n=453

% o

f p

atie

nts

PC

R n

on

-det

ecta

ble

8%

9%

7%11%

5% 9%

71%80%

0%

20%

40%

60%

80%

100%

Telbivudine, n=222 Lamivudine, n=221

% o

f p

atie

nts

PC

R n

on

-det

ecta

ble

Di Bisceglie A, et al. Presented at AASLD 2006

<QL QL-3 Log 3-4 Log >4 Log

HBeAg Positive HBeAg Positive HBeAg Negative HBeAg Negative

*

*

* P < 0.05

40

40Telbivudine Is A Good Option for Therapy for

HBeAg-Positive Patients

49%49% of Telbivudine Treated Patientsof Telbivudine Treated Patients

Achieve PCR Negativity (≤300 copies/mL)Achieve PCR Negativity (≤300 copies/mL) at Week 24 at Week 24

86%86% PCR Negative PCR Negative

Week 104Week 104

49%49% Seroconversion Seroconversion

Week 104Week 104

2%2% ResistanceResistance

Week 92Week 92

BaselineALT ≥ 2 x ULN

N=558

85%85% ALT Normalization ALT Normalization

Week 104Week 104

41

41Telbivudine Is A Good Option for Therapy for

HBeAg-Negative Patients

80%80% of Telbivudine Treated Patientsof Telbivudine Treated Patients

Achieve PCR Negativity (≤300 copies/mL)Achieve PCR Negativity (≤300 copies/mL) at Week 24 at Week 24

88%88% PCR Negative PCR Negative

Week 104Week 104N=78/86N=78/86

2%2% Resistance at Resistance at

92 weeks92 weeks

49%49% Seroconversion Seroconversion

Week 104Week 104

All telbivudine-treatedHBeAg-Negative Patients

N=588

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Start Telbivudine

Early Virologic Response Efficacy at Week 24

HBV DNAHBV DNAPCR NegativePCR Negative

(<300 copies/mL)(<300 copies/mL)

HBV DNAHBV DNA≥300–<10,000 copies/mL

HBV DNAHBV DNA

> 10> 10 ，， 000 copies/mL000 copies/mL

Maintain Telbivudine Week 52 - Monitor HBV DNA closely

How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?

If PCR NegativeIf PCR Negative

Maintain Telbivudine MonotherapyMaintain Telbivudine MonotherapyIf 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.

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Start Telbivudine

Early Virologic Response Efficacy at Week 24

PCR NegativePCR Negative (<300 copies/mL)(<300 copies/mL)

HBV DNAHBV DNA≥300–<10,000 copies/mL

HBV DNA > 10,000 copies/mL

Assessment of Primary Response at week 12

How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?

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.

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