Post Conference Update: Highlights from the American Association of the Study of Liver Diseases MARK SULKOWSKI, MD Associate Professor of Medicine Johns

Post Conference Update: Highlights from the American Association of the Study of Liver Diseases

MARK SULKOWSKI, MDMARK SULKOWSKI, MD

Associate Professor of Medicine

Johns Hopkins University School of Medicine

Medical Director, Viral Hepatitis Center

Johns Hopkins Medical Institution

Baltimore, Maryland

2

Learning Objectives (CME, CE, CPE)

● At the completion of this educational activity, participants should be able to:

- Discuss significant developments in the diagnosis and management of hepatitis B

- Summarize new drugs and treatment strategies for hepatitis B

- Describe toxicity of recent hepatitis therapies, drug side effects, and strategies for management

- Identify new therapeutic strategies to avoid or overcome antiviral resistance

- Highlight diagnosis and management approaches for hepatitis B in individuals co-infected with HIV

Epidemiology and Natural History of HBV Infection

4

Estimated Prevalence of Chronic Hepatitis B in Foreign-Born Persons Living in the United States

Centers for Disease Control and Prevention (CDC) estimates that <0.5% of the US population (800,000-1.4 million) are living with CHB

— Published estimates of CHB in foreign-born (FB) populations in the United States vary and are limited

— Recent studies taking into account all FB persons estimate prevalence of CHB in United States at ~2.0 million persons

Study to determine estimated prevalence of CHB in FB persons in the United States

— Census data used to estimate number of FB persons in the United States from 93 countries/regions

— Published CHB prevalence rates by countries/regions used to model low, mid, and high rates of CHB each

— Number of FB persons with CHB estimated by multiplying each FB population by its prevalence rate

Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.

5

Total and Foreign-Born US Population, 1970-2008

FB persons living in the United States increased from 20 million in 1990 to 41 million in 2008

050

100150200250300

350400450

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

FB

US

Pop

ulat

ion

(mill

ions

)

OtherAsiaLatin AmericaEuropeTotal US Population

OtherAsiaLatin AmericaEuropeTotal US Population

Tot

al U

S P

opul

atio

n (m

illio

ns)

5

1015202530

354045

0

4.7% FB 7.9% FB 13.6% FB


6

Published CHB Prevalence Rates and Low, Mid, and High CHB Rate Assumptions: China

Low, Mid, and High Rate Estimate Assumptions

Published CHB Rate From Review or Model

Published CHB Rate in Immigrants

Published CHB Rate From Population Study

Number in parentheses= sample size

CHB prevalence rates, China

0%

5%

10%

15%

20%

25%

Blood d

onors

, Sing

apor

e, 19

87

(662

)

Popula

tion,

six ci

ties

Pregn

an

t wom

en, N

ative

toHon

gKon

g (1

,2

20)

Pro

fe

ss

ion

al, te

chnic

al, a

dmin

worke

rs(1

,23

2)

Wom

en, J

ilin P

rovin

ce, N

E Chin

a (1

00)

Dep

artm

ent s

tore

emplo

ye

es, B

eijing

(361

)

Low

estim

ate

Pregn

ant w

omen

, Main

land

m

igran

ts to

HK(9

85)

Gen

eral

hosp

ital p

at

ients,

Hon

g Kon

g

(300

)

Pregn

ant w

omen

, Hon

gKon

g(7

07)

Agricu

lture

& fa

ctory

worke

rs(2

,277

)

Chines

e-bo

rnpe

rsons

in S

F Bay ar

ea

(1,0

16)

Pregn

ant w

omen

(14,

575)

Wom

en o

f child

bear

ingag

e(G

olds

tein

MODEL)

Chines

ear

m

y vete

rans

(100

)

Main

landbo

rnChin

ese

adole

scen

tsin

HK

Chines

e-

born

perso

nsin

UK(1

17

)

Gener

alpo

pulat

ion(O

ster M

ODEL)

Mid

estim

ate

Villa

ges in

sout

hern

Taiw

an

(6

,0

95)

Wom

enin

rura

l are

as(1

,1

80)

Govt e

mplo

ye

es, M

ainlan

d

migr

ants

toHK

(2

2,70

7)

Ran

do

msa

mple

of

gene

ral

popu

lat

ion (6

,5

00)

Gen

eral

popu

lation

, J

iangs

upr

ovinc

e(1

01)

Barbe

rs, B

eijing

(316

)

Highes

timate

Gen

eral

popu

lation

, Fuji

an(3

,809

)

Contro

l pop

ulatio

n, Y

angtz

e

River r

egion

(114

)

Steel

worke

rs,Sha

ngha

i (69

0)

Chin

ese-

born

perso

nsin

NYC(5

66

)

IVdr

ug

user

s

Ethnic

Yao

Prison

er

s

Ethnic

Tibe

tan

Fam

ily

mem

bers

of H

BsA

g

+

carri

ers

Per

cent

HB

sAg-

posi

tive

wer RiskGroups

Higher RiskGroups

Chinese-bornpersonsin UK

Chinese-bornpersonsin NYC

Chinese-bornpersons in

San Francisco

LowEstimate10.0%

MidEstimate13.6%

HighEstimate17.0%

CHB Prevalence Rates: China

0%

5%

10%

15%

20%

25% Low Estimate10.0%

Low Estimate10.0%

Chinese-BornPersons in

San Francisco


San Francisco


UK


UK

Mid Estimate13.6%

Mid Estimate13.6%

High Estimate17.0%

High Estimate17.0%


NYC


NYCP

erce

nt

HB

sAg

Po

siti

ve


7

Published CHB Prevalence Rates and Low, Mid, and High CHB Rate Assumptions: IndiaCHB prevalence rates, India

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

11%

12%

Per

cent

HB

sAg-

posi

tive

Lower RiskGroups

Higher RiskGroups

LowEstimate

0.2%

MidEstimate

1.0%

HighEstimate

2.0%

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

11%

12%

CHB Prevalence Rates: IndiaLower RiskGroups

Lower RiskGroups

Low Estimate0.2%

Low Estimate0.2%

Mid Estimate1.0%

Mid Estimate1.0% High Estimate

20.%High Estimate

20.%

Higher RiskGroups

Higher RiskGroups

Per

cen

t H

BsA

g P

osi

tive

Low, Mid, and High Rate Estimate Assumptions

Published CHB Rate From Review or Model

Published CHB Rate From Population Study

Number in parentheses= sample size


8

Percent of FB Population and FB With CHB by Place of Birth

Asia

South/Latin America

Africa

Europe/Oceania

North America

0% 5% 10% 15% 20% 25% 30% 35%

China

Vietnam

Philippines

Korea

India

Other Asia

Mexico

El Salvador

Caribbean

South America

Other Latin America

Western Africa

Eastern Africa

Other Africa

Eastern Europe

Southern Europe

Other Europe

Oceania

North America

Total FB Population (%)

FB With CHB (%, mid estimate)

Pla

ce o

f B

irth

Percent in United States


9

Study Results

Number of FB persons with CHB in the United States ranges from 850,000 to 2,240,000 persons

