Introduction

Eugene R. Schiff, MD

Leonard Miller Professor of MedicineChief, Division of Hepatology

Director, Center for Liver DiseaseUniversity of Miami School of Medicine

Miami, Florida

When Do You Start Therapy?

HBV DNA >104-5 c/mL

ALT 1–2 x ULN

When Do You Start Therapy?

HBV DNA >104-5 c/mL

ALT 1–2 x ULN

What Are the First-Line Therapeutic Options?

Adefovir

Entecavir

Peginterferon

Lamivudine?

When Do You Start Therapy?

HBV DNA >104-5 c/mL

ALT 1–2 x ULN

What Are the First-Line Therapeutic Options?

Adefovir

Entecavir

Peginterferon

Lamivudine?

How Do You Manage Resistance,

Breakthrough, and Suboptimal Response?

Choice of drug

Monitor patient status

Switch or add-on therapy

Compliance

When Do You Start Therapy?

HBV DNA >104-5 c/mL

ALT 1–2 x ULN

What Are the First-Line Therapeutic Options?

Adefovir

Entecavir

Peginterferon

Lamivudine?

How Do You Manage Resistance,

Breakthrough, and Suboptimal Response?

Choice of drug

Monitor patient status

Switch or add-on therapy

Compliance

When Do You Stop Therapy?

HBeAg seroconversion?

HBV DNA <104-5 c/mL?

Normalization of ALT?

When Do You Initiate HBV Therapy?

Kris V. Kowdley, MD

Professor of MedicineSchool of Medicine

University of Washington Medical CenterSeattle, Washington

Natural Progression of HBV

Chronic Infection Cirrhosis Death

1. Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.3. Perrillo RP, et al. Hepatology. 2001;33:424.

5%–10%1

Liver Failure

30%1

23% in 5 y2

Liver Cancer (HCC)

Chronic HBV is the 6th leading indication of liver transplantation in the US3 (~5%)

Liver Transplantation

Acute flare

6% in 5 y2

UndetectableSerum

HBV DNA

HBeAg Lossor

Seroconversion

HBsAgClearance

Treatment Endpoints in Chronic Hepatitis B

TreatmentEndpoints

Decreased HAIand Fibrosis

Normal ALT

cccDNA Clearance

Objectives of Therapy

Decrease hepatic inflammation Decrease rate of progression to fibrosis Decrease incidence of long-term sequelae

(cirrhosis, end-stage liver disease, hepatocellular carcinoma)

Goals of Treatment in HBV

• Suppression of viral replication• Eradication of serum HBV DNA• HBeAg seroconversion• Liver histology improvement or

stabilization• HBsAg loss

Anti-HBV Treatment Guidelines

Type Year Author

AASLD (US) Evidence-based 2001; updated 2004

Lok ASF, et al1,2

NIH conference* (US)

Position paper 2000/2001 Lok ASF, et al3

US Algorithm* Position paper 2004 Keeffe EB, et al4

EASL (Europe) Evidence-based 2003 de Franchis R, et al5

APASL (Asia) Consensus statement

2003 Liaw YF, et al6

*New published reports coming out soon.

1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Lok ASF, et al. Hepatology. 2004;39:857. 3. Lok ASF, et al. Gastroenterology. 2001;120:1828. 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87. 5. de Franchis R, et al. J Hepatol. 2003;39:S3. 6. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239.

Accepted Criteria for Therapy

For patients without cirrhosis– HBV DNA >105 copies/mL1,2

– ALT >2 x ULN1,2

For patients with cirrhosis– ALT criteria not necessary1-3

– HBV DNA thresholds are variable1-3

1. Lok ASF, et al. Hepatology. 2004;39:857. 2. de Franchis, et al. J Hepatol. 2003;39:S3. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239.

HBV DNAHBeAg (copies/mL) ALT Management

+ >105 ≤2 x ULN Follow

+ >105 >2 x ULN Treat

– >105 >2 x ULN Treat

– – ≤2 x ULN Follow

+/– >105 Cirrhosis If compensated, treat;if decompensated*, refer

for liver transplant

+/– – Cirrhosis If compensated, observe;if decompensated*, refer

for liver transplant

Which Patients Should Be Treated?AASLD Guidelines1

1. Lok ASF, et al. Hepatology. 2004;39:857. 2. INTRON® A (interferon alfa-2b) Product Information. Kenllworth, NJ: Schering Corporation: 2004. 3. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.

*Do not use interferon or peginterferon if the patient has decompensated cirrhosis.2,3 Specific treatment recommendations are made elsewhere in this activity.

