Associate Professor of MedicineDivision of Gastroenterology & Hepatology

Indiana University School of MedicineIndianapolis, IN

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

PAUL KWO, MDPAUL KWO, MD

Faculty:Content Development and Training

Douglas T. Dieterich, MDProfessor of MedicineDivision of Liver DiseasesMount Sinai School of Medicine New York, New York

Paul Y. Kwo, MDAssociate Professor of Medicine Division of Gastroenterology Indiana University School of MedicineIndianapolis, Indiana

Mark S. Sulkowski, MDAssociate Professor of MedicineJohns Hopkins University School of MedicineMedical Director, Viral Hepatitis CenterJohns Hopkins Medical InstitutionBaltimore, Maryland

Tram Tran, MDMedical DirectorLiver TransplantationCedars Sinai Medical CenterAssociate Professor University of California Los Angeles School of Medicine Los Angeles, California

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 recent hepatitis therapy toxicity, drug interaction

and side effect data 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

Wait-list Mortality Among Liver Transplant Candidates with CHB

● Comparison of outcomes for CHB and other liver disease etiologies on LTx wait-list (1995-2006)- CHB pts (N=2,236): 36% Asian

Pacific; 15% HCC

● Wait-list Outcomes Comparison: - CHB deaths significantly higher- CHB LTx rates significantly lower- Post- MELD: CHB higher death and

lower LTx rates persisted

● Conclusions: - CHB pts on wait-list have worse

outcomes than other liver disease etiologies

- Early Diagnosis and intervention for CHB are essential to improve outcomes

Kim W, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 3.

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

00 22 44 66 88 1010 1212 1414 16161818 2020 2222 2424 26262828 3030 3232 3434 3636

Months Post-ListingMonths Post-Listing

DeathDeathLTxLTx

Pro

ba

bil

ity

Pro

ba

bil

ity

CholestaticHCV

OtherCHB

CholestaticHCV

OtherCHB

Hepatic Steatosis Associated with Severe Fibrosis in CHB

● Comparison of steatosis and insulin resistance (IR) in CHB and chronic hepatitis C (CHC) and effect on fibrosis (N=340)- Steatosis prevalence similar- IR rate higher in CHC

● For CHB, severe fibrosis (F3-F4) independently associated with: Older age (OR 1.054, p=0.02) Low platelet levels (OR 0.984,

p=0.003) High Υ-GT (OR 1.019, p=0.04) Steatosis >10% (OR 3.601, p=0.01) Moderate-severe

necroinflammatory activity (OR 8.111, p=0.005)

● Conclusion: CHB has high rate of steatosis, which is associated with fibrosis

Petta S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1334.

Comparison of patients with CHB and CHC

VariableChronic

hepatitis B (n=170)

Chronic hepatitis C

(n=170)P

Type 2 Diabetes present (%) 3.6% 8.8% 0.04

PLT (X 103/mm) 194.7 ± 49.1 213.6 ± 62.6 0.001

Υ-GT (IU) 39.8 ± 32.9 68.5 ± 62.2 <0.001

Cholesterol (mg/dL) 190.5 ± 44.4 171.1 ± 37.8 <0.001

HOMA (score) 2.38 ± 1.81 2.78 ± 1.80 0.04

Insulin Resistance (HOMA>2.7) (%) 25.9% 42.2% 0.002

Steatosis ≥10% (%) 31.2% 38.8% 0.14

Risk of Liver Disease Progression to HCC

● Retrospective study comparing clinical outcomes of NAFLD and CHB ± NAFLD (N=700)- Mean follow-up 7.6 years

● No survival difference (p>0.05)

● CHB plus NAFLD had higher risk of progression to HCC than CHB and NAFLD alone (p=0.001)

Ye D, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 976.

0.1250.125

0.00.0

0.1000.100

0.0750.075

0.0500.050

0.0250.025

0.0000.000

0.00.0 4.04.0 6.06.0 8.08.0 10.010.0 12.012.0 14.014.0

Time of Follow-up (Years)Time of Follow-up (Years)

Cu

mu

lati

ve

Ha

zard

of

De

ve

lop

me

nt

to H

CC

Cu

mu

lati

ve

Ha

zard

of

De

ve

lop

me

nt

to H

CC

CHB + NAFLDCHBNAFLD

CHB + NAFLDCHBNAFLD

Cumulative Risk of HCC

Quality of Care of CHB in a Managed Care Setting

● Retrospective study using database of pts in managed care from 2001-2007 (N=250,401)

● Epidemiology and quality of care for CHB pts evaluated (N=1,163)

● Finding: Significant numbers of CHB pts did not have appropriate follow-up, screening or testing - For 2006 and 2007:

• No primary care follow-up in 31% and 26%

• No gastroenterology visit in 74% and 71%

● Conclusion: Significant deficiencies exist in quality of care for CHB in managed care setting

Sy T, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1341.

Per

cent

of P

atie

nts

Lack of Screening and Testing in CHB Patients

27 23

63

80

46

0102030405060708090

100

Without Screening for HCVWithout Screening for HCCWithout Documented HIV TestingWithout Testing for HAV ImmunityWithout imaging Surveillance

Diagnosis and Management of CHB by Primary Care Physicians

● Online surveys of PCPs regarding CHB in Asian-American pts (N=393)

● Most PCPs consider CHB serious and prevalent, but many don’t screen all Asian-American pts for CHB

● PCPs diagnosed over half of CHB in their practice

• 50% monitored without Tx; ~33% received CHB Tx

• ALT and HBV DNA commonly used to determine whether to Tx

• ~62% not familiar with current CHB Tx guidelines

● PCPs likely to refer CHB pts with advanced disease, worsening rapidly, or with resistance to Tx

● Conclusion: PCPs would benefit from more education regarding CHB and Tx guidelines

Upadhyaya N, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 394.