— 52%-62% from Asia— 13%-15% from Africa— 9%-18% from Central America

Average CHB prevalence rate among the FB population is 2.0%-5.4%


10

New CDC Recommendations:HBV Screening for FB Persons From Countries With

Intermediate HBV Prevalence Rates (≥2%)*

CDC List of Countries With Hepatitis B Prevalence ≥2%

Region HBsAg prevalence ≥2%

Africa All countries

Asia All countries

Australia and South Pacific All countries except Australia and New Zealand

Middle East All countries except Cyprus and Israel

Eastern Europe All countries except Hungary

Western Europe Malta, Spain, and indigenous populations in Greenland

North America Alaska Natives and indigenous populations in Northern Canada

Mexico and Central America Guatemala and Honduras

South America Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas of Bolivia, Brazil, Columbia, and Peru

Caribbean Antigua-Barbuda, Dominica, Grenada, Haiti, Jamaica, St. Kitts-Nevis, St. Lucia, and Turks and Caicos Islands

*September, 2008; change from ≥8%


11

Study of FB Persons in the United States With CHB: Conclusions

Number of FB persons with CHB in the United States may be higher than previously thought

High CHB prevalence rate and related morbidity and mortality argue for building surveillance systems

— Will help develop programs for prevention, earlier diagnosis, and linkage to care

New CDC recommendations extending screening to FB persons from countries with intermediate HBV prevalence could identify more than 250,000 additional FB persons with CHB


12

Evaluation of ALT Determination for Assessing Chronic Hepatitis B (CHB)

Study of 1,335 CHB patients enrolled into registration trials of TDF and ADV to evaluate:

— Concordance between ≥2 ALT values ≤60 days apart

— Liver histology with a single normal range ALT (NRALT)

— Risk factors for significant liver disease

— Association of established (men ≤43 U/L; women ≤34 U/L) and new (men ≤30 U/L; women ≤19 U/L) ALT ULN values with liver disease severity

Pretreatment ALT measured on ≥2 occasions (screening, baseline)— All patients had ≥1 screening ALT >ULN

— Intermittent ALT elevation, ≥1 NRALT (IE ALT)

— Persistent ALT elevation, all ALT values >ULN (PE ALT)

All patients had a liver biopsy between screening and baseline visits

Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.

13

IE ALT*(n=60)

PE ALT†

(n=275) P value

Age (yrs)Mean±SDRange≥40 yrs old

39.4±11.520-65

32 (53.3%)

38.8±12.016-69

607 (47.6%)

0.658

Gender (% men) 63% 76% 0.031

Race (% Asian) 42% 41% 0.930

HBeAg positive 17 (28%) 748 (58.8%) <0.001

Baseline HBV DNA (log10 copies/mL)Mean±SD Range

6.3±1.33.6-9.0

7.8±1.22.2-10.9

<0.001

Baseline ALT‡ (U/L)Mean±SD Range

44.6±31.66-223

144.2±127.036-1459

<0.001

Patient Demographics andDisease Characteristics

*Intermittent ALT elevation, ≥ 1 NRALT ; †Persistent ALT elevation, all ALT values > ULN; ‡ALT ULN: men ≥43 U/L; women ≥34 U/L


14

Liver Histology in Patients With Intermittently Versus Persistently Elevated ALT*

*ALT ULN: men ≤43 U/L; women ≤34 U/L

19/5919/5919/5919/59

581/1246581/1246581/1246581/1246

33/5933/5933/5933/59

993/1247993/1247993/1247993/1247

0

20

40

60

80

100

0

20

40

60

80

100

P=0.030

80%

56%

Knodell Fibrosis Score 3 Knodell Necroinflammatory Score 6

P<0.001

IE ALT PE ALT

32%

47%

IE ALT PE ALT

% o

f P

atie

nts

% o

f P

atie

nts


15

Normal ALT at Baseline in IE ALT* Patients With Significant Liver Disease

*ALT ULN: men ≤43 U/L; women ≤34 U/L

0

20

40

60

80

100

Knodell Fibrosis Knodell Necroinflammatory

17/1917/19

89%

79%

% o

f P

atie

nts

Wit

h N

RA

LT

at B

asel

ine

% o

f P

atie

nts

Wit

h N

RA

LT

at B

asel

ine 26/3326/33


16

Results Using Established ALT ULN

No demographic or disease characteristics associated with significant liver disease

In patients with IE ALT using established ALT, none of the following associated with Knodell fibrosis score ≥3 or Knodell necroinflammatory score ≥6:

— Age (below/above 40 years)— Gender— Asian/non-Asian ethnicity— HBeAg status— HBV viral genotype— Baseline ALT — Baseline HBV DNA


17

Patients With Elevated ALT:Liver Fibrosis and Eligibility for CHB Tx

*ALT ULN: men ≤43 U/L; women ≤34 U/L†ALT ULN: men ≤30 U/L; women ≤19 U/L

Per

cen

t W

ith

Bas

eli

ne

AL

T >

2x U

LN

72%65%

90% 88%

0102030405060708090

100

Knodell Fibrosis Score ≥3 Eligibility for Tx

Est ALT ULN* New ALT ULN†


18

Study of ALT in CHB: Conclusions

Patients with IE ALT with established ALT ULN often have significant liver disease, which cannot be excluded by a single normal ALT test

Early repeat testing of normal ALT (eg, ≤2 months interval) in CHB patients may

— Reveal elevated ALT— Identify patients with underlying liver disease

Using New ALT ULN — Most patients with significant underlying liver disease

have ALT >2 x ULN— 34% more patients are eligible for treatment


19

Age-Specific Prognosis AfterHBeAg Seroconversion

Cohort study of CHB prognosis in different age groups following spontaneous HBeAg seroconversion

441 with HBeAg seroconversion followed ≥1 year— At seroconversion:

• 388 <40 years of age• 53 ≥40 years of age

Annual incidence of CHB-related complications for entire population:— 1.9% with hepatitis relapse— 0.2% developed cirrhosis— 0.6% developed hepatocellular carcinoma

All significantly higher among HBeAg seroconverters ≥40 years of age:— Hepatitis relapse (P=0.005)— Development of cirrhosis (P<0.0001)— Development of hepatocellular carcinoma (P=0.024)

Conclusion: after HBeAg seroconversion, patients remain at risk for CHB-related complications, especially if ≥40 years of age at seroconversion

Chen Y-C, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 815.

20

Perinatal Transmission of HBV:Effect of Viral Load and HBeAg Status

Study to evaluate the rate of and maternal virologic factors associated with perinatal HBV transmission

— HBsAg+ pregnant women identified during antenatal screening

— 87 HBeAg+; 202 HBV DNA positive— All infants routinely offered HBIG and HBV vaccination

124 infants tested for HBV at 9 months of age— HBV transmission in 3 infants (2.4%)

• All had mothers with HBV DNA >8 log10 c/mL and HBeAg+• Transmission rate 7.2% HBV DNA >8 log10 c/mL and 5.5% HBeAg+

— All uninfected infants were anti-HBs positive and HBsAg negative

Perinatal transmission can occur despite prophylactic measures, primarily in HBeAg+ women with HBV DNA >8 log10 c/mL

Wiseman E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 827.