US Treatment Algorithm UpdateHBeAg+ Compensated Disease

• No treatment• Monitor every 6–12 mo

• Monitor every3–12 mo (immune tolerant)

• Consider biopsy, if age >35–40 y, and treat if significant disease

Treat

HBeAg Positive

ALT ElevatedALT Normal

HBV DNA≥105 c/mL

HBV DNA<105 c/mL

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

US Treatment Algorithm UpdateHBeAg– Compensated Disease

• No treatment• Monitor every 6–12 mo

• Monitor ALT, or• Consider biopsy, since

ALT often fluctuates, and treat if significant disease

• Long-term treatment required

• Treat• Long-term treatment

required

HBeAg Negative

ALT ElevatedALT Normal

HBV DNA≥104 c/mL

HBV DNA<104 c/mL

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

May Choose to Treat or Observe

Treat

HBV DNA(PCR)

HBV DNA<104 c/mL

HBV DNA≥104 c/mL

US Treatment Algorithm UpdateCompensated Cirrhosis

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

• Observe

• Wait list for transplant

• Treat• Wait list for transplant

HBV DNA Detectable by PCR?

No Yes

US Treatment Algorithm UpdateDecompensated Cirrhosis

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

Wang C, et al. Hepatology. 2005;42:573A.

Prevalence of Fibrosis Among Patients with Immunotolerance

14 immunotolerant individuals recruited– HBV DNA ≥106 copies/mL (median 5.1 x 107; range 4.5 x 103–

3.4 x 108)– 2 normal ALT measurements within 2 years prior to liver

biopsy (median 28 U/L; range 13–77 U/L)– Liver histology measured with Batts and Ludwig scoring

79% of individuals had fibrosis– Stage 1, 36%—Stage 2, 43%– No cirrhosis or septal fibrosis

Baseline mean ALT poorly correlated with liver biopsy stage– R2 coefficient = .08

Role of Liver Biopsy in Patients with Normal ALT and High Viral Load

190 individuals with HBV DNA >10,000 copies/mL– Persistently normal ALT*, n = 57

24% of individuals with persistently normal ALT levels had stage 2–4 fibrosis

Multiple Regression Analysis for Stage ≥2 Fibrosis

Parameter OR 95% CI P Value

ALT 1.778 1.235–2.558 .0020

Inflammation grade 6.790 4.010–11.500 <.0001

Age 1.053 1.027–1.080 <.0001

Alcohol intake 2.741 1.160–6.476 .0216

*Persistently normal ALT, 2 measurements 6 months apart.

Courtesy of M. Lai, MD.Lai M, et al. Hepatology. 2005;42:720A.

Clinical Significance of Viral Replication

Worsening Histology, Including Cirrhosis

HCC

Viral Replication

Elevated ALT

Baseline HBV DNA Level and Relative Risk of HCC

Multivariate-adjusted relative risk of HCC by cohort (N = 3653) entry serum HBV DNA level (94% of subjects with ALT <1 x ULN)

Adjusted for gender, age, smoking, alcohol consumption

0

7

<300 300–9.9x103 1.0–9.9x104 1.0–9.9x105 >105

Rel

ativ

e R

isk

1 1.1

2.3

6.66.1

HBV DNA (copies/mL)

654

32

1

Chen C-J, et al. JAMA. 2006;295:65.

Baseline HBV DNA Level and Cumulative Incidence of HCC

0

2

4

6

8

10

12

14

16

<300 300–<104 104–<105 105–<106 ≥106

N = 3653, 11-y follow-up

Cum

ulat

ive

Inci

denc

e of

HC

C

Chen C-J, et al. JAMA. 2006;295:65.

HBV DNA (copies/mL)

1.3 1.37

3.57

12.17

14.89

Baseline HBV DNA Level and Relative Risk of Cirrhosis

Iloeje UH, et al, Gastroenterology. 2006;130:678.

0

10

<300 300–9.9x103 1.0–9.9x104 1.0–9.9x105 >105

N = 3653, 11-y follow-up

Rel

ativ

e R

isk

1 1.42.5

5.9

9.8

Adjusted for gender, age, smoking, alcohol consumption

HBV DNA (copies/mL)

7654321

98

Effect of Lamivudine on Incidence of HCCTime of Diagnosis of HCC

Reprinted with permission, from Liaw YF, et al. N Engl J Med. 2004;351:1521. Copyright © 2004 Massachusetts Medical Society. All rights reserved.

Months

Lamivudine

Placebo

Dia

gnos

is o

f HC

C (

%)

0

10

60 12 18 24 30 36

P = .047

Effective Viral Suppression ReducesLevel of Inflammation on Biopsy

Mommeja-Marin H, et al. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37:1309. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

Review of 26 prospective studies (3428 patients)

Med

ian

Impr

ovem

ent i

n H

AI

HBV DNA Median log10 Decrease

r = 0.96P < .000003N = 3428

Post-treatment vs baseline

0

1

2

3

4

5

1 2 3 4 5-1-2

Goals of Treatment Are Changing!