PCP Beliefs and Screening

Per

cent

of p

rovi

ders

9788

32

0

20

40

60

80

100

CHB Serious in Asian-Americans

CHB Prevalent in Asian-Americans

CHB Screening of all Asian-Americans

Quantitative HBs Antigen Levels in CHB

● HBsAg quantified in 4 infection phases in HBV mono-infected, Tx-naïve pts (N=226) - HBe (+) immune tolerance (IT)

- HBe(+) immune clearance (IC)

- HBe(-) low replicative (LR)

- HBe(-) hepatitis (ENH)

● Results: - HBsAg varied in different HBV phases (p<0.001)

- HBsAg/HBV DNA ratio highest in LR

- HBsAg correlated with HBV DNA in persistent HBV, not in consecutive phases

- HBsAg correlated with HBV DNA (R=0.74, P<0.0001)

- HBsAg and HBV DNA correlated with HBV GT D

- Acute HBV baseline HBSAg correlated with HBV DNA

● Conclusion: Varying levels of HBsAg may represent natural course of infection

Jaroszewicz J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1482.

Serum HBsAg in different phasesof persistent HBV

Serum HBsAg in different phasesof persistent HBV

0

300000

250000

200000

IT IC LR ENHH

BsA

g [

IU/m

L]

150000

100000

50000

Long-term Serial HBV-DNA Levels after Spontaneous HBeAg Seroconversion

● Assessment of serial HBV DNA levels in CHB pts by ALT levels after spontaneous HBeAg seroconversion - Persistently normal ALT (PNALT, N=58)

- Minimally elevated ALT: ≥1 ALT 1-2 x ULN (MALT, N=52)

● MALT had significantly higher overall HBV DNA levels than PNALT (p=0.008)

● These data suggest that HBV DNA level <5 log10 copies/ml and PNALT are appropriate criteria for inactive HBV

Chen Y, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1499.

HBV DNA Levels (log10 c/mL)

Mean

level

<4 log10 in all

assays

<5 log10 in all

assays

≥5 log10

Only 1 assay ≥ 2 assays

PNALT 3.00±1.48 20.7% 72.4% 20.7% 6.9%

MALT 3.50±1.47 15.4% 51.9% 19.2% 28.9%

p value <0.0001 0.636 0.043 1.000 0.005

HBeAg Seroconversion During Treatment Does Not Lead to Durable Remission of CHB● Evaluation of pts with HBeAg

seroconversion on nucleos(t)ide analog (NA) Tx (N=48)- Median follow-up: 58 months (N=44)- NA Tx Used: 27 LAM, 13 ADV, 5 ETV, 2 TDF, 1

ADV + LAM

● 74% with HBeAg seroreversion by 3 years after HBeAg seroconversion

- High HBV DNA independent predictor of seroreversion (HR 1.36 per, P=0.006)

● Virologic recurrence occurred in 66%- Associated with drug resistance in 53%

● Conclusions:- HBeAg seroconversion not durable in a

majority of cases- NA should be continued indefinitely or until

HBsAg seroconversion

Reasons for Recurrence

Durable Remission after HBeAg Seroconversion

Perquin M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 219.

Pro

po

rtio

n o

f P

atie

nts

(%

)

0

20

40

60

80

100

0 12 24 36 48

N=42N=4235%35%

Treatment MonthTreatment Month

HBeAg negative and HBV DNA < 10,000 copies/mL

Per

cen

t o

f P

atie

nts

50%

67%

33%

20%17%

7% 7%

0%

0%

10%

20%

30%

40%

50%

60%

70%

Virologic Recurrence Serologic and VirologicRecurrence

Resistance

Treatment Discontinuation

Non-compliance

Suboptimal Suppression

Risk of HCC in CHB

● Retrospective-prospective study of CHB patients +/- cirrhosis (CI) on HBV therapy > 12 months (n=956)

● Cumulative HCC rate: 4.8% (46/956) within 3.9 yrs

● Cumulative HCC rate increases with CHB disease severity, older age and male gender

Papatheodoridis G, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 137.

HR (95% CI) P

Severity of liver disease

CHB only Referent ---

Compensated CI 2.3 (1.2-4.6) 0.016

Decompensated CI 3.7 (1.3-10.0) 0.012

Age group at treatment onset (yrs)

< 50 Referent ---

50-60 7.7 (1.7-34.5) 0.007

> 60 16.7 (3.9-72.1) <0.001

Gender

Male Referent ---

Female 0.3 (0.1-0.8) 0.003

Causes of Death with CHB in US

● Cohort study of HMO members with CHB (n=6,689)- 48% women; 68.3% Asian-Pacific, 11.8% White- Minimal Exposure to HBV antivirals

● HBV related deaths- 10 year death rates: women < men (1.2% vs 4.8%), except within ages 20-29- Predictors of death in both sexes: age, pre-existing decompensated cirrhosis, HCC, cancer and diabetes. - White and unknown race were additional predictors in men.

● Causes of death by age group:

● CHB-related deaths: 40%

Age Deaths

Cause of death (% within age group)

HBV: HCC HBV: DCC Cancer C-V Others/unknown

N N % N % N % N % N % N %

0-19 473 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0

20-29 745 5 0.7 1 0.1 0 0.0 3 0.4 0 0.0 1 0.1

30-39 1773 30 1.7 7 0.4 3 0.2 8 0.5 3 0.2 9 0.5

40-49 2019 86 4.3 31 1.5 15 0.7 15 0.7 10 0.5 15 0.7

50-64 1338 187 14.0 70 5.2 26 1.9 40 3.0 23 1.7 28 2.1

65 and over

341 131 38.4 28 8.2 24 7.0 27 7.9 27 7.9 25 7.3

TOTAL 6689 439 6.6 137 2.1 68 1.0 93 1.4 63 0.9 78 1.2

Szpakowski J and Tucker L. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 79.

