What to Start:Treatment

naïve – PegIFN or Nucleos(t)ide

Analogues

Case

• 28 yo man accountant from the US– Acquired HBV in college during period of

“experimentation”– Not previously vaccinated

– History of mild depression several years ago but no recent problems except “stress” with work and 2 small children

• No symptoms

• No current medications

Case

• Evaluation:– AFP = 9 ng/mL

– HBeAg +

– ALT = 124 (< 40 U/L)

– HBV DNA = 8.8 million c/mL

– HBV genotype not done

– Liver CT scan = “normal appearance to the liver without hypervascular lesion”

Case

• Liver biopsy not recommended – He meets guidelines for therapy

• He returns with his wife to discuss treatment options– He currently feels well and is not anxious

to take medications long-term

– His wife has been concerned about his “stress” level, particularly at home

Debate

1. Peginterferon alfa: Short and to the point (seroconversion)

2. Oral nucleoside or nucleotide analogues: Durable, dependable,and cost-effective

Peginterferon Alfa:Short and to the point

(seroconversion)

HBV Treatment in theUnited States: 2009

1957Interferon

discovered

1991Interferon alfa-2b

approved for HBV

1998Lamivudine (3TC) approved as first

nucleoside analogue for HBV

1991 3TC anti-HBV and anti-HIV activity

discovered

1990 PMEA anti-HBV

activity discovered

2002Adefovir dipivoxil (PMEA prodrug)

approved for HBV

1998 Entecavir anti-HBV activity discovered

2005Entecavir and

peginterferon alfa-2a approved for HBV

2006Telbivudine

approved for HBV

2001 Telbivudine anti-HBV activity discovered

2008Tenofovir approved

for HBV

Duration of HBV Treatment

• HBeAg positive– 6-12 months after HBeAg seroconversion to

minimize relapse rate

– Long-term therapy may be required

• HBeAg negative– Relapse common after cessation of therapy

– Long-term treatment currently recommended

• Cirrhosis– Long-term therapy may be required

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

HBV Genotypes as Predictorsof Response to Interferon-Alfa:

Multivariate Analysis

OR(95% CI)

P value

HBV genotype

A vs. D3.620

(2.316-5.657)0.0001

B vs. D2.621

(1.618-4.245)0.0001

C vs. D3.184

(2.054-4.936)0.0001

ALT >5 vs. ≤5 xULN1.432

(1.056-1.940)0.02

HBeAg neg. vs. pos.2.124

(1.527-2.966)0.0001

Conclusion: Multivariate analysis adjusted for treatment identified genotype D, HBeAg negative status and normal ALT level as independent predictors for failing to achieve SVR

% S

VR

0

20

40

60

Genotype A

10

30

50

Genotype B

Genotype C

Overall SVR

HBeAg pos SVR

HBeAg neg SVR

Genotype D

Independent Predictors for SVRSVR by Genotype and HBeAg Status

Erhardt A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 883.

Lau GK, et al. NEJM. 2005;352(26):2682-2695.

Peginterferon-2a and/or Lamivudine in Patients with HBeAg-Positive Chronic HBV

Patients with HBeAg-positive chronic hepatitis B

(N = 814)

Peginterferon alfa-2a 180 µg/week+ Oral placebo once daily

(n = 271)

Peginterferon alfa-2a 180 µg/week+ Lamivudine 100 mg/day

(n = 271)

Lamivudine 100 mg/day

(n = 272)

Week 48

24 weeksfollow-up

Randomized 1:1:1

Patients stratified according to geographic

region and ALT level

Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Positive Chronic HBV

Responses at End of Follow-Up (week 72)

0

10

20

30

40

50

60

70

80

90

100

Pa

tie

nts

(%

)

32%

PegIFN-2a (n=271)

PegIFN-2a + lamivudine (n=271)

Lamivudine (n=272)

27%

19%

32%34%

22%

14%

5%

41% 39%

29%

14%

HBV DNA<400 copies/mL

HBeAgSeroconversion

HBV DNA<105 Copies/mL

Normalized ALT

PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures.