1980s: Reduce severity of liver disease

Goals of Treatment Are Changing!

1980s: Reduce severity of liver disease

1990s: Reduce viral replication

Goals of Treatment Are Changing!

1980s: Reduce severity of liver disease

1990s: Reduce viral replication

2000s: Prevent cancer?

Initial Therapy:What Are the Therapeutic Options

and Considerations?

Robert G. Gish, MD

Medical DirectorLiver Transplant Program

California Pacific Medical CenterSan Francisco, California

Current FDA-Approved Anti-HBV Therapies

Interferon alfa-2b Lamivudine Peginterferon alfa-2a Adefovir Entecavir

Lamivudine

LamivudineConsiderations for Use

Short-term therapy– Chemotherapy– Immune suppressants– Pregnancy

Cost Lamivudine no longer a first-choice

therapy due to high rate of resistance1

1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

Peginterferon

PeginterferonConsiderations for Use

HBeAg+– Genotype A1,2

– ALT >80 IU/mL2

– HBV DNA <108 copies/mL2

– Compensated liver disease guidelines3-6

– Monoinfected– No psychiatric or medical contraindications

HBeAg-– No specific populations that benefit over others7

– Modest number of patients negative by PCR long-term7

Consider PEG IFN before nucleos(t)ide therapy due to defined treatment intervals and high HBeAg seroconversion rates

Should not be used in decompensated cirrhosis8

1. Janssen HL, et al. Lancet. 2005;365:123. 2. Lau G, et al. N Engl J Med. 2005;352:2682. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239. 4. De Franchis R, et al. J Hepatol. 2003;39:S3. 5. Lok AS, et al. Gastroenterology. 2001;120:1828. 6. Lok ASF, et al. Hepatology. 2004;39:957. 7. Marcellin P, et al. Hepatology. 2005;42:580A. 8. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.

32% 32%

27%

34%

19%22%

0

20

40

60

HBeAg Seroconversion HBV DNA <100,000 copies/mL

PEG IFN (n = 271)

PEG IFN + lamivudine (n = 271)

Peginterferon alfa-2a ± Lamivudine 24-Weeks Posttreatment, Overall

Patie

nts

(%)

With permission from Chow WC, et al. Hepatology. 2005;42:576A.

P < .001 P < .012

Lamivudine (n = 272)

52%

30% 31%

22%22%

29% 28%

18%20%

23%

18% 18%

0

20

40

60

A B C D

12/23 4/18 3/15 23/76 24/82 17/73 50/162 43/156 29/162 2/9 2/11 3/17

Patie

nts

with

H

BeA

g Se

roco

nver

sion

(%)

P = .002*

Genotype

P = .002*

*Mantel Haenszel Chi Square test stratified for the effect of HBV genotype

Peginterferon alfa-2a ± Lamivudine at 24-Weeks Posttreatment

HBeAg Seroconversion, by Genotype

With permission from Chow WC, et al. Hepatology. 2005;42:576A.

PEG IFN (n = 271)

PEG IFN + lamivudine (n = 271)

Lamivudine (n = 272)

Adefovir

5-Year Data Now Available

AdefovirConsiderations for Use

HBeAg+ and HBeAg- infection Continued use if 1-log reduction every 3 mo

and HBV PCR negative at 12–15 mo1,2

– If resistant to adefovir, switch to or add lamivudine, or switch to entecavir3

1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion. 3. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.

The Efficacy of Adefovir Dipivoxil is Sustained in HBeAg- Patients Over 5 Years

68%75%

71% 72%77%

67%

78%75%

0

20

40

60

80

100

Patie

nts

%

Serum HBV DNA < 1000 copies/mL

ALT Normalization

Treatment Duration (Weeks)

48 96 144 192 48 96 144 192

67%

240

69%

240

5-year cohort of patients

Hadziyannis S, et al. Management of Hepatitis B: 2006: NIH. April 6–8, 2006.

Long-Term Adefovir in HBeAg- InfectionProportion of Patients with Improved Ishak Fibrosis Scores

Over Time

8/24 (33%)

11/24 (46%)†

17/24 (71%)

P = .005*

*Cochran-Armitage exact test of trend over time for 5-y cohort. †LOCF (no improvement) n = 9 for 4-y cohort; n = 15 for 5-y.‡1 patient received concomitant lamivudine.

7/22 (32%)†

12/22 (55%)‡

5-y cohort 4-y cohort

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5Years of Adefovir Treatment

Isha

k Fi

bros

is R

educ

ed ≥

1 P

oint

(%)

Hadziyannis S, et al. Hepatology. 2005;42:754A. Reprinted with permission.