Simulation Modeling of CHB Progression in US

● Markov state transition model used to assess natural Hx of CHB across lifetime of 3 cohorts: no infection, immune, and CHB (HBsAg+)

● No infection and immune had higher life expectancies compared to CHB

● In CHB:- HBeAg+ had shorter projected

lifespans- High HBV DNA most important factor

associated with decreased life expectancy

- Spontaneous seroconversion rates significantly affect outcomes

Group Cohort Years

1 No Infection 44.60

2 Immune 44.60

3 Chronic (weighted average of 6

subgroups) 37.71

3a HBeAg positive, high viral load,

normal LFTs 27.54

3b HBeAg positive, low viral load,

normal LFTs 34.52

3c HBeAg negative, high viral

load, normal LFTs 33.27

3d HBeAg negative, low viral load,

normal LFTs 34.92

3e HBeAg positive, normal LFTs

(immune tolerant) 30.67

3f HBeAg negative, normal LFTs

(chronic asymptomatic) 36.82

Kaiser TE, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 420.

CHB Burden in a Median Endemic Country

● A model to determine potential burden of CHB in Turkey- Estimated 3.5 million people (4.8%) with CHB and 775, 170 (25%) with high

HBV DNA and elevated ALT levels

● Estimated Outcomes (%) of CHB Pts over a 20-year period:

Toy M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 404.

CHB Stage at Entry n Cirrhosis Decompensated

Cirrhosis HCC Liver transplant Death

Total 858,121 36% 9% 10% 4% 22%

No cirrhosis 748,147 33% 6% 8% 3.7% 15%

HBeAg(+) 356,606 15% 3% 3% 1.7% 8%

HBeAg(-) 391,541 46% 9% 13% 2.2% 31%

Cirrhosis 109,973 100% 26% 23% 4% 77%

HBeAg(+) 18,703 100% 31% 10% 2% 76%

HBeAg(-) 91,270 100% 24% 26% 2% 77%

CHB Mortality Affectedby Treatment

● Long term therapy with low resistance profile drug:- 88% mortality reduction (17% to

2%) for non-cirrhotics and (77% to 26%) for cirrhotics

● Long term therapy with high resistance (Lamivudine) profile drug:- 46% mortality reduction- If salvage therapy liver related

deaths will be prevented by 73%

Toy M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 404.

Mortality of CHB patients who are non-cirrhotic at entry

0%

10%

20%

30%

40%

50%

2008

Natural History

High Resistance Drug

Salvage Treatment

Low Resistance Drug

2013 2018 2023 2028Year

0%

20%

40%

60%

80%

100%

2008 2013 2018 2023 2028Year

Mortality of CHB patients who are Cirrhotic at entry

De

ath

(%

)D

ea

th (

%)

Who Should Perform Percutaneous Liver Biopsy?

● Prospective comparison of liver biopsies (LBx) by radiology residents (R) at single VA center or single hepatologist (H)

● Methods: - R: CT guided, anterior, epigastric using 16-

gauge automatic needle• 115 LBx, 19 (16.5%) repeat Bx

- H: lateral approach within the anterior to mid-clavicular lines using 14 gauge tru-cut needle• 127 LBx, no repeat Bx

● Results: - Longer specimens for H than R

- More portal tracts for H than R

● Conclusions:- LBx by lateral approach preferable

- Training programs should have formal requirements for LBx competence

Talwani R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1651.

Comparison of Liver Biopsies

Hepatology Radiology P

Mean Bx Length (mm) 1.51 +/- 0.41 0.94 +/- 0.57 <0.001

Mean Number of Portal Tracts per Bx 16.05 +/- 0.77 7.49 +/- 0.65 <0.001

# of Specimens ≥10mm 93/100 43/100 <0.001

# of Specimens ≥15mm 52/100 17/100 <0.001

# of Specimens with ≥6 Portal Tracts 99/100 52/100 <0.001

Economic Advantages of Transient Elastography In CHB

● Study evaluating number of HBsAg+ patients (n=98) requiring liver biopsy (LBx) using international guidelines or Chan algorithm- Chan algorithm: LBx only if intermediate liver Transient elastography

● Results:- Fewer LBx if Chan algorithm used rather than APASL guidelines (20 vs. 84)- Annual cost savings from reduced liver biopsy = $83,328

Guirgis M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 498.

No LBx (n=14)

No LBx (n=14)

LBx (n=84)LBx

(n=84)

AGE ≥40(64)

ALT ≥ HNALTDNA ≥2000

Age <40(20)

LBx According To APASL GuidelinesLBx According To APASL Guidelines

LBx according to Chan algorithmLBx according to Chan algorithm

Normal ALT

≤5.0kPaReassurance

n=42

>5.0-6.0kPaObserve

n=9

>6.0-9.0kPaLBxn=12

>9.0-12.0kPaConsider Tx

n=5

>12.0kPaConsider Tx

n=4

Elevated ALT

<5.0kPaReassurance

n=6

>5.0-7.5kPaObserve

n=8

>7.5-12.0kPaLBxn=8

>12.0-13.4kPaConsider Tx

n=0

>13.4kPaConsider Tx

n=3

Prognostic Value of Non-invasive Diagnostics for Liver Fibrosis in CHB and CHC

● Liver fibrosis evaluated in pts with CHB and CHC (n=200)- 3 study groups: Doppler

Ultrasonography (DUS), transient elastography (TE) and FibroTest (FT)

- Liver biopsies in all pts on day of noninvasive test

● All found to be accurate in diagnosing severe fibrosis (F2-F4) in pts with CHB and CHC

● Conclusion: DUS, TE and FT all appear to be reliable in diagnosing severe fibrosis and to have clinical utility

SAPI: Splenic Artery Pulsatility Index.

MVPV: Mean Velocity of Portal Vein blood flow. Pavlov C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1660.

ROC-curves of Severe (F2-F4)Liver Fibrosis Diagnostics

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

Transient ElastographyAUROC=0.888 (p<0.001)

FibroTestAUROC=0.884 (p<0.001)

DUS SAPIAUROC=0.843 (p<0.001)

DUS MVPVAUROC=0.695 (p=0.001)

Se

ns

itiv

ity

Specificity

CHB and Risk for Pancreatic Cancer?