Lau GK, et al. N Engl J Med 2005;352:2682-2695.

Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV

• Observational study: 4-yr follow-up of randomized phase III trial

Marcellin P, et al. AASLD 2008. Abstract 919.

*PegIFN-treated patients eligible for participation in long-term follow-up.

Patients with HBeAg-negative, HBsAg-positive

chronic HBV infection

(N = 537)

PegIFN alfa-2a 180 μg/wk + Placebo(n = 177)*

PegIFN alfa-2a 180 μg/wk + LAM 100 mg/day

(n = 179)*

LAM 100 mg/day(n = 181)

Wk 48

4-yr follow-up

Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV

Responses at End of Follow-Up (week 72)

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

43%

PegIFN-2a (n=177)

PegIFN-2a + lamivudine (n=130)

Lamivudine (n=130)

43%

29%

19% 20%

59% 60%

44%

7%

HBV DNA<400 copies/mL

HBV DNA<20,000 Copies/mL

Normalized ALT

PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures.

Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.

* Marcellin et al. N Engl J Med 2004** 4-year analysis of patients from initial study who entered long-term follow-up

Long-term Follow-up Studyin HBeAg-negative CHB:

Study Design

Lamivudine 100 mg qd

PEGASYS 180 μg qw + 100 mg lam qd

PEGASYS 180 μg qw + placebo qd

48 weeks

Initial study*

EOT(week 48)

6 monthspost-EOT

Long-term study

4 yearspost-EOT**

HBsAg Clearance Increases After End of Treatment with

PEG-IFNα-2a +/- LAM

1

3

5

7

9

11

Pa

tie

nts

wit

hH

Bs

Ag

cle

ara

nc

e (

%)

N=230

3%

6%

8%

11%

1 2 3 4Years after EOT

HBsAg Level as Predictor of Long-term Durability

of PegIFN Response• Higher response rates at 6 mos associated with Wk 12 HBsAg

≤ 1500 IU/mL vs > 1500 IU/mL in all patients

Marcellin P, et al. AASLD 2008. Abstract 919.

6-Mo Post-treatmentResponse Rates, %

Overall(N = 250)

Wk 12 HBsAg ≤

1500 IU/mL (n = 78)

Wk 12 HBsAg >

1500 IU/mL (n = 172)

P Value(HBsAg ≤ vs > 1500 IU/mL)

HBV DNA≤ 2000 IU/mL

36 55 27 < .001

HBV DNA≤ 80 IU/mL

17 36 9 < .001

HBsAg clearance 3 6 2 .112

Long-term Follow-up After Interferon Therapy:

NIH Experience• 103 patients received

interferon between 1984-1991– 30% were responders

(lost HBeAg and HBV DNA [by bDNA assay])

• Analysis reviewed long-term outcomesin responders and nonresponders– Mean follow-up time:

6.2 years (range: 1-11)

Lau DT, et al. Gastroenterology. 1997:113;1660-1667.

*P value not provided

Responders Nonresponders

Outcomes at Long-term Follow-up

P < .001

Per

cen

tag

e

0

20

40

60

80

100

NormalALT

HBV DNANegative

(PCR)

HBeAgNegative

HBsAgNegative

86

72

100

65

86

11

53*

8

P = .0001

P = .0001

Side effects in HBV patients are lower than HCV

1. Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355. 2. Fried M, et al. N Engl J Med. 2002;347:975-982. 3. Zeuzem S, et al. Gastroenterol. 2004;127:1724-1732. 4. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.