21

High Prevalence of Hepatic Steatosis and Impact on Fibrosis in HBV

Retrospective study to evaluate effect of hepatic steatosis on HBV progression

— 220 CHB pts (63% male; 68% Asian; 51% HBeAg+) Overall, 34% with hepatic steatosis

— Hepatic steatosis associated with:• Male gender (40% vs 24%; P=0.034)• Older age (44 vs 36 yrs; P<0.0001)• Higher BMI (27 vs 24; P<0.00057)

— Pts with hepatic steatosis more likely to have• Hepatic fibrosis (70% vs 56%; P=0.005)• Bridging fibrosis/cirrhosis (29% vs 16%; P=0.022)

— Similar trends for HBeAg-positive and HBeAg-negative CHB No differences regarding hepatic inflammation, iron deposition,

elevated ALT, or HBV DNA Conclusion: hepatic steatosis is a significant factor in CHB-related

disease

Bleibel W, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 831.

22

Predictors of Liver-Related Morbidity and Mortality in CHB

Retrospective study of HBsAg-positive pts referred to hepatology department of French hospital since 1980 (N=1300)

— Pts co-infected with HIV, HDV, and HCV excluded (n=207)

Cox regression analysis used to determine predictors of liver-related mortality and morbidity

Factors assessed:— Age— Sex— Ethnic origin— Alcohol consumption— Baseline HBeAg status— ALT— Serum HBV DNA

HBeAg- HBeAg+ P value

Median follow-up (years) 5.0 6.7 <0.0001

Mean age (years) 39.6 35.0 <0.0001

Male (%) 69.0 68.5 0.89

Caucasian/African/Asian (%) 22.1/52.4/25.5 30.0/20.5/49.5 <0.0001

Alcohol 0/≤50/>50 g/day (%) 83.2/11.5/5.3 80.6/15.3/4.1 0.27

HBV DNA <4/4-<6/≥6 log10 c/mL (%)

47.8/20.9/19.0 3.0/7.0/84.5 <0.0001

Median ALT (IU/L) 32 62.5 0.09

Anti-HBV Tx (%) 46.7 81.0 <0.0001

Liver decompensation (%) 8.0 11.0 0.16

HCC (%) 3.8 3.5 0.84

Liver-related death (%) 3.2 3.5 0.86

Liver transplantation (%) 0.3 1.0 0.21

Baseline Characteristics (n=1093)

Ngo Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 1944.

23

Factors Associated WithComplications of HBV


Follow-Up (Months)Follow-Up (Months)

667 8005334002671330.00

0.25

0.50

0.75

1.00

0

Follow-Up (Months)Follow-Up (Months)

667 8005334002671330.00

0.25

0.50

0.75

1.00

0

667 8005334002671330.00

0.25

0.50

0.75

1.00

0 667 8005334002671330.00

0.25

0.50

0.75

1.00

0

Su

rviv

al

Wit

ho

ut

Co

mp

lic

ati

on

s (

%)

Female

Male

HBV DNA <4 log

HBV DNA ≥4 log

ALT <2x ULN

ALT ≥2x ULN

<35 years of age

≥35 years of age

HBV DNA Level

Gender

Elevated ALT

Age

24

Multivariate Analysis of Factors Associated With Liver-Related Morbidity and Mortality

Factor Risk Ratio 95% CI P value

Age ≥35 years 1.06 1.04-1.07 <0.0001

Male gender 1.95 1.07-3.55 0.03

Elevated ALT 1.00 1.00-1.00 0.0001

Alcohol ≥50 g/day 1.00 1.00-1.01 0.0004

HBV DNA >4 log 1.81 1.07-3.03 0.03

Conclusions:— In chronic HBsAg carriers, liver-related morbidity and

mortality are associated with elevated HBV DNA and ALT, older age, male gender, and alcohol consumption

— Reduction of alcohol consumption along with HBV treatment may reduce liver-related morbidity and mortality in HBsAg carriers


Therapeutic Strategies for HBV Treatment

26

Tenofovir Versus Adefovir inAsian Patients

TDF has shown superior efficacy to ADV in treatment-naïve CHB patients in 2 pivotal studies

Efficacy and safety of TDF among Asian CHB patients participating in TDF studies GS-174-0102 (HBeAg-) and GS-174-0103 (HBeAg+) were reported

Week 2405-Year

Liver Biopsy

Week 48Liver Biopsy

Paired Biopsies in 391 TDF (92%) and

192 ADV (89%)

Pretreatment Liver Biopsy

RA

ND

OM

IZA

TIO

N 2

:1

TDF 300 mg (n=426*)

ADV 10 mg (n=215*)

Open Label8 Years

Double Blind

TDF 300 mg

≥ Week 72 Option forFTC+TDF if Viremic

Lee S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 980.

27

Tenofovir Versus Adefovir in Asian Patients: Results

189 Asian pts were enrolled across the 2 studies

Asians comprised ~30% of all patients

— 127/426 (30%) on TDF— 62/215 (29%) on ADV

TDF demonstrated superior HBV DNA suppression relative to ADV in Asian patients following 48 weeks of randomized treatment

Efficacy, safety, and resistance analyses were consistent with the results of the overall studies

TDFTDF ADVADV

0

10

20

30

40

50

60

70

80

90

100

HBV DNA <400c/ml(69 IU/ml)

Normal ALT Histologic response

Pe

P<0.001

Missing=FailureMissing=Failure

Per

cen

tag

e (%

)P

erce

nta

ge

(%)

85%

42%

72%65%

77%71%

Lee S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 980.

28

Study 102: 2-Year TDF Treatment and ADV Switch Data in HBeAg- With CHB

Week 48 phase 3 data showed TDF superior to ADV:—HBV DNA <400 copies/mL: 93% TDF vs 63% ADV (P<0.001)

96-week data presented

Randomized, double-blind comparison of TDF vs ADV for HBeAg- chronic hepatitis B HBV DNA >105 c/mL and ALT >ULN and <10x ULN Knodell necroinflammatory score ≥3 LAM experienced or naïve

Marcellin P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 146.

Week 240Liver Biopsy

Week 48Liver Biopsy


RA

ND

OM

IZA

TIO

N 2

:1

Tenofovir 300 mg (n=250)

Adefovir 10 mg (n=125)

Open Label8 Years

Double Blind

TDF 300 mg

Week 96 End of Study

5 Years2 Years

Week 72 HBV DNA ≥400 copies/mL Option to Add Emtricitabine (FTC) to TDF in a Fixed-Dose Tablet

1 Year

TDF 300 mg

29

Study 102: HBV DNA <400 copies/mL

TDF demonstrated durable, potent antiviral activity through Week 96:— 99% of patients on therapy had HBV DNA <400 copies/mL

No resistance to TDF detected after 2 years on TDF monotherapy

ITT Analysis

Randomized Double Blind

Pe

rce

nta

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=0.67291%

89%

250

125

234

122

245

125

243

124

248

120

247

123

242

123

243

122

TDF-TDF n=

ADV-TDF n=

On-Treatment Analysis

Randomized Double Blind

Pe

rce

nta

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=0.16699%100%

250

125

214

109

242

123

239

121

242

117

241

117

226

110

224

109

TDF-TDF n=

ADV-TDF n=

LAM Exp.

97%

100%

LAM Exp.

93%

96%

Marcellin P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 146.