● Retrospective study of pts who had HBV testing between 1995-2008 (n=95,920)

● Risks for pancreatic cancer assessed according to HBV status

● Univariate analysis found previous HBV exposure associated with pancreatic CA (HR 2.493, p<0.001), but multivariate model (which included race, sex and age) did not:

● When cohort analysis is adjusted for covariates, only age and diabetes are predictors of pancreatic cancer

Tang J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1486.

Variable Hazard Ratio 95% CI P – Value

Previous HBV Exposure 1.411 0.877-2.271 0.156

Active HBV Infection 1.075 0.149-7.764 0.943

Race (African American) 1.134 0.755-1.704 0.943

Age 1.077 1.062-1.093 <0.001

Sex (male) 1.023 0.691-1.516 0.908

HIV 1.274 0.398-4.080 0.683

Diabetes 1.884 1.268-2.800 0.002

Studies GS-102 and GS-103: Safety and Tolerability of TDF in Patients with CHB

TDF 300 mg

TDF 300 mg

Week 240Liver Biopsy

Week 48Liver Biopsy

Pre-treatment Liver Biopsy

RA

ND

OM

IZA

TIO

N 2

:1

Tenofovir 300 mg

Adefovir 10 mg

Open-label8 Years

Double Blind

Week 144 End of Study

5 Years2 Years

Week 72 HBV DNA ≥400 copies/mL: Option to add FTC) to TDF in a fixed dose tablet

1 Year

Randomized, Double-Blind, Comparison of TDF vs. ADV for CHB

Patients (n=)HBeAg- (GS-102) TDF → TDF (n=250) 219

ADV → TDF (n=125) 109

HBeAg+ (GS-103) TDF → TDF (n=176) 136

ADV → TDF (n=90) 76

Marcellin P, et al. 44th EASL; Copenhagen, Denmark; April 22-26, 2009; Abst. 925.

22

Study 102 (HBeAg Negative):HBV DNA <400 Copies/mL (ITT)

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

Pat

ien

ts (

%)

88%

WeeksWeeks

Double-BlindDouble-Blind Open-LabelOpen-Label

TDF to TDFADV to TDF

93%

87%P<0.001

63%

Marcellin P, et al. Hepatology. 2009;50(suppl):532A-533A. Abstract 481.

18% of patients were lamivudine experienced and of these 93% and 96% of TDF to TDF and ADV to TDF patients had HBV DNA <400 copies/mL at week 96.

0 24 48 72 96 120 144

23

Study 103 (HBeAg Positive):HBV DNA <400 Copies/mL (ITT)

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

Pat

ien

ts (

%)

0 24 48 72 96 120 144

72%

WeeksWeeks

Double-BlindDouble-Blind

Heathcote EJ, et al. Hepatology. 2009;50(suppl):533A-534A. Abstract 483.

Open-LabelOpen-Label

TDF to TDFADV to TDF

76%

71%

P<0.001

13%

Study 103: Comparison of Long-term Outcomes of TDF and ADV Arms

● At Year 3 of Study 103, 80% of patients remained on treatment- 93% had HBV DNA <400 copies/mL (OT)- 8% cumulative probability of HBsAg loss- No resistance to TDF- Favorable tolerability profile with no change in creatinine levels

Heathcote E, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 483.

Cu

mu

lati

ve P

rob

abil

ity

Fu

nct

ion

Est

imat

e

0.10

0.05

0.000 12 24 36 48 60 72 84 96 108 120 132 144

Weeks on Study

8%

At Week 48 all patientsinitiate Open-Label TDF

TDF-TDFADV-TDF

Cumulative Probability of HBsAg Loss

TDF in Asian Patients: 72 Week Results

● Efficacy and safety of TDF among Asian patients with HBeAg- (Study 102) or HBeAg+ (Study 103) CHB evaluated at week 72- Asians comprised ~30% of all patients

● No differences between Asian and non-Asian patients regarding TDF antiviral efficacy, safety or tolerability

● HBeAg loss and seroconversion are slowly increasing over time in Asian pts

Lee S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 490.

Serologic Response Among Asian Patients (OT)Serologic Response Among Asian Patients (OT)

Per

cent

of P

atie

nts

17

22

28

17 18 19

0

10

20

30

40

50

Week 48 Week 96 Week 144

HBeAg Loss Anti-Hbe

Long-term follow-up of CHB Patients Treated with TDF

● Mono-infected CHB Patients treated with TDF (300 mg/day) at 19 centers from 2002-2009 (n=194)- Majority with previous NA Tx, mainly

LAM (57%)

● 75% achieved HBV DNA <400 copies/mL by 1 year- 92% achieved HBV DNA <400

copies/mL by 2 years- Pts with slow decrease in HBV DNA

often had ADV resistance

● Small, significant decrease in HBsAg levels

● No resistance to TDF

De Man A, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 221.

Probability of Achieving HBV DNALevel <400 copies/mL

0

100

80

60

40

20

0 3 6 9 12

Pa

tie

nts

wit

h H

BV

DN

A <

40

0 c

op

ies

/mL

(%

)

Months of TDF Treatment

ETV-022: Loss of HBsAg after Treatment with ETV or LAM

● Evaluation of HBsAg loss by HBV genotype in study ETV-022- HBeAg(+) nucleoside-naïve adults with CHB, elevated

serum ALT, and compensated liver disease- Randomized to double-blind treatment for up to 96 weeks

with ETV (0.5 mg/day) or LAM (100 mg/day), with up to 24 weeks of off-treatment follow-up

● HBsAg was measured at regular intervals during on- and off-treatment follow-up

Gish R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 388.

ETVLVD

ETVLVD

ETV-022: Loss of HBsAg and HBV Genotypes

● 18 pts treated with entecavir had HBsAg loss- 8.4% and 13.5% for genotype A and D, respectively

Gish R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 388.