Safety of Adefovir Dipivoxil Over 4–5 Years

Renal safety– No on-treatment hypophosphatemia– 4 patients (3%) had confirmed increases in creatinine ≥0.5

mg/dL Maximum value 1.5 mg/dL Maximum increase 0.8 mg/dL

Adverse events – 3 patients permanently discontinued adefovir due to an

adverse event– Serious adverse events occurred in 24 patients (19%)

None were related to adefovir 3 patients developed hepatocellular carcinoma

Hadziyannis S, et al. Hepatology. 2005;42:754A.

Entecavir

2-Year Data Now Available

EntecavirConsiderations for Use

Nucleoside-naive infection– HBeAg+– HBeAg-

Lamivudine-resistant infection Continued use if 1-log reduction every 3

months1,2

– If not, add tenofovir or adefovir

1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion.

Entecavir Phase 3 StudiesHistologic Endpoints – Primary

Efficacy Endpoint

Study 022*HBeAg+

Study 027*HBeAg–

Study 026†

LVD-Refractory

ETV 0.5 mg

(n = 314)

LVD100 mg

(n = 314)

ETV 0.5 mg

(n = 296)

LVD100 mg

(n =2 87)

ETV 1 mg

(n =1 24)

LVD100 mg

(n = 116)

Overall histologicimprovement

72% 62% 70% 61% 55% 28%

Fibrosis no worse 89% 82% 84% 79% 87% 70%

Necroinflammatory>2-point decrease

74% 64% 73% 64% 55% 32%

Ishak fibrosis scoreimprovement

39% 35% 36% 38% 34% 16%

Primary analysis: only patients with evaluable baseline biopsy included; missing/inadequate week-48 biopsy counted as failures. *Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders.

FDA. Entecavir briefing document. February 10, 2005.

ETV = entecavir; LVD = lamivudine.

Entecavir Phase 3 StudiesSelected Secondary Efficacy Endpoints

Study 022*HBeAg+

Study 027* HBeAg–

Study 026†

LVD-Refractory

ETV 0.5 mg

LVD100 mg

ETV 0.5 mg

LVD100 mg

ETV 1 mg

LVD100 mg

HBV DNA PCR <400 copies/mL 72% 42% 95% 77% 22% 1%

Log HBV DNA byPCR (meanchange frombaseline)

-7.0 -5.5 -5.2 -4.7 -5.1 -0.5

HBeAgseroconversion 21% 18% NA NA 8% 3%

ALT normalization (<1 x ULN) 69% 61% 78% 71% 65% 17%

FDA. Entecavir briefing document. February 10, 2005.ETV = entecavir; LVD = lamivudine.

*Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders.

Entecavir vs Lamivudine in HBeAg+ Infection* Virologic Response at Week 48 and

Through Week 96

*Nucleoside-naive infection.†EOD (end of dosing) is defined as the last observation on-treatment.

64%

40%

0

20

40

60

80

100

Entecavir

% H

BV

DN

A <

300

copi

es/m

L 156/243 66/164

LamivudineWeek 48 Week 48

81%

39%

197/243 64/164

EOD* EOD†

Gish RG, et al. Hepatology. 2005;42:267A.

Entecavir (n = 354)

Lamivudine (n = 355)

50

31%

26%

5%3%

110/354 92/355 18/354 10/3550

10

20

30

40

HBeAg Seroconversion HBsAg Loss

% P

atie

nts

Entecavir (n = 354)

Lamivudine (n = 355)

Gish RG, et al. Hepatology. 2005;42:267A.

*Nucleoside-naive infection.

Entecavir vs Lamivudine in HBeAg+ Infection* Serologic Response at Week 48 and

Through Week 96

All Treated HBeAg- Patients: Cumulative Confirmed HBV DNA Undetectable by PCR

Through Week 96

0102030405060708090

100

EntecavirLamivudine

ALT 1 x ULNHBV DNA < 300 copies/mL

89% 84%94%

77%

P < .0001

P < .05

With permission from Shouval D, et al. 41st EASL. April 26–30, 2006. Abstract 45.

Patie

nts

(%)

Tenofovir

A Medication in Evolution

TenofovirPotential Role

We need phase 3 trial results Coinfected patients Lamivudine-resistant infection (HIV negative)

– Yes, if the patient fails Adefovir

and Entecavir

Adefovir partial responder = incomplete responder– Yes, if fails entecavir

Telbivudine

Awaiting final results Robust viral suppression High HBeAg seroconversion Good safety profile 5%+? resistance: need all patients who are

DNA positive on treatment, screened for mutations

Summary of Three RecentInternational Meetings

HBV DNA quantification is emerging as the best single indicator of patient prognosis, including HCC1,2

Use the anti-HBV agent with the highest rate of HBV DNA suppression/negativity1

For HBeAg+ patients, also consider the rate of HBeAg seroconversion and durability of seroconversion (PEG IFN)3

Resistance is bad and has multiple implications1

Liver biopsy still has a role in selecting patients for treatment1

Long-term data are available on entecavir (2 years) and adefovir(5 years) in terms of safety and efficacy1,3

New data from China have shown equal efficacy for both adefovir and entecavir compared with data from licensing studies2

1. NIH - Management of Hepatitis B: 2006. 2. 2006 Shanghai-Hong Kong International Liver Congress: 2006. 3. 41st EASL: 2006.