30

Study 103: 2-Year TDF Treatment and ADV Switch Data in HBeAg+ With CHB

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

Randomized, double-blind comparison of TDF vs. ADV for HBeAg+ chronic hepatitis B HBV DNA >106 c/mL and ALT ≥2x and <10x ULN Knodell necroinflammatory score ≥3 Nucleos(t)ide naïve

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

Week 240Liver Biopsy

Week 48Liver Biopsy


RA

ND

OM

IZA

TIO

N 2

:1

Tenofovir 300 mg (n=250)

Adefovir 10 mg (n=125)

Open Label8 Years

Double Blind

TDF 300 mg

Week 96 End of Study

5 Years2 Years

Week 72 HBV DNA ≥400 copies/mL Option to Add Emtricitabine (FTC) to TDF in a Fixed-Dose Tablet

1 Year

TDF 300 mg

31

Study 103: HBV DNA <400 copies/mL

TDF demonstrated durable, potent antiviral activity through Week 96:—82% of pts viremic on ADV at Week 48 were <400 c/mL on TDF at Week 96

No resistance to TDF detected after 2 years on TDF monotherapy

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

On-Treatment AnalysisRandomized Double Blind

Pe

rce

nta

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=0.37489%85%

176

90

142

79

173

88

165

85

166

84

160

85

148

83

144

81

TDF-TDF n=

ADV-TDF n=

Pe

rce

nta

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=0.80178%

78%

176

90

165

86

174

89

170

88

172

88

171

90

168

89

164

87

TDF-TDF n=

ADV-TDF n=

ITT AnalysisRandomized Double Blind Open Label

32

Long-Term Use of Tenofovir Reduces Liver Fibrosis in HIV/HBV Co-Infection

Study assessed the effect of TDF on liver fibrosis 130 co-infected patients treated with TDF and

followed for a median of 29.5 months— At baseline, 45 patients presented with Fibrometer®

stage F0-F1, 29 patients with stage F2, and 56 patients with stage F3-F4

Assessments included:— Fibrometer® (platelets, prothrombin time, AST,

α2-macroglobulin, hyaluronic acid, urea, age)— Paired liver biopsies

Lacombe K, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 914.

33

Reduction in Fibrosis Scores by Fibrometer® and Paired Liver Biopsies

Conclusion: In a population with HIV/HBV co-infection, TDF induced a significant decrease in fibrosis and histologic activity level after mean treatment duration of 29.6 months

Fibrometer ® Paired Liver Biopsies

Lacombe K, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 914.

F0-F1(remained,

n=8)

F2(remained,

n=6)

F3-F4(remained,

n=11)

n=1n=1

n=1n=1n=4n=4

n=7n=7n=0n=0

0Time after treatment initiation (months)

12 24 36

0.20

0.40

0.60

0.80

1.00

F3-F4

F2

F0-F1

DA

VG

Fib

rom

eter

® S

core

34

HBV Genotype Is the Strongest Predictor of Response to Interferon-Alfa Treatment

Pooled analysis evaluating effect of HBV genotype on treatment outcome following IFN-α for 6-12 mos for CHB (N=1,229)

— Standard interferon-α (n=298), pegylated interferon-α (n=491), pegylated interferon-α with lamivudine (n=440)

— HBeAg status: positive (n=703), negative (n=526)— HBV genotypes: A (n=174), B (n=245), C (n=464), D (n=346)

HBV genotype determined by direct sequencing of X or S gene

Sustained virologic response determined 6 mos after Tx and defined as:

— Normalization of ALT— HBV DNA <20,000 c/mL— In HBeAg+, HBeAg seroconversion

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

35

HBV Genotypes as Predictors of Response to Interferon-Alfa: Multivariate Analysis

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

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

% 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

OR(95% CI) P value

HBV genotype

A vs D 3.620(2.316-5.657) 0.0001

B vs D 2.621(1.618-4.245) 0.0001

C vs D 3.184(2.054-4.936) 0.0001

ALT >5 vs ≤5x ULN

1.432(1.056-1.940) 0.02

HBeAg neg vs pos 2.124(1.527-2.966) 0.0001

Independent Predictors for SVRSVR by Genotype and HBeAg Status

36

ETV-060: Histologic Assessment of Long-Term ETV Treatment in CHB

Open-label, rollover study assessed histologic improvement in patients who had evaluable liver biopsies after receiving at least 3 years of ETV therapy

— Subset of studies that enrolled nucleoside-naïve (n=66) or LAM-refractory (n=84) pts

Histologic improvement defined as

— ≥2-point decrease in Knodell necroinflammatory [NI] score

— ≥1-point decrease in Knodell fibrosis score

Thirty-seven naïve patients and 27 LAM-refractory patients had biopsies from 3 required time points (baseline, Week 48, and Week 148)

Katano Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 889.

37

Results of Histologic Assessment ofLong-Term ETV in CHB

Liver histology improved significantly after 3 years of continuous ETV Tx

Treatment beyond 48 weeks resulted in continued improvement in fibrosis scores in both naïve and LAM-refractory patients

≥1-Point Decrease Knodell Fibrosis Score

Pa

tie

nts

%

≥2-Point Decrease Knodell NI Score*

*P<0.0001; †P=0.0002; ‡P=0.043 (all compared with baseline)

†

‡

*

Katano Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 889.

17

47

12

32

0

20

40

60

80

100

Week 48 Week 148

Nucleoside Naïve LAM Refractory 84

100

58

89

0

20

40

60

80

100

Week 48 Week 148

38

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

Han S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. 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-responders(At Week 48 or who became non-responders during Year 2)

151 Virologic Responders(At Week 96)

11 Responders(At Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up)

Week 144

ETV-022 ETV-901

Week 96 5 Years

NR=8

VR=198

R=37

243

Study DesignStudy Design

39

Studies ETV-022/-901: Baseline Characteristics


Age, mean (years) 35 36

Male (%) 77 80Race:

Asian (%)

Non-Asian (%)

58

42

6436

HBV DNA by PCR, mean (log10 copies/mL)

9.62 9.91

ALT, mean (U/L) 140 122

HBV genotype (%) A B C D Other

27

1931

1013 26

2730

4 13

ETV-022(N=354)

ETV-901

(N=146)

40

Studies ETV-022/-901: Proportion With HBV DNA <300 c/mL Through 5 Years


Pro

po

rtio

n o

f P

atie

nts

(%

)H

BV

DN

A <

300

cop

ies/

mL

55%

Year 1

83%

Year 2

89%

Year 3

67%

n= 236/354

Year 4

91%

80/146

116/140 116/131 98/108

Year 5

88/94

94%Year 1

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

20

40

60

80

100

0

41

Studies ETV-022/-901:Long-Term HBV DNA Suppression

Conclusion: Long-term treatment with ETV results in durable suppression of HBV DNA replication, with 1 person developing ETV resistance over 5 years of surveillance


0

2

4

6

8

10

12

0 Year 1 Year 2 Year 3 Year 4 Year 5

Mea

n H

BV

DN

A

(lo

g10

co

pie

s/m

L)

300 copies/mL

n= 146 146 140 131 108 94

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

42

Studies ETV-022, -027, and -901: Long-Term ETV Reverses Fibrosis/Cirrhosis in CHB

Long-term histologic results for a subset of patients (n=57) treated with ETV for a median of 280 weeks

— Nucleoside-naïve HBeAg+ and HBeAg- patients treated with ETV in studies ETV-022 or ETV-027 who:

• Had a liver biopsy in study ETV-901 and

• Received a minimum of 3 years cumulative ETV therapy

Co-primary end points— Histologic improvement (≥2-point decrease in Knodell

necroinflammatory score and no worsening of Knodell fibrosis score) compared with baseline

— Improvement in Ishak fibrosis score (≥1-point decrease) compared with baseline

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

43

Ishak Fibrosis Score

1

2

3

4

5

6

Missing

0

Pat

ien

ts (

n)

Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Years 3-7

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; October 31-November 4, 2008; San Francisco, CA. Abst 894.