Characteristics of Patients with and without HBsAg loss

Proportion of Patients with HBsAg Loss by Genotype (Week 120)

Genotype

% w

ith H

BsA

g Lo

ss

Patients with HBsAg Loss

N=28

Patients without HBsAg Loss

N=681

Male 82% 75%

Asian 14% 59%

Caucasian 79% 38%

Mean Viral Load(log10 copies/mL)

9.8 9.6

Mean Knodell macroinflammatory score 9.1 7.7

Median serum ALT (U/L) 163 101

5.1%

0%

10%

13.5%

0.9%

2.9%

8.4%

2.8%

0%0%

7.1%

1.3%

0%

4.1%

0

2

4

6

8

10

12

14

16

A B C D F Other Total

Entecavir Use in Nucleos(t)ide-naïve CHB: Clinical Experience

● Safety and efficacy of ETV examined in an Italian, multicenter cohort study (n=376)- Age 58 yrs; Male 75%; HBeAg(-) 83%;

Cirrhotics 47%- Median follow-up: 21 months

● Results:- High Virologic response rates through

week 96- High baseline HBV DNA associated with

partial virologic response at week 48 (> 8 log U=27% vs. < 8 log U=6%)

- Progressive decline of liver stiffness (9.3 to 7.0 kPa by Fibroscan)

- No resistance detected

● ETV effective in NA-naive pts in clinical practice

Lampertico P, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 220.

Und

etec

tabl

e H

BV

DN

AU

ndet

ecta

ble

HB

V D

NA

Undetectable HBV DNA (LLQ <12 IU/mL) with ETV

65

9095

0

50

100

Week 24 Week 48 Week 96

Efficacy and Safety of Long-term LdT for CHB

● Evaluation of efficacy and safety of 4 years of continuous LdT- Open-label trial enrolling patients

from GLOBE Study (n=399)

- 213 HBeAg-positive; 186 HBeAg-negative

● High rates of efficacy through 4 years of therapy

● Early virologic response (wk24) predictive of favorable outcome

● Safety profile unchanged- CK elevation (16%), myalgia (6%),

myopathy (0.5%), myositis (0.5%)

Liaw Y. et al. 60th AALD; Boston, MA; October 20-November 3, 2009; Abst. 482

Four year cumulative seroconversion rate inHBeAg-positive patients

Four year cumulative seroconversion rate inHBeAg-positive patients

Efficacy at 4 years in patients with undetectable HBV DNA at Week 24 of GLOBE study

Efficacy at 4 years in patients with undetectable HBV DNA at Week 24 of GLOBE study

HBeAg-positive patientsHBeAg-positive patients HBeAg-negative patientsHBeAg-negative patients

HBV DNA undetectableHBV DNA undetectable ALT NormalizationALT Normalization HBeAg SeroconversionHBeAg

Seroconversion

928688 90

51

0

20

40

60

80

100

24

3846

51

0

10

20

30

40

50

60

Year 1 Year 2 Year 3 Year 4

Lactic Acidosis in CHB PatientsTreated with ETV

● Evaluation of 16 patients with decompensated liver cirrhosis treated with ETV

● 5 developed lactic acidosis (LA), between 4 and 240 days after starting ETV

● LA correlated with MELD score, INR, bilirubin, and creatinine (p<0.005 each)

Lange C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 217.

Lactic Acidosis During Treatment with Entecavir

Lactic Acidosis During Treatment with Entecavir

No LA N=11

LAN=5

MELD score ≥22

MELD score < 22

Lactic Acidosis in CHB Patients Treated with ETV: Severity of Disease and Outcomes

● LA reversible after ETC D/C (n=4)

● 1 death due to LA

● Conclusion: ETV should be used cautiously in CHB pts with high MELD score

Lange C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 217.

Characteristics of Lactic Acidosis in 5 PatientsCharacteristics of Lactic Acidosis in 5 Patients

Patient A

Patient B

Patient C

Patient D

Patient E

LA

LA

LA

LA

LA

pH 7.1, lactate 200 mg/dL

pH 7.2, lactate 50 mg/dL

pH 7.3, lactate 65 mg/dL

pH 7.4, lactate 26 mg/Dl, BE – 5 mmol/L

pH 7.4, lactate 35 mg/DL, BE – 5 mmol/L

Tenofovir

Tenofovir

Lamivudine

OLT

0 240Day of entecavir-therapy

Sustained Response in CHB Patients Treated With Peginterferon Alfa-2a

● Study to evaluate relationship of on treatment decline in HBsAg and sustained response rates- HBeAg-negative pts received peginterferon

alfa-2a (180 ug/wk) +/- LAM (100 mg/day) for 48 wks and followed for 5 years post-Tx (N=230)

● Analysis at 6 months and 5 yrs post-Tx:- Sustained immune control

(HBV DNA 10,000 copies/mL)- HBsAg clearance

Brunetto M, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 452.

HBsAg and Long-term Outcomes at 5 Years Post-Treatment

● On Tx HBsAg decline is associated with sustained post-Tx response● Highest response (sustained immune and HBsAg clearance)

with continuous decline in HBsAg levels

Brunetto M, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 452.

Proportion of patients achieving HBsAg clearance 5 years post-treatment according to HBsAg decline on-treatment

Decline PatternP

atie

nts

with

HB

sAg

clea

ranc

e 5

yrs

post

-tre

atm

ent (

%)

23/61 4/19 1/6

Proportion of patients in either the 6 month or 5 year analysis populations in each of the HBsAg decline groups

Decline Pattern

Pat

ient

s (%

)

80/155 61/120 23/155 19/120 7/155 61/120 45/155 34/120

6 Months (n=155)

5 Years (n=120)

6 Months (n=155)

5 Years (n=120)

29%

5%

15%

52% 51%

16%

5%

28%

0

10

20

30

40

50

60

Continuous Late Decline withRelapse

No Decline

0%

17%

11%

23%

0

5

10

15

20

25

Continuous Late Decline withRelapse

No Decline

Extended Treatment With PegIFN in Patients With HBeAg-Positive CHB

● Study evaluating whether extending peginterferon alfa-2a to 72 weeks improves HBeAg seroconversion rate in partial responders (N=31)- Partial responders: no HBeAg seroconversion at week 48, but HBV DNA

<10,000 copies/mL

Zhu Y, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 453.