Experts’ Approach to Managing Resistance, Breakthrough, and Suboptimal Response

Norah A. Terrault, MD, MPHAssistant Professor of Medicine

Department of Gastroenterology University of California, San Francisco

San Francisco, California

Definitions of Resistance

Genotypic resistance– Mutations in HBV genome that occur during therapy and confer drug

resistance Virologic breakthrough

– Rebound of serum HBV DNA levels by ≥1 log after prior decline– Follows development of genotypic resistance

Clinical breakthrough– Virologic breakthrough with increase in ALT levels, worsening

histology, or liver function Phenotypic resistance

– Decreased in vitro susceptibility to antiviral drugs associated with genotypic resistance

Dynamics of Drug Resistance

Pallier C, et al. J Virology. 2006;80:643. Reprinted with permission from American Society of Microbiology.

Lamivudine, 100 mg/day

HBV DNA

ALT

AST

HBV-

DNA

(IU/m

L)ALT/AST (IU/m

L)

Lamivudine-sensitive

Lamivudine-resistant

Real-time PCR cutoff

bDNA cutoff

109

106

103

500

400

300

200

100

M0 M2 M4 M6 M8 M10 M12 M14 M16 M18 M20 M22 M24 M26 M28 M30 M32 M34 M36

0%/100%

50

100%/0%

Lok AS, et al. Gastroenterology. 2003;125:1714.

Manifestations of Drug Resistance

Relapse of HBV DNA ALT elevation Decline in liver synthetic function Worsening of liver decompensation

– Can be acute presentation Liver-related death Need for liver transplantation

Viral mutations conferring resistance are less frequent& delayed in onset with adefovir and entecavir versus lamivudine

24%

2%

42%

11%

53%

70%

0

10

20

30

40

50

60

70

80

Year 1 Year 2 Year 3* Year 4*

Inci

denc

e of

Res

ista

nce

(%)

Lamivudine1

(YMDD)

Adefovir (N236T+A181V)2

0%

18%

Entecavir3

0%0%

1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 3. Colonno R, et al. Hepatology. 2005;42:573A.

Note: Agents were not compared in head-to-head trial

Incidence of Resistance in Nucleos(t)ide-Naive Patients

*No 3- or 4-year resistance data available for entecavir

Predictors of Genotypic Resistance

Lamivudine– Baseline HBV DNA level1,2

– HBV DNA >103 IU/mL at 24 weeks3

– Male gender, higher HAI grade, higher BMI1 Adefovir

– HBV DNA >103 IU/mL at 48 weeks4

– Older age, genotype D, adefovir monotherapy (vs adefovir plus lamivudine)5

Entecavir?

1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Zoulim F, et al. J Viral Hepatitis. 2006;13:278. 3. Yuen MF, et al. Hepatology. 2001;34:785. 4. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 5. Fung SK, et al. J Hepatol. 2006;44:283.

8%13%

32%

64%

200 103 104 >104

HBV DNA Levels (c/mL) at 24 wk

Patie

nts

with

Res

ista

nce

(%)

4%

26%

67%

HBV DNA Levels (c/mL) at 48 wk

Patie

nts

with

Res

ista

nce

(%)

0

20

40

60

80

100

<103 103–106 >106

Lamivudine1 Adefovir2

1. Yuen et al. Hepatology. 2001;34:785. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36.

Risk of Resistance Predicted by HBV DNA Levels During Treatment

0

20

40

60

80

100

1. Lai CL, et al. N Engl J Med. 2006;354:1011. 2. Chang et al. N Engl J Med. 2006;354:1001. 3. Hadziyannis S, et al. N Engl J Med. 2003;348:800. 4. Marcellin P, et al. N Engl J Med. 2003;348:808.

*Only lamivudine and entecavir compared head-to-head

Changes in HBV DNA Levels During 48 Weeks of Treatment

Nucleos(t)ide-Naive Compensated HBV*

Lamivudine Entecavir Adefovir

Change HBV DNA baseline to wk 48

-4.5 HBeAg-1

-5.4 HBeAg+2

-5.0 HBeAg-1

-6.9 HBeAg+2

-3.91 HBeAg-3

-3.52 HBeAg+4

% with undetectable HBV DNA

72% HBeAg-1

36% HBeAg+2

90% HBeAg-1

67% HBeAg+2

51% HBeAg-3

21% HBeAg+4

Locarnini S, et al. Antiviral Therapy. 2004;9:679.