0 20 40 60 80 100

D/C

Dose Reduction

Fever

Fatigue

Myalgias

Rigors

Depression

HBV[4]

HCV[3]

HCV[2]

HCV[1]

PegIFN: Summary

• High rate of seroconversion with carefully selected patients– High ALT

– Favorable genotype

• Finite course of therapy

• No resistance (ever)

• Side effects are better with HBV– No Ribavirin

– Different patient group

Oral Nucleos(t)ide Analogues:

Durable and Dependable

Anti-viral Agents: Safety, Tolerability, Cost and

Risk:Benefit

LAM ADV Entecavir Telbivudine Tenofovir

Dosing QD QD QD QD QD

TolerabilityWell

tolerated

Well tolerated,

Watch serum Cr

Well tolerated

Well tolerated,

Watch CPK

Well tolerated,

Watch serum Cr

Pregnancy C C C B B

Approximate cost for 1 year

2,500 6,500 8,700 6,000 6,000

Potency Moderate Modest High High High

Resistance High Moderate Low High Low

Dienstag JL. New Eng J Med 2008;359:1486-500

HBeAg-positive Chronic HBVHBV DNA Suppression and HBeAg

Seroconversion at End of 1 year

44

21

6760

80

2112

21 22 21

0

10

20

30

40

50

60

70

80

90

LAM ADV ETV TBV TDF

HBV Undetectable HBeAg seroconversion

Dienstag JL. New Engl J Med. 2008

HBeAg-negative Chronic HBVHBV DNA Suppression at

End of 1 Year

7364

90 8895

0102030405060708090

100

LAM ADV ETV TBV TDF

HBV Undetectable

Dienstag, JL

Cumulative Incidence of HBV Resistance

24

0 0.24

0

38

30.5

22

0

49

11

1.2

67

18

1.2

70

29

1.20

20

40

60

80

LAM ADV ETV LdT TDF

%

Year 1 Year 2 Year 3 Year 4 Year 5

EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med;359:1486

Tenofovir

• Potent, predictable response

• Easy once per day regimen

• No food effect

• Long-term data (HBV and HIV)

• No issues with LAM resistance

• Category B in Pregnancy (in case his wife decides to get pregnant)

• Randomized, Double-Blind, Comparison of TDF vs. ADV for HBeAg(+) Chronic Hepatitis B

• HBV DNA >106 c/mL and ALT ≥2x and <10xULN• Knodell Necroinflammatory score ≥3

• Nucleos(t)ide Naïve• Week 48 Phase 3 data showed TDF superior to ADV:

– HBV DNA <400 copies/mL: 76% TDF vs. 13% ADV (p<0.001)• 96 week data presented

Study 103: Two Year TDFTreatment and ADV Switch Data

in HBeAg(+) with CHB

Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.

RA

ND

OM

IZA

TIO

N

1:1

Tenofovir 300 mg (n = 250)

Adefovir 10 mg

(n=125)

Double Blind

TDF 300 mg

TDF 300 mg

Open-Label

Week 240Liver Biopsy

Week 48Liver Biopsy

Pre-treatment Liver Biopsy

Week 96 End of Study

HBV DNA ≥400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet

Week 72

Study 103: HBV DNA <400 copies/mL

• TDF demonstrated durable, potent antiviral activity through Week 96:

• 82% of pts viremic on ADV at wk 48 were <400 c/mL on TDF at wk 96

• No resistance to TDF detected after 2 years on TDF monotherapy

Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.

Perc

enta

ge (%

)

0

10

20

30

40

50

60

70

80

90

100

960

20

50

100

08 16 24 32 40 48 56 64 72 80 88

Weeks on Study

P=0.801

78%

78%

17690

16586

17489

17088

17288

17190

16889

16487

TDF-TDF n=ADV-TDF n=

ITT AnalysisRandomized Double Blind Open Label

On Treatment AnalysisRandomized Double Blind

Perc

enta

ge (%

)

0

10

20

30

40

50

60

70

80

90

100

960

20

50

100

08 16 24 32 40 48 56 64 72 80 88

Weeks on Study

Open Label

P=0.374

89%85%

17690

14279

17388

16585

16684

16085

14883

14481

TDF-TDF n=ADV-TDF n=

No Evidence of TDF Resistance at Two Years

• Genotypic changes observed at Week 96/last on TDF among HBeAg- and HBeAg+ TDF treated patients

Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.