Study DesignStudy Design

Peginterferon alfa-2a(180 µg/week; n=65)

Peginterferon alfa-2a(180 µg/week; n=16)

0 48 72

Follow-up off Tx (n=15)

Extended Treatment With Peginterferon Alfa-2a in Patients With HBeAg-Positive CHB:

Results Through 72 Weeks

● With Extension Tx:- HBeAg and HBsAg levels continued to decline- Partial responders achieved HBeAg clearance (38%),

HBeAg seroconversion (31%) and HBsAg clearance (19%)

Zhu Y, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 453 .

HBsAg levels continue to decrease during peginterferon alfa-2a extension

HBsAg levels continue to decrease during peginterferon alfa-2a extension

HBeAg levels continue to decrease during peginterferon alfa-2a extension

HBeAg levels continue to decrease during peginterferon alfa-2a extension

Qu

an

tita

tive

HB

sAg

le

vels

(IU

/mL

)

Qu

an

tita

tive

HB

eA

g

leve

ls (

s/co

)Extension Group (N=16) Follow-up Group (N=15)

191

161144

131

229

176 176 173

>250>250

0

50

100

150

200

250

300

Baseline Week 12 Week 24 Week 48 Week 72

1061

310248

185

51

827

256

138 105

207

0

200

400

600

800

1000

1200

Baseline Week 12 Week 24 Week 48 Week 72

Capsid Assembly Inhibitors Active Against HBV Variants Resistant to Nucleos(t)ides

● HBV capsid is an icosahedral complex of 120 capsid protein dimers- Phenylpropenamides (AT-61 & AT-130) and heteroaryl-dehydropyrimidines

(BAY-41 4109) interfere with HBV capsid assembly

● In vitro study using HepG2 stable cell lines expressing HBV mutants resistant to Nucleos(t)ide analogs- Treated twice a week with increasing concentrations of AT-61, AT-130 and

BAY-41 4109

- Encapsidated DNA was quantified to determine concentration of drug that inhibits 50% of viral genome replication (IC50)

● Replication of WT and resistant variants was suppressed by all 3 drugs without cytotoxicity

● Targeting HBV nucleocapsid assembly or stability may represent a novel approach for HBV treatment

Billioud G, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 393.

ADV + LAM Associated with Fewer Long-term Symptoms than ADV Alone in CHB patients

● NIH study: randomized, controlled trial evaluating ADV + LAM (N=22) or ADV alone (n=19)

● Data on 8 symptoms evaluated at baseline, one and four years- fatigue, nausea, poor appetite,

headaches, muscle aches, itching, irritability, depression/sadness

● 95% of pts reported one or more symptoms at baseline

Martino AC, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 473.

Baseline demographics and clinical characteristics

Variables ADV + LAM (n=22)

ADV (n=19)

Age (yrs) 46.7 ± 13.7 45.6 ± 13.2

Male 72.7% 94.7%

Race

Asian 40.9% 52.6%

White 40.9% 42.1%

Black 18.2% 5.3%

HBeAg positive 77.3% 73.7%

Responders 63.6% 31.6%

ALT (U/L) 181.4 ± 250.9 88.8 ± 55.2

HBV DNA log10 c/mL 8.0 ± 1.6 7.9 ± 2.0

HAI score (0-18) 8.1 ± 2.7 7.9 ± 2.4

Cirrhosis (0-6) 5 (22.7) 2 (10.5)

ADV + LAM vs. ADV: Fewer Long-term Symptoms with Combination Therapy and Treatment

Response

● Symptomatic improvement was observed at 1 yr- ADV alone similar to ADV + LAM

except more nausea reported with ADV alone (P <.006)

● At year 4, significantly more symptoms in the ADV group including fatigue, nausea, poor appetite, myalgia, and mood

● Non-responders (n=19) had less symptomatic improvement

● HBV therapy was associated with improvement in symptoms- ADV/LAM was more effective than ADV

likely due to higher response

Martino AC, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 473.

Fatigue By Tx Arm and Response Fatigue By Tx Arm and Response

Pat

ient

Per

cent

Pat

ient

Per

cent

0

0.05

0.1

0.15

0.2

Baseline Week 48 Week 192

LAM/ADV

ADV

0

0.05

0.1

0.15

0.2

Baseline Week 48 Week 192

Responders

Non-responders

LAM + ADV vs. ETV in Treatment-naïve, CHB Patients

● Retrospective evaluation of a single center experience with combination therapy vs. monotherapy in CHB pts (N=256)

● Tx-naïve patients treated with:- LAM (100 mg/day) + ADV (10

mg/day) (N=197)

- ETV (0.5 mg/day) (N=59)

● Patients had similar baseline characteristics

Carey I, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 417.

Baseline clinical characteristics

ETV (n=59) LAM+ADV (n=197)

Males 79% 78%

Median age (years) 39 40

HBeAg+ 29% 35%

Cirrhosis 37% 34%

Duration (months) 12.3 ± 0.5 17.9 ± 1.1

HBV DNA log10

(IU/ml)5.3 ± 0.3 4.9 ± 0.1

HBV DNA >104 IU/ml 36% 38%

ALT (IU/L) 90.0 ± 13.3 88.3 ± 15.2

Platelets (x109/ml) 208 ± 5 193 ± 8

LAM + ADV vs. ETV in Treatment-naïve, CHB Patients: Efficacy and Safety Outcomes

● LAM + ADV and ETV had similar proportions achieve complete response (HBV DNA < 12 IU/mL)

● NR rates similar in each group - 1 pt in each group developed VB

- No viral mutations with drug resistance; including those with VB or NR

● Safety was similar with no difference in serum creatinine or eGFR over time- Serum phosphate levels fell

significantly in the LAM+ADV group but not in the ETV group

Carey I, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 417.