0

10

20

30

40

50

60

Baseline Week 48 Long-Term

44

Continued LdT Results in High Rates of Maintained Response in HBeAg-Positive Patients

Maintained Treatment Response (HBeAg seroconversion and HBV DNA <300 copies/mL) 66/86 (76.7%)

Maintained PCR negativity (HBV DNA <300 copies/mL) 73/88 (83.0%)

ALT normalization 77/85 (90.6%)

Maintained HBeAg loss 88/88 (100.0%)

Maintained HBeAg seroconversion 80/86 (93.0%)

HBsAg loss 3/88 (3.4%)

HBsAg seroconversion 1/88 (1.1%)

Maintained HBeAg loss and HBV DNA <5 log10 copies/mL 88/88 (100.0%)

Maintained HBeAg seroconversion and HBV DNA <3 log10 copies/mL

71/86 (82.6%)

Virologic failure (HBV DNA ≥1000 copies/mL) 8/88 (9.1%)

Continued telbivudine treatment in patients results in high rates of maintained treatment responses and control of CHB at 3 years

Long-term telbivudine treatment can lead to HBeAg clearance/seroconversion

Study evaluating maintained treatment response to LdT at week 156 HBeAg-positive CHB patients on LdT who achieved HBeAg seroconversion and

undetectable HBV DNA by week 104 and followed to week 156

Gane E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 942.

45

Cost-Effectiveness Simulation Analysis of TDF, LAM, ADV, and ETV in HBeAg-Negative CHB Patients

Study evaluating the impact of initiating treatment with TDF, LAM, ADV, and ETV on cost and quality of life in HBeAg- patients in the United States

Simulation analysis using a Markov model developed to predict incidence and cost of CHB-related complications

— Patients assumed to be treatment naïve at initiation of Tx

— Assigned levels of viral suppression and risk of developing viral resistance specific to their treatment

— Patients who became resistant could switch or add on another treatment

— Patients who developed resistance to initial and subsequent treatments were assumed to discontinue treatment, and incidence of complications was modeled assuming no further viral suppression

Deniz H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 976.

46

Results of Cost-Effectiveness Simulation Analysis

TDF LAM ADV ETV

Total pharmacy and medical cost per patient (US$)

117,794 152,336 138,950 141,409

Cost of initial and subsequent HBV treatments (US$)

94,781 101,990 105,449 117,648

Quality-adjusted life years 10.28 8.93 9.72 10.28

Conclusion: Although the long-term medical costs associated with care and treatment of HBeAg-negative patients are not completely known, this study suggests that TDF will be a more cost-effective treatment than LAM, ADV, and ETV

Deniz H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 976.

New Therapies and Strategies for HBV Treatment

48

Clevudine (L-FMAU)

CLV is a pyrimidine nucleoside analog— No mitochondrial toxicity — Inhibition of synthesis of dsDNA from ssRNA

Randomized, placebo-controlled trial – 30 mg/day— HBV DNA reduction of 5.10 log10 c/mL at week 24— Prolonged suppression 24 weeks after dosing (-2.02 log)

Resistance profile similar to other L-nucleosides— M204I; L180M; 204I/V; A181T

Phase 3 clinical trials for US registration; approved in Korea (Bukwang Pharmaceuticals)

Byung CY, et al. Hepatology. 2007;45:1172 - 1178.

49

CLV Versus LAM Comparison in HBeAg-Positive CHB Patients

Randomized, blinded trial (N=55)— CLV 30 mg/d vs

LAM 100 mg/d— Entry: treatment naïve, HBV DNA

>3 million c/mL; ALT >1x ULN At 48 weeks, all analyses

favored CLV:— More pts with HBV DNA

<300 c/mL— Greater HBV DNA decrease

• CLV: 4.7 log (3.3-6.2)• LAM: 3.2 log (0.2-5.7)

— More HBe seroconversion(17% vs 8%)

— Less resistance (0 vs. 9 patients)

Conclusion: CLV more effective than LAM in HBeAg-positive CHB pts

Pat

ien

ts (

%)

Lau G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 911.

HBV DNA <300 c/mLat Week 48

59

72

32

46

0

20

40

60

80

100

Week 32 Week 48

CLV LAM

50

Clevudine: Efficacy and Resistance 34 treatment-naïve pts with CHB (24 HBeAg+) treated with CLV (30

mg/d) for median 52 weeks— Mean HBV DNA 7.3±1.1 log10 c/mL— Mean ALT 263±234 U/L— Cirrhosis – 10 patients

Results— HBeAg negative: 10/10 HBV DNA undetectable at week 24— HBeAg positive:

• 58.3% and 75% undetectable at weeks 24 and 48

• 2 pts with viral breakthrough at weeks 48 and 56 – mutation rtM204I detected in both

Conclusions: — CLV effective in CHB— rtM204I a common mutation in CLV failure

Kwon SY, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 943.

51

CLV Versus ETV in Treatment-Naïve CHB

Non-randomized, cohort study of treatment-naïve CHB pts (N=148)

— CLV 30 mg/day (n=39) vs ETV 0.5 mg/day (n=109)

— Longer treatment with ETV (16.6±2.8 mos) compared with CLV (9.9±3.3 mos) (P<0.001)

Similar HBV DNA suppression observed

Conclusions:— CLV and ETV appear similarly

potent at 48 weeks

— Longer F/U needed to assess long-term HBV DNA suppression and resistance profiles

Pat

ien

ts (

%)

Sul H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 912.

HBV DNA <140 c/mL

44.4

55.9

13.5

30.8

55.3

12.7

0

20

40

60

80

100

12 wks 24 wks 48 wks

ETV CLV

52

In Vitro Simvastatin Is Active Against Drug-Resistant and Wild-Type HBV Strains

In vitro, simvastatin inhibits HBV extracellular virion production and intracellular DNA intermediate forms

Study in which cultured HBV-producing HepG2.2.15 cells treated with 9 consecutive daily doses of SIM, LAM, or ADV

Comparable efficacy of SIM, LAM, and ADV against clinically relevant resistant viruses found

Clinical studies are needed to test in vivo significance and utility of SIM in treatment of CHB

Bader T, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 877.

SIM EC50 (uM) LAM EC50 (uM) ADV EC50 (uM)

WT 8.2 0.2 1.5

M204V 9 >100 1.8

N236T 9.3 0.6 8.1

53

In Vitro Interferon Gamma: Anti-HBV Activity With and Without LAM or ADV

IFN γ-1b is a type 2 IFN that binds to a unique cell surface receptor In vitro model, HepG2.2.15 cells transfected with wild-type HBV

— Treated with IFN γ-1b or peginterferon α-2a 2 days after plating or LAM or ADV 3 days after plating

— IFN γ-1b also combined with peginterferon α-2a, LAM, or ADV All showed potent antiviral activity

— LAM and ADV activity increased in presence of IFN γ-1b Models support in vivo testing of IFN γ-1b alone or in combination

with nucleos(t)ide analogs in CHB

Blatt L, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 898.