Methods to Prevent Resistance

Maximize antiviral activity – Select most effective regimen– Change if poor response

Maximize genetic barriers to resistance– Avoid sequential therapy– Choose drugs requiring multiple resistance

mutations Increase pharmacologic barriers

– Patient compliance– Drug doses appropriate for renal function

Summary of Strategies to Minimize Drug Resistance in Treatment-Naive HBV Infected

Patients First-line therapy = adefovir, entecavir, peginterferon Avoid lamivudine

– Limit to those with low-level virus and expected short-duration therapy

Monitor response and be prepared to modify (ie, add or change) if indicated– Fail to see progressive viral load decline– Persistence of HBV DNA (≥ 103 log IU/mL) at 6 months;

certainly at 12 months

Monitoring During Treatment

Assessment of initial response– Progressive decline in HBV DNA levels is the goal– Suboptimal response warrants change in antiviral strategy– Recommend following HBV DNA levels every 3 months

Detection of virologic breakthrough (resistance)– Recommend following HBV DNA levels every

3 months once suppressed– Confirm HBV DNA results (decisions should not be based

on single viral load result) – Make treatment change before clinical breakthrough

Response to Second-Line Therapy by Type of Resistance

Adapted from Lampertico P, et al. Hepatology. 2005;42:1414.

Virologic breakthrough (<6 log HBV DNA)

Virologic breakthrough (6–8 log HBV DNA)

Clinical breakthrough (> 8 log HBV DNA)

P < .0001

Patie

nts

with

Und

etec

tabl

e H

BV

DN

A

Patients still at risk

28 3 1 0 0 0 0 0 032 22 14 10 9 6 5 4 214 13 12 11 10 9 5 4 3

Months0 3 6 9 12 15 18 21 240

20

40

60

80

100

Management of Drug-Resistant HBV Disease

Add or change antivirals– If resistant to lamivudine

Change to adefovir or entecavir Add adefovir

– If resistant to adefovir Change to entecavir Add lamivudine

– If resistant to entecavir Change to adefovir

Conclusions

Resistance is a risk with all oral nucleos(t)ide antiviral agents– Highest with lamivudine– Known risk factors = baseline HBV DNA level and HBV DNA

level at 24 and 48 weeks of treatment Monitor for lack of HBV DNA suppression (≥103 IU/mL) and

virological breakthrough– Both scenarios require change of therapy

Treat when virologic breakthrough apparent; do not wait until clinical breakthrough occurs (ALT increase)

If using oral antivirals, combination therapy is better long-term strategy than sequential therapy

Ching-Lung Lai, MDProfessor of Medicine and Hepatology

Department of MedicineUniversity of Hong Kong

Queen Mary HospitalHong Kong, China

Duration of Therapy — How Long Do You Treat?

Effect of Timing of Infection

1. Lai CL, et al. Lancet. 2003;362:2089. 2. Hoofnagle JH, et al. Hepatology. 1987;7:758.

Asians, Africans, some Mediterraneans

Prolonged immune tolerance and immune clearance phases

Respond less well to immunomodulatory therapy

Disease continues to progress in a proportion of anti-HBe patients

Majority of Caucasian patients No immune tolerance phase Disease of relatively short

duration Respond better to

immunomodulatory therapy Disease nonprogressive after

HBeAg seroconversion, with HBV DNA levels undetectable by hybridization assays—“healthy carriers”2

Patients Infected During Early Childhood1

Patients Infected During Adolescence/Adulthood

“Healthy” Hepatitis B Carrier 19871-2

– HBeAg seroconversion to anti-HBe– HBV DNA not detectable by (relatively insensitive)

hybridization assays 20013

– HBeAg seroconversion Preceded by decrease in HBV DNA levels to

105 copies/mL (20,000 IU/mL) Followed by ALT normalization “Inactive” HBsAg carrier state

1. Hoofnagle JH, et al. Hepatology. 1987;7:758. 2. Di Bisceglie AM, et al. Gastroenterology. 1987;93:1236. 3. Lok AS, et al. Gastroenterology. 2001;120:1828.

Current Endpoints of Treatment

HBeAg+ – HBeAg seroconversion1

– HBeAg seroconversion, HBV DNA ≤105 copies/mL (20,000 IU/mL) and ALT normalization2

– HBeAg seroconversion +/- HBV DNA undetectable by PCR3

HBeAg– – HBV DNA undetectable by PCR plus ALT normalization1,3

1. Lok ASF, et al. Hepatol 2004;39:857. 2. de Franchis R, et al. J Hepatol. 2003:39:S3. 3. Liaw YF, et al. Liver Int. 2005;25:422.