MonthsMonths

% o

f P

atie

nts

% o

f P

atie

nts

Proportion of Complete Responders(HBV DNA <12 IU/mL)

Proportion of Complete Responders(HBV DNA <12 IU/mL)

48

60 61

72 74

43

56 55

69 71

0

25

50

75

100

3 6 9 12 18

LAM + ADV

ETV

ETV + TDF for patients with CHB, Advanced Fibrosis and Multiple Previous Treatment Failures

● Open-label cohort from 8 European sites evaluating ETV + TDF combination therapy in CHB pts (N=39) with:- Chronic HBV and advanced

fibrosis

- HBV drug resistance (LAM and/or ADV) or partial response

- 3 lines of prior antiviral Tx (median)

● Median TDF + ETV Tx of 10.5 months (range 1-42)

Petersen J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 405.

Patient characteristics

Median Age (years) 48

Male 90%

Median ALT (x ULN) 1.2

HBeAg positive 59%

Median HBV DNA (log10 IU/mL) 4.2

HBV genotype (A:B:C:D:E) 2:3:3:20:2

Previous therapy ADV + LAM ADV + ETV TDF + LAM LAM ADV ETV TDF

13521675

ETV + TDF for patients with CHB, Advanced Fibrosis and Multiple Previous Treatment Failures: Outcomes

● Results:- Median HBV DNA decline of

3.5 log10 copies/mL (P=0.0001)

- 79% HBV-DNA undetectable (< 80 IU/ml)

- 13% HBeAg and 2% HBsAg loss

- No safety concerns• No report of increase creatinine

• No clinical decompensation

• No Deaths

● Conclusion: ETV + TDF an effective rescue therapy in Tx-experienced, CHB pts

Petersen J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 405.

HBeAg and HBsAg Loss

HBV DNA Viremia

Baseline 3 6 9 12 15 18

1011

1010

1009

1008

1007

1006

1005

1004

1003

1002

LLoD

1915 17 17 16 10

1

1

4567

Time (month)

1

15 8 3

8 5 1

6

6

1

1

4

Log 1

0 c

opie

s/m

L

2%

13%

HBeAg loss HBsAg loss

Treatment-induced and Vaccine Escape HBV Mutants in Patients with HIV/HBV

● HIV-HBV patients followed prospectively for 3 years (N=308)- 3 – 6 month assessments of HBV

DNA and clinical outcomes

- Positive HBV DNA samples sequenced every 12 months

● 221 patients had genotypic analysis- 84% had prior LAM exposure

- HBV DNA suppression increased as TDF use (63%) increased in the cohort (18.1% 66.6% undetectable)

Lacombe K, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 218.

HBV DNA Detection and Treatment Used During Follow-up

HBV DNA Detection and Treatment Used During Follow-up

* p<0.001* p<0.001**

**

**

**

Per

cent

of P

atie

nts

Month

0

10

20

30

40

50

60

70

80

90

100

Inclusion 12 24 36

HBV DNA > 194 UI/mL (%) 3TC or FTC TDF ADV

Treatment-induced and Vaccine Escape HBV Mutants in Patients with HIV/HBV: Findings

● Analysis of S gene sequence for vaccine escape mutations at positions 120 and 145- 6% at the start of the cohort- 12% at end-of-follow up (2.1% per patient year)

● Escape variants on S gene selected by LAM (E164D and I195M) were found in 18.8% at inclusion (Incidence 1.8 100/PY)

● Polymerase mutations conferring LAM resistance (M204I, M180L, V173L) were >50% and remained in viremic patients

● 4 patients on TDF had virologic failure; no clear evidence of genotypic resistance

Lacombe K, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 218.

High Rates of HBeAg Seroconversion and HBsAg Loss in HIV/HBV Patients Treated with TDF + FTC

● Observational cohort

● 107 patients with HIV/HBV- 78% Males- 65% HBeAg(+)- HBV DNA 4.35 log10 IU/L- ART included TDF (62%), FTC (30%)

and/or LAM (46%)

● Median follow-up of 61 months:- ~90% with HBV DNA <350 IU/mL- 56% HBeAg seroconversion- 6.6 – 7.9% HBsAg loss

● Rates of seroconversion and HBsAg loss higher with TDF/FTC or LAM compared to TDF alone (P>0.05)

Kosi L, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 391.

Cumulative Annual ProbabilityCumulative Annual Probability

Pat

ien

t P

erce

nt

9.75

6.2

7.4

0

2

4

6

8

10

12

HBeAg SC HbsAg loss(HBeAg+)

HbsAg loss(HBeAg-)

Entecavir in Patients with HBV/HDV Co-infection

● 15 patients in Turkey with detectable HDV RNA and elevated ALT treated with ETV (1mg) daily x 1 year- Follow-up on 12 patients

(2 D/C for non-safety reasons)

● All patients achieved undetectable HBV DNA

● HDV RNA level unchanged except in 2 pts with low HDV RNA/high HBV DNA prior to treatment who achieved undetectable HDV RNA- No change observed in HBsAg level

● ETV may be effective in a subset of patients with HBV/HDV but many do not have an HDV response

Onder F, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 913.

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0Basal 6 Months 12 Months

HDV RNA

HBV DNA

HDV RNA

HBV DNA

Vira

l Loa

d (lo

g 10 co

pies

/mL)

Management of HBV Disease in Asian Patients on Disease Modifying Anti-Rheumatic Drug

● Disease Modifying Anti-Rheumatic Drug (DMARD) therapy in patients with rheumatoid arthritis (RA) and HBV infection may lead to liver flare- No guidelines for HBV screening

in this population

● RA cohort of Asian patients (N=505)- Mean age 46.3 years

- 79.5% Female

● ~75% not screened for HBV

● Among those screened, 2 pts HBsAg(+)

Bebb O, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 1353.