1

0

10

20

30

40

50

60

70

80

90

100HB eAg - (n =2)HB eAg + (n =12)

(1) (1)

(2)

(0)

(8)

(2)

Patie

nt P

erce

nt

Patients with HBV DNA ≥400 copies/mL

No Polymorphic Site Conserved SiteChange Changes Changes

0

10

20

30

40

50

60

70

80

90

00HB e Ag - (n =4)

HB e Ag + (n =3)(3)(2)

(1)(1)

(0)(0)

Patients Experiencing Virologic Breakthrough

No Polymorphic Site Conserved SiteChange Changes Changes

HBsAg Loss is observed with oral antivirals

• Loss of HSbAg has not been commonly seen with oral anti-HBV therapies

• Approximately 0.5% of HBsAg carriers will spontaneously clear HBsAg yearly

• TDF achieved HBsAg loss of 3.2% at week 48 and 5% at week 64

Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.

Rates of HBsAg Loss in Approved Antiviral Therapies Among Treatment-

Naïve Patients with HBeAg+ CHB*

Loss of HBsAg

Standard IFN-

5 MU qd or 10 MU tiw 12-24 wk 7.8%

PegIFN 180 mcg qw

Wk 483%

PegIFN + Lamivudine

180 mcg qw + 100 mg 48 wk 3%

Lamivudine100 mg qd

48-52 wk<1%

Adefovir10 mg qd

48 wk0

Entecavir0.5 mg qd

48 wk2%

Telbivudine600 mg qd

52 wk0%

* Adapted from AASLD Guidelines, 2007.

Entecavir

• Potent predictable effect

• Easy once per day regimen

• Must take 2 hours away from food

• Long term data

• Likely to have resistance issues because of previous LAM exposure

• No data on pregnancy in female partners

Studies ETV-022/-901: Entecavir Therapy in HBeAg(+) CHB

Study DesignStudy Design

Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.

ETVN=354

Responders [R]HBV DNA <0.7 MEq/mL by bDNA and HBeAg loss

Virologic Responders [VR]HBV DNA <0.7 MEq/mL by bDNA and HBeAg(+)

Non-responders [NR]HBV DNA ≥0.7 MEq/mL by bDNA

NR=19

VR=247

R=74

Week 48

21 Non-respondersAt Week 48 or who became non-responders during Year 2

151 Virologic RespondersAt Week 96

11 RespondersAt Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up

Week 144Week 96 5 Years

NR=8

VR=198

R=37

243

ETV-022 ETV-901

Studies ETV-022/-901: Proportion with HBV DNA <300 c/mL

Through 5 Years

Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.

HBeAg(+) ETV Long-term Cohort (ETV-022→ETV-901)

94%91%89%83%

55%

67%

0

20

40

60

80

100

236/354 80/146 116/140 116/131 98/1 88/94

Year 1 Year 1 Year 2 Year 3 Year 4 Year 5

Ishak Fibrosis Score

Fibrosis Regression with continuous ETV

0

10

20

30

40

50

60

Baseline Week 48 Long-term

1

2

3

4

5

6

Missing

0

Pat

ien

ts (

n)

• 96% of patients in the Long-term Histology Cohort who received continuous treatment with ETV achieved histologic improvement

• All patients with advanced fibrosis/cirrhosis at baseline (Ishak fibrosis score ≥4) demonstrated an improvement in fibrosis

Liaw Y-F, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 894.

Distribution of Ishak FibrosisScores at Baseline, Year 1, and Years 3–7

Viral suppression leads to improved clinical outcomes: HCC and ESLD

YF Liaw et al. N Engl J Med. 2004;351:1521-1531.

Time After Randomization (Months)

0

5

10

15

20

25

0 6 12 18 24 30 36

% W

ith D

isea

se P

rogr

ess

ion

Placebo (n=215)

YMDDm (n=209) (49%)

Wild Type (n=221)

YMDDm

Placebo

5%

13%

21%

WT

Oral agents: Summary

• Potent, once daily therapy

• High genetic barrier with carefully selected agents – TDF, ETV

• Very few side effects (particularly compared to PegIFN)

• Proven liver disease regression and prevention of ESLD/HCC

Discussion