Ultimate Aim of Treatment for Chronic Hepatitis B

To prevent/delay the development of complications of cirrhosis and hepatocellular carcinoma

HBeAg seroconversion, HBV DNA reduction, and ALT normalization are only means to achieve the ultimate aim

HBeAg Seroconversion to Anti-HBe

“Healthy” Hepatitis B Carrier

Probably true for some patients who acquirethe HBV infection at adolescence/adulthood, ie, Caucasian patients

Manno M, et al. Gastroenterology. 2004;127:756.

Risk of Cirrhosis/HCC for Northern Italian HBV Carriers

296 HBsAg carriers detected at blood donation– Mean follow-up 30 years– No increase in liver-related morbidity or mortality

compared with controls– 32.2% cleared HBsAg (1% per year)

Possible explanation for lack of increase in liver-related mortality– “Healthy” subjects with no co-morbidity– Normal ALT– Instruction to abstain from alcohol– Age of acquiring the HBV infection

Survival After HBeAg Seroconversion

Reprinted with permission, from Niederau C, et al. N Engl J Med. 1996;334:1422. Copyright © 1996 Massachusetts Medical Society. All rights reserved.

Prop

ortio

n of

Pa

tient

s Su

rviv

ing

IFNControl

103 IFN-treated vs 53 untreated patients followed for a mean of 50 months

Predominantly adult-acquired infection

53/103 patients receiving IFN achieved HBeAg seroconversion

7/53 control patients achieved HBeAg seroconversion

Clearance of HBeAg

No clearance of HBeAg

1.0

0.8

0.6

0.4

0.2

0.096847260483624120

Month

1. Lai CL, et al. Lancet. 2003;362:2089. 2. Laras A, et al. J Viral Hepat. 1998;5:241. 3. Chan HL, et al. Hepatology. 2000;31:763. 4. Yuen MF, et al. J Infect Dis. 2002;186:1335.

HBeAg Seroconversion and Precore/Core Promoter Mutations

HBeAg+– Disease progresses both histologically and clinically

after HBeAg seroconversion in patients who acquire the HBV infection at birth/early childhood, ie, Asians and some Mediterraneans1

HBeAg– – Mediterraneans >90% precore mutations2

– Asian 45%3–56.5%4 precore mutations 41%3–69.5%4 core promoter mutations

Liaw YF, et al. Hepatology. 1988;8:493.

Development of CirrhosisHBeAg Seroconversion to Anti-HBe

684 Taiwanese patients– HBV infection acquired in early childhood

Mean follow-up 35.3 months Development of cirrhosis

– HBeAg+ 6.9%; annual incidences 2.4%– Anti-HBe 4.0%; annual incidences 1.3%

(P = NS)

Cumulative Risk of Complications Among Asian Patients with Chronic HBV

Median Age of Study Population = 38 y

Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group.

Ris

k of

C

ompl

icat

ions

(%)

Follow-up (Months)

N = 3233

1801501209060300

15

12

9

6

3

0

Age and Anti-HBe Status at Time of Complications

Yuen MF, et al. Gut. 2005;54:1610.

Median Age (y) anti-HBe (%)

HBeAg seroconversion 35 -All complications 57.2 73.5Ascites 57.7 68.8SBP 60.0 76.7Varices 54.3 76.3Encephalopathy 58.5 65.0HCC 59.0 81.1

3233 Chinese patients Infection acquired in early childhood Mean follow-up 46.9 months

SBP = spontaneous bacterial peritonitis; HCC = hepatocellular carcinoma.

Progression of DiseaseHBeAg Seroconversion to Anti-HBe

In patients acquiring the disease at birth/early childhood, disease progresses after HBeAg seroconversion

Majority of complications occurs after HBeAg seroconversion

HBV DNA <105 copies/mL (20,000 IU/mL)

Chu CJ, et al. Hepatology. 2002;36:1408.

HBV DNA Levels Associated with HBeAg Clearance

165 Chinese patients– 51% patients HBV DNA >105 copies/mL (20,000

IU/mL) at HBeAg seroconversion– 45% HBeAg– patients with active disease

(ie, high ALT levels) and HBV DNA <105 copies/mL (20,000 IU/mL)

Conclusion: not possible to define cut-off HBV DNA value for HBeAg– patients with active and inactive disease

Yuan HJ, et al. J Viral Hepatitis. 2005;12:373.

79 Chinese with cirrhosis-related complications (158 controls)– 32.9% HBeAg+, 67.1% anti-HBe+– In anti-HBe+ patients with complications

37.7% HBV DNA <105 copies/mL (20,000 IU/mL) 24.5% HBV DNA <104 copies/mL (2000 IU/mL)

The most important factor associated with development of cirrhosis complications and HCC is HBV DNA level (which can become <104 copies/mL [2000 IU/mL] at the time of complications)

HBV DNA Levels and Cirrhosis-Related Complications

Chen CJ, et al. JAMA. 2006;295:65.