*Increased potency

IFN gamma IFN alfa-2a LAM ADV

EC50 20 pg/mL 90 pg/mL 540 nM 620 nM

+IFN γ-1b _ _ ↑ 6-fold * ↑ 15-fold*

54

Combination Therapy: EASL Clinical Practice Guidelines—Management of CHB

As of yet, no data to support de novo combination therapy in Tx-naïve patients receiving first-line nucleos(t)ide analogs (ETV or TDF)

Some experts recommend de novo combination therapy to prevent resistance in high-risk patients (eg, high HBV DNA level) or persons in whom resistance is life threatening (eg, cirrhosis, transplant)

— TDF plus either LAM or FTC may be considered in such patients

Combination (“add-on”) therapy is recommended for patients with treatment failure

— Agents that do not share cross-resistance

European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B. J Hepatol. 2008 [Epub ahead of print].

55

4-Year Follow-Up of “Add-On” ADV in LAM-Resistant Patients

LAM-resistant pts treated with add-on ADV (10 mg/d) plus LAM (100 mg/d) for mean of 55 mos (N=145)

— 73% cirrhotic; 92% HBeAg negative

Results:— Overall, 81% HBV DNA undetectable, with continued improvement through 5 years

of Tx

— 84% ALT normalization— 3 developed new rtA181T (2 became undetectable); no rtN236T observed— 23 pts with increase serum Cr >0.5 mg managed with ADV dose adjustment (10 mg

QOD) with stabilization or improvement

Conclusion:In patients with LAM-resistant HBV, ADV add on to LAM is an effective and safe Tx strategy

Lmpertico P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 906.

58 68 78 88 86

0

50

100

1 2 3 4 5

Year

% H

BV

DN

A

Un

det

ecta

ble

by

Yea

r o

f T

x

56

5-Year “Add-On” ADV in LAM-Resistant Patients

Prospective, single-center cohort (N=41) — HBeAg-negative CHB with LAM resistance— Median HBV DNA 6 million c/mL

ADV (10 mg/d) plus LAM (100 mg/d) Results:

— Significant HBV decline through 5 years of Tx— ALT normalization in 93% at 5 years of Tx— No ADV resistance observed

Conclusion: ADV+LAM is effective in HBeAg-negative CHB with LAM resistance

Pat

ien

ts (

%)

Hadziyannis S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 924.

6881 86 86 9588 85

93 92 93

020406080

100

Year 1 Year 2 Year 3 Year 4 Year 5

HBV DNA ≤250 c/mL

ALT Normalization

57

De Novo ADV+LAM Compared With “Add-On” ADV to LAM

Retrospective, single-center, cohort study (N=201)

Pts receiving ADV+LAM for median 17 months (range 3-48)

— De novo (n=151)• HBeAg+ 38%; cirrhosis 38%; mean

HBV DNA 4.9 log

— “Add-on” (n=50)• HBeAg+ 68%; cirrhosis 80%; mean

HBV DNA 4.0 log

De novo strategy more effective — Greater virologic suppression

— 3 “add-on” pts acquired ADV-R in setting of prior LAM-R

Carey I, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA.Abst 930.

HBV DNA Suppression

-5

-4

-3

-2

-1

03 6 12 18

MonthsL

og 1

0 H

BV

DN

A c

/mL

De Novo Add On

58

CLV Compared With LAM as “Add-On” in Patients With ADV Failure

Open-label, non-randomized cohort followed for ~12 months; evaluated adding CLV (30 mg/d) or LAM (100 mg/d) to ADV after viral failure

450 LAM-resistant CHB pts treated with ADV — 29 with viral breakthrough on ADV after median 60 months— 6 with ADV-resistant variants: rtA181VT or rtN236T— CLV added (n=12); LAM added (n=17)

Similar outcomes regarding effectiveness, safety, and tolerability No additional resistance mutations observed

CLV+ADV (n=12)

LAM+ADV(n=17) P value

Baseline HBV DNA (median log10 c/mL) 6.43 6.13 NR

HBV DNA ↓ at wk 24 (median log10 c/mL) - 2.97 - 2.27 0.28

% HBV DNA undetectable at wk 24 50% 29% 0.22

Park NH, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 961.

59

Switch to ADV+ETV in Patients Failing ADV+LAM

Observational, open-label, cohort study of switching ETV (1 mg/d) for LAM in pts failing ADV+LAM (N=13)

— Failure after ADV+LAM combination (n=9) or sequential (n=4)— Baseline HBV DNA 2x105 c/mL (range 9x103-4x107)

Results (median of 10 mos)— Median ↓ 3 log10 c/mL (range 1.6-4.3)

• 10/13 with HBV DNA <400 c/mL

• 2/3 without full suppression had rtA181T variant

— Significant reduction in ALT (median 0.72 ULN, P=0.034)— No significant adverse events

Further research on nucleotide analog (ADV or TDF) plus ETV is warranted

Schollmeyer J, et al. October 31-November 4, 2008; San Francisco, CA. Abst 925.

60

ETV+TDF in Patients With Multi-Drug-Resistant CHB

Open-label, single-center, cohort study 12 treatment-experienced patients with CHB-related cirrhosis

— 11/12 with genotypic resistance to LAM±ADV— 7/12 received LAM+ADV at time of switch— HBV DNA level 5x106 c/mL (7x104-7x109)

TDF (245 mg/d) plus ETV (1 mg/d) for median 6 months — No AEs or decompensation observed— Median ↓ HBV DNA 4.6 log10 c/mL (1.7-7.8) — 9/12 with HBV DNA <400 c/mL

Further research is needed to test TDF+ETV combination

Schollmeyer J, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 985.

61

De Novo TDF+LAM or FTC Is Associated With Early Virologic Response in HIV/HBV Co-Infected Patients

Retrospective study comparing de novo vs add-on therapy for HBV in HIV/HBV co-infected patients

— Group 1: TDF plus either LAM or FTC (n=15)

• Never received or no LAM in 4 years

— Group 2: LAM initially with add-on TDF (n=46)

Results— More Group 1 achieved HBV DNA

<3 log at 6 mos— 14 pts in Group 2 had HBV DNA decrease

<1 log at 6 mos• 7 considered noncompliant

• 7 had HBV clearance at median of 20 mos.

— LAM baseline resistance higher in Group 2 (46% vs 11%, P=0.026)

Conclusion: de novo therapy leads to an earlier virologic response than add-on therapy

Pat

ien

ts (

%)

100%

77%

Percent <3 log10 IU/mL at 6 Mos

Lada O, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 922.

0

20

40

60

80

100

Group 1 Group 2

62

Treatment of CHB in HIV/HBV Co-Infected Patients With TDF Containing HAART

HIV/HBV co-infected patients naïve to antiretroviral therapy (N=47)

— Median CD4 count 42 cells/mm3

— Median HBV DNA 8 log10 IU/mL— 34/47 (64%) HBeAg positive

Treated with combination HAART containing TDF alone (n=11) or TDF+FTC or LAM (n=36)

— Median follow-up 27 months— Median TDF exposure 25 months

Matthews G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 907.

63

High Rate of HIV and HBV Suppression With TDF-Containing HAART

HIV responses— All HIV RNA <50 c/mL— Median CD4 count 342 cells/mm3 after Tx

HBV responses— HBV DNA

• 72% <20 IU/mL

• 94% <400 IU/mL

• No patient >1000 IU/mL

— HBeAg loss 36%— HBeAb seroconversion 33%— HBsAg loss 6%

Conclusion: TDF-containing ART with and without FTC or LAM was very effective in controlling HIV and HBV in HIV/HBV co-infected patients with advanced HIV disease

Matthews G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 907.