505 Asian Patients

424 on DMARD

103 tested for HBVDuring ALT Flare

N=2HBsAg(+)

(2%)

N=101HBsAg(-)

(98%)

Patient Testing For HBV in Asian DMARD Patients

13%

1%

24%38%

4%10%

48%

Management of HBV Disease in Asian Patients on Disease Modifying Anti-Rheumatic Drug

● ALT flares common in pts on DMARD and most unrelated to HBV:

● Of 2 pts found to be HBsAg+ on testing during flare:- Both HBeAg negative with detectable HBV DNA- Treated with LAM with successful outcome

● Conclusion: HBV screening should be routine prior to initiating DMARD in patient with RA, particularly high risk patient groups

Bebb O, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1353.

ALT rise not on DMARD

ALT rise on DMARD, no HBV test

ALT rise on DMARD, HBV -ve

ALT rise not on DMARD

ALT rise on DMARD, no HBV test

ALT rise on DMARD, HBV -ve

No ALT rise

No data

ALT rise on DMARD, HBV +ve

No ALT rise

No data

ALT rise on DMARD, HBV +ve

ALT riseon DMARD

HBV Disease Reactivation in Cancer Patients Receiving Chemotherapy

● Retrospective review of all cancer patients at Memorial Sloan-Kettering (2003- 2009) who had HBV DNA > 1000 c/mL and acute ALT or AST flare

● 217 patients had HBV DNA > 1000 copies/mL

● 21 had concomitant abrupt increase in serum ALT and/or AST- Median HBV DNA 7.2 log10 c/mL- Most patients had lymphoma or

leukemia - Immunosuppressive therapy was

initiated a median of 21 days (range 5-141) prior to reactivation

Mendelsohn R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1328.

Malignancy in Enrolled PatientsMalignancy in Enrolled Patients

Lymphoma

Leukemia

Solid Tumors

Lymphoma

Leukemia

Solid Tumors

58%

32%

10%

HBV Disease Reactivation in Cancer Patients Receiving Chemotherapy

● Among patients with HBV flare, serious clinical outcomes were observed - 4 pts died due to liver disease

● Based on these data, all patients at MSKCC are screened for HBV since 2006- HBV prophylaxis is give to

prevent flare

- Only 2 cases since the protocol was started; both did not follow the protocol

Mendelsohn R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1328.

Pat

ient

Num

ber

17

4 4

1

3

0

5

10

15

20

Hospitalization Mortality

Delay in CA txt Liver Transplant

Fulminant Liver Failure

HBV Transmission Among Infants of Chinese-American Mothers with CHB

● Newborns at risk for HBV were retrospectively identified at 2 New York hospitals (N=641)

● Contact was attempted to test infants for HBV - Loss to FU ~50% in this population

● 76 mother-81 infant pairs tested- 9.2% HBV transmission rate

despite standard HBIG and vaccine - Risk factors include HBeAg(+)

● Perinatal transmission occurs in the US- Infants of HBsAg(+) mothers

should be followed closely

Mi L, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 1438.

69 mother with babies HBsAg-

7 mothers with babies HBsAg +

Mean Age +/- SD (range) 29.0 +/-4.7 (20.6-40.9)

29.4 +/-5.9 (22.5 -38.0)

HBeAg Status

Positive 16 (30.8%) 5 (83.3%)

Negative 36 (69.2%) 1 (16.7%)

HBV DNA (copies/ml)

< 160 8 (30.8%) 0

160-108 13 (50%) 0

> 108 5 (19.2%) 3 (100%)

Mean Prenatal ALT (U/L) +/- SD (range)

26.8 +/-12.9(8 -73)

26.6 +/-11.4 (15 - 45)

Assessment of TDF-Containing Regimens in Pregnancy Using the ART Pregnancy Registry

● APR is a international, prospective exposure registration cohort to monitor teratogenic effects of ART- Established 1989

- TDF data collected since 2001

● 1301 cases (1045 live births) receiving TDF regimens- Majority HIV infected women

exposed to combination ART

- 9 women HBV mono-infected

Brown RS, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 407.

TDF Regimens Maternal Demographics at Registration (Pregnancies Enrolled=1,186)

Median Age (years) 30

Race

Black 63.2%

Hispanic 16.3%

White 11.8%

Asian 2.2%

Other 2.6%

CD4+ T-Cell Count at Start of Pregnancy

≥ 500 cells/µL 23.3%

200-499 cells/µL 48.9%

<200 cells/µL 21.4%

HIV Infected

A. Asymptomatic, acute (primary) HIV or PGL 56.7%

B. Symptomatic, not (A) or (C) 5.7%

C. AIDS – indicator conditions 31.4%

HIV UninfectedHIV post-exposure prophylaxis 0

Hepatitis B mono-infected 0.7%

TDF-Containing Regimens in Pregnancy: Findings from the Antiretroviral Pregnancy Registry

● Congenital anomaly rate with TDF containing ART:- 2.4% (95% CI: 1.4-3.8) for

1st trimester - 1.6% (95% CI: 0.6-3.4) for

2nd/3rd trimester

● Similar to CDC’s population-based birth defects surveillance system and other ART regimens

● Data on other HBV agents (except LAM) are limited

Brown RS, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 407.

Birth Defect Rates By Trimester of Earliest Exposure to TDF Regimens and All ARV Regimens in APR

Earliest Exposure to ARVs

TDF Regimens

All ARV Regimens

1st Trimester

Number of Defects / Live Births 16/678 130/4530

Prevalence (95% CI) 2.4% (1.4 – 3.8)

2.9% (2.4 – 3.4)

2nd or 3rd Trimester

Number of Defects / Live Births 6/385 147/5874

Prevalence (95% CI) 1.6%(0.6 – 3.4)

2.5%(2.1 – 2.9)

Birth Defect Prevalence for First Trimester Exposure to Anti-HBV Drugs

Regimen Defects / Live Births Prevalence, % (95%CI)

Lamivudine 93/3226 2.9 (2.3, 3.5)

Tenofovir DF 16/678 2.4 (1.4, 3.8)

Adefovir dipovoxil 0/37 0

Entecavir 0/8 0

Telbivudine 0/3 0

Studies 102 and 103: TDF Resistance Surveillance in CHB Patients

● TDF resistance surveillance performed in patients with HBeAg- (Study 102) or HBeAg+