The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)–HBV

Study, Taiwan

Prospective, multicenter, observational cohort study 3851 HBsAg+ subjects with baseline HBV DNA levels

for HCC and cirrhosis analysis– 3653 seronegative for anti-HCV and included in

study

Persistent HBV Viral Load Elevation Is Associated with Greatest Risk of HCC

REVEAL Study

289 study participants, last follow-up serum samples not available

Cohort Entry Examination <104

104–105

104–105

104–105

105

105

105

Serum level of HBV DNA (copies/mL) Multivariate-Adjusted RR**

(95% CI) 1.0 (referent)1.6 (0.7–3.9)0.5 (0.1–3.6)3.5 (1.4–9.2)3.8 (1.7–8.4)

7.3 (3.5–15.3)10.1 (6.3–16.2)

Follow-Up Examination Not tested

<104

104–105

105

<104

104–105

105

*Adjustment for gender, age, cigarette smoking, and alcohol consumption

Chen CJ, et al. JAMA. 2006;295:65.

Disease Progression in Early Childhood-Acquired Infection

For patients acquiring the hepatitis B infection in early childhood, disease progression can occur when HBV DNA levels are <104 copies/mL (2000 IU/mL)

ALT Normalization

Men Women

AST (IU/L)20–29 2.5 3.330–39 8.0 18.2

ALT (IU/L)20–29 2.9 3.830–39 9.5 6.6

Conclusion: People with AST and ALT levels in the upper ranges of “normal” are at risk of liver disease/mortality

Kim HC, et al. BMJ. 2004;328:983.

ALT Levels and Liver-Related MortalityKorea Medical Insurance Corporation 94,533 men; 47,522 women 35–59 years of age

Relative Risk for Liver-Related Mortality compared with Serum Aminotransferase Levels at Baseline <20 IU/L

ALT and Hepatic Complications

Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group.

Months of Follow-Up

Ris

k of

C

ompl

icat

ions

(%)

ALT <0.5 X ULN

ALT 0.5–1 X ULN

ALT >2–6 X ULN

ALT >1–2 X ULN

ALT >6 X ULN

0

10

20

30

0 30 60 90 120 150 180

3233 Chinese CHB patients Stratified: ALT < 0.5 x ULN

ALT > 0.5–1 x ULN, ALT > 1–2 x ULNALT > 2–6 x ULN, ALT > 6 x ULN

ALT and Hepatic Complications

Risk for cirrhosis (including HCC) complications lowest when ALT < 0.5 x ULN

Risk significantly higher when ALT 0.5–1 x ULN Risk highest when ALT >1–2 x ULN

Yuen MF, et al. Gut. 2005;54:1610.

Treatment Endpoints and Infection Acquired at Birth/Early Childhood

In patients who acquire the HBV infection at birth/early childhood, disease progression continues– After HBeAg seroconversion (and HBsAg

seroclearance)– At HBV DNA levels <105 copies/mL (20,000

IU/mL)– At ALT levels >0.5–2 x ULN

Current treatment endpoints stop treatment with patients still at risk

Summary For patients acquiring the disease in adolescence/adulthood

– HBeAg seroconversion with HBV DNA levels at <105 copies/mL (20,000 IU/mL) and ALT normalization may be adequate endpoints

For patients acquiring the disease in early childhood– HBeAg seroconversion is not an adequate endpoint,

more a “way station” in the natural history of HBV infection– Ideal endpoints of treatment

HBV DNA permanently low (<104 copies/mL [2000 IU/mL] preferably undetectable by PCR)

ALT < 0.5 x ULN Clearance of cccDNA from the liver—not currently

feasible

Conclusion

Eugene R. Schiff, MD

Leonard Miller Professor of MedicineChief, Division of Hepatology

Director, Center for Liver DiseaseUniversity of Miami School of Medicine

Miami, Florida

When Do You Initiate HBV Therapy?

Parameters– HBV DNA levels >104-5 copies/mL– ALT levels >1–2 x ULN

Factors– HBeAg+ vs HBeAg–– Cirrhosis vs no cirrhosis– Compensated vs decompensated disease

Initial Therapy: What Are the Therapeutic Options and Considerations?

First-line therapy– Adefovir– Entecavir– Peginterferon alfa-2a

Lamivudine no longer considered first-line therapy due to high rate of resistance, except in specific settings

How Do You Manage Resistance, Breakthrough, and Suboptimal

Response?

Choose antivirals with a low likelihood of resistance

Monitor the response every 3 months to ensure viral suppression is achieved

If viral suppression is not achieved, change/add antiviral agent(s)

Reinforce the importance of adherence

How Long Do You Treat?

Traditional endpoints– HBeAg seroconversion– HBV DNA <105 copies/mL (20,000 IU/mL)– Normalization of ALT

These endpoints may be insufficient for patients with infection acquired at birth or early childhood

Potential ideal endpoints– HBV DNA undetectable– ALT within normal limits