64

PegIFN alfa-2a With or Without Ribavirin for CHB

RBV inhibits viral replication and modulates immune response

— Role in CHB unknown

Multicenter, randomized, clinical trial in HBeAg-negative CHB patients (N=133)

— Male, 74%; mean age, 42.2 yrs; HBV genotype D, 80%— PegIFN alfa-2a 180 mcg weekly plus either placebo or

RBV 1000-1200 mg/d for 48 weeks

Janssen H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 991.

65

RBV Does Not Improve Response Compared With PegIFN Alone for HBeAg-Negative CHB

Week 48 End of Treatment

Week 72 End of Follow-Up

PegIFN+Placebo

(n=69)

PegIFN+RBV

(n=64)

PegIFN+Placebo

(n=69)

PegIFN+RBV

(n=64)

HBV DNA <10,000 c/mL 67% 55% 20% 19%

HBV DNA <400 c/mL 52% 28% 9% 6%

ALT normal 41% 53% 41% 52%

Conclusion: No benefit to adding RBV to PegIFN Tx in HBeAg-negative CHB

Janssen H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 991.

Resistance IssuesWith HBV Treatment

67

HBV Resistance to Nucleos(t)ide Analogues

As anti-HBV therapy may be indefinite for the large majority of patients, treatment and prevention of long-term resistance is a major issue

Pre-existing resistance may be important to recognize in order to tailor first-line anti-HBV therapy

The resistance profile of TDF, the latest approved drug for treatment of CHB, was studied and discussed in particular at this meeting

68

Most Common HBV Cross-Resistance Mutations

Durantel, et al. Hepatology. (2004); Brunelle, et al. Hepatology. (2005); Yang, et al. Antivir Ther. (2005); Villet, et al. Gastroenterology. (2006); Delaney, et al. Antimicrob Agents Chemother. (2006); Villet, et al. J Hepatol. (2007); Brunelle, et al. Antimicrob Agents Chemother. (2007); Qi, et al. Antivir Ther. (2007);Tenney, et al. Antimicrob Agents Chemother. (2004 & 2007) ; Villet, et al. J Hepatol. (2008).

*(+L180M+ M204I/V)

Lamivudine Telbivudine Entecavir Adefovir Tenofovir

Wild-type S S S S S

M204l R R I/R S S

L180M+M204V R R I S S

A181 T/V I S S R S

N236T S S S R I

I169T+V173L+M250V* R R R S S

T184G+S202lI/G* R R R S S

69

Rates of HBV Resistance Over Time in HBeAg-Positive, Treatment-Naïve Patients

Marcellin P, et al. J Hepatol. 2005;42(suppl2):31-32; Lai CL, et al. Hepatology. 2006;44(suppl):222A;Colonno R, et al. Hepatology. 2006;44(suppl):229A; Shiffman ML, et al. Hepatology. 2004;40(suppl):172A; Chung YH, et al. Hepatology. 2006;44(suppl):698A; Heathcote J, et al.Hepatology. 2007;46 (suppl 1):861.

0

10

20

30

40

50

60

70

Lamivudine Adefovir Entecavir Telbivudine Tenofovir

Year 1

Year 2

Year 3

Year 4

Year 5

Pat

ien

ts W

ith

Res

ista

nce

(%

)

70

Rates of HBV Resistance Over Time in HBeAg-Negative, Treatment-Naïve Patients

ETVLAM ADV LdT CLVFTC TDF

Pat

ien

ts W

ith

Res

ista

nce

(%

)

0%

20%

40%

60%

80%

1

3

5

Years2

4

Marcellin P, et al. J Hepatol. 2005;42(suppl2):31-32; Lai CL, et al. Hepatology. 2006;44(suppl):222A;Colonno R, et al. Hepatology. 2006;44(suppl):229A; Shiffman ML, et al. Hepatology. 2004;40(suppl):172A; Chung YH, et al. Hepatology. 2006;44(suppl):698A; Heathcote J, et al. Hepatology. 2007;46 (suppl 1):861.

71

Pre-Existing Antiviral Resistance Mutations

Pre-existing HBV antiviral resistance (AVR) mutations in treatment-naïve CHB patients is believed to occur at a low frequency

— Lamivudine ~10%— Entecavir ~1%-2%

Pre-existing AVR may significantly compromise antiviral efficacy in the treatment of CHB

However, clinical significance of pre-existing AVR mutations is unknown

Ludwig AD, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 884.

72

Prevalence and Effect of Pre-Existing Antiviral Resistance Mutations

Prevalence of AVR mutations was determined using INNO-LiPA HBV DRv2 and DRv3 line probe assay and confirmed by direct sequencing in treatment-naïve CHB patients (N=313)

Patient Characteristics (N=313)Patient Characteristics (N=313)

Mean age (years) 48±13

%Male:% female 61:39

% HBeAG-positive 41

Mean ALT (U/L 84±171

Mean HBV DNA (IU/mL) 7.0±2.4

Mean platelets (Bil/L 228±67

% Cirrhosis (on ultrasound or liver biopsy) 12

HBV genotype (A/B/C/D) 6/35/55/3

Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 888.

Resistance DetectedResistance Detected

RT Substitution Frequency (%)

L80V/I 4V173L 0L180M 3

M204V/I 12A191V/T 1

I233V 1N236T 0A194T 0.7

T184G/L 1S202C/I 2M250V 2

73

0

1

2

3

4

5

6

7

8

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

Effect of Pre-Existing Antiviral Resistance Mutations

Mutation associated with 180/204 resistance pathway: 12%

Mutant virus was always detected as a mixed species

— rt180+rtM204 represents >90%

— rt180 or rt204 in isolated cases

ETV-resistance mutations: 5% Mutations assoc. with rt181/236

resistance pathway: 0%-1% Effect of pre-existing AVR

on anti-HBV therapy was analyzed

— LAM resistance affects LAM but not TDF efficacy


0

1

2

3

4

5

6

7

8

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

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

LAM 100 mg dailyLAM 100 mg dailyEffect of LAM in a Patient With Pre-existing LAM-Resistant MutationEffect of LAM in a Patient With Pre-existing LAM-Resistant Mutation

Time on LAM (mos)Time on LAM (mos)

HB

V D

NA

(lo

g10

IU

/mL

)H

BV

DN

A (

log

10 I

U/m

L)

AL

T (

IU/m

L)

AL

T (

IU/m

L)rtL180M+

rtM204I

HBe Ag+,Anti-HBe- HBe Ag+,

Anti-HBe-

HBe Ag+,Anti-HBe-

HBe Ag+,Anti-HBe-

100

90

80

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0

TDF 300 mg dailyTDF 300 mg daily

Effect of TDF in a Patient With Pre-existing LAM-Resistant MutationEffect of TDF in a Patient With Pre-existing LAM-Resistant Mutation

Time on TDF (mos)Time on TDF (mos)

HB

V D

NA

(lo

g10

IU

/mL

)H

BV

DN

A (

log

10 I

U/m

L)

AL

T (

IU/m

L)

AL

T (

IU/m

L)

rtL180M+rtM204I

HBe Ag+,Anti-HBe-

HBe Ag+,Anti-HBe-

HBe Ag+,Anti-HBe-

HBe Ag+,Anti-HBe-

PCRnegative PCR

negative

HBV DNA ALT

HBV DNA ALT

74

Conclusion: Pre-Existing AVR in Treatment-Naïve, CHB Patients

Pre-existing ARV resistance can be found in treatment-naïve CHB patients

— rt180/204 mutation is relatively common— rt184/202/250 mutations also are detectable— rt181/236 mutation is much less common

Prevalence of LAM-related resistance in naïve pts compromises utility of LAM, but not TDF, monotherapy as first line

AVR testing among treatment-naïve patients is important in order to tailor and optimize anti-HBV therapy


75

rtA194T Does Not Reduce TDF Efficacy in Patients With LAM-Resistant CHB

Study to determine effect of rtA194T on Tx response to TDF in patients with LAM-resistant HBV

Consecutive, Tx-experienced adults with CHB enrolled and tested for antiviral resistance (N=283)

— Resistance testing if virologic breakthrough (HBV DNA increase > 1 log IU/ml compared with nadir) and failure to achieve undetectable HBV DNA in 6 months of therapy

10 patients found to harbor rtA194T (all in association with rtL180M and rtM204V/I)

— All had been treated with LAM for mean duration of 42 months

Mean age (years) 48

Males (N) 7

HBeAg+ (N) 4

Cirrhosis (N) 7

HBV DNA (log IU/mL) 5.52.5

Breakthrough on LAM (N) 6

Suboptimal response on LAM (N) 4

Baseline Characteristics of 10 Pts With rtA194T

Baseline Characteristics of 10 Pts With rtA194T


76

Effect of rtA194T on TDF Salvage Therapy

Results— 5 patients received salvage TDF

• 4 with TDF (300 mg/d) and 1 with TDF+FTC (200 mg/d)

— All had >3 log IU/mL reduction in HBV DNA at 3 months of Tx

— 4 undetectable HBV DNA with normal ALT (mean F/U 5.8 mos)

Conclusions— rtA194T does not reduced TDF efficacy— rtA194T may represent a viral polymorphism or

compensatory mutation rather than a signature mutation leading to nucleotide resistance


77

Resistance Mutations to Nucleos(t)ide Analogs During TDF Therapy

Retrospective study to evaluate the development of HBV mutations during TDF treatment

48 patients with CHB treated with TDF for ≥12 mos — 43 previously treated with LAM (mean 27 mos)

— 33 previously treated with ADV (mean 13 mos)

At baseline and during TDF Tx, HBV resistance evaluated when HBV DNA detectable

— At baseline TDF Tx: • WT: 20 patients

• LAM-R: 22 patients

• ADV-R: 6 patients

Boemmel F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 913.

78

Effect of ADV-Resistance Mutations on TDF Therapy

Effectiveness of TDF therapy— Baseline ADV-R:

• ADV-related mutations remained detectable during TDF Tx

• 1/6 pt achieved HBV DNA <400 c/mL at 12 mos (P<0.0001)

— 4 pts without ADV-R at baseline developed ADV-related mutations on TDF (3 ADV and 1 LAM pre-treated)

• ADV-R variants (rtA181T, rtA181V, rtA181T+rtN236T) became detectable between mos 5 and 11 of TDF Tx

• 3/4 achieved an HBV DNA <400 c/mL by month 12 of TDF Tx

— No new mutations or HBV DNA breakthrough were observed during TDF Tx

Conclusion: HBV variants associated with ADV and LAM resistance can become transiently detectable during TDF treatment, but these mutations do not seem to affect response to TDF on short-term follow-up

Boemmel F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst. 913.

79

Genotyping

(HBV pol / RT)

Method: 2 Years’ TDF Resistance in Patients With CHB

Patients were enrolled in 1 of 2 randomized studies of TDF (HBeAg- or HBeAg+)

Population di-deoxy sequencing

of serum HBV pol/RT— Covers AA 1-344 of pol/RT

(AA 1-266 of HBsAg)

— Able to detect AA substitutions present at ≥25% of viral quasi-species population

Phenotypic analyses conducted in HepG2 cells transiently transfected with a pool of recombinant HBV plasmid DNA derived from patient serum HBV

Virology Analysis Plan

All patients:– At baseline– Yearly if HBV DNA

≥400 c/mL (≥69 IU/mL)– At discontinuation of

TDF mono-therapy if HBV DNA ≥400 c/mL

Any patient post-baseline with:

– Conserved site changes in pol/RT

– Virologic breakthrough– Polymorphic site

changes

Phenotyping

(HBV pol / RT)

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

80

Results: 2 Years’ TDF Resistance in Patients With CHB


Genotypic Changes Observed at Week 96/last on TDF Among HBeAg- and HBeAg+ TDF-Treated Patients

Genotypic Changes Observed at Week 96/last on TDF Among HBeAg- and HBeAg+ TDF-Treated Patients

Patients Experiencing Virologic Breakthrough

0

10

20

30

40

50

60

70

80

90

100

No Change Polymorphic SiteChanges

Conserved SiteChanges

HBeAg- (n =4)

HBeAg+ (n=3)(3)(2)

(1)(1)

(0)(0)0

10

20

30

40

50

60

70

80

90

100

No Change PolymorphicSiteChanges

Conserved SiteChanges

HBeAg- (n=2)

HBeAg+ (n=12)

(1) (1)

(2)

(0)

(8)

(2)

Pat

ien

ts (

%)

WW

81

Results: 2 Years’ TDF Resistance in Patients With CHB

Patient pol/RTTenofovir EC50 (µM)

Fold Change

Patient TDF EC50 (µM) Fold Change


Phenotypic Analysis in Patients With

Conserved Site Changes in HBV pol/RT

8356–Baseline Wild-type 12.4±3.6

8356–Week 72 rtL101L/F 13.8±0.6 1.1

8356–Week 72 (clone) rtL101F 10.0±6.2 0.7

7916–Baseline Wild-type 9.9±3.4

7916–Week 72rtV173L, rtL180M, rtM204V

12.5±6.3 1.3

1674–Baseline (HBeAg-) 8.0±1.0

1674–Week 72 7.7±1.5 1.0


1669–Week 96 11.1±7.7 1.1


6852–Week 96 10.5±4.4 0.9


7957–Week 80 8.3±1.5 0.8

1553–Baseline (HBeAg+) 11.2±5.3

1553–Week 96 11.3±5.7 1.0


3958–Week 88 11.1±2.5 1.0


4957–Week 88 11.6±4.6 1.0

Phenotypic Analysis in Patients With Breakthrough on TDF (n=7)

82

Conclusion: 2 Years’ TDF Resistance in Patients With CHB

No HBV pol/RT amino acid substitutions associated with resistance to TDF were detected through 96 weeks of TDF monotherapy

— Annual resistance surveillance on-going through Year 8 (Week 384)

Virologic breakthrough was infrequent and not associated with phenotypic resistance to TDF

— The majority of patients experiencing virologic breakthrough had evidence of non-adherence

Development of conserved site changes was rare and not associated with phenotypic resistance to TDF


Documents

Post Conference Update: Highlights from the American Association of the Study of Liver Diseases MARK SULKOWSKI, MD Associate Professor of Medicine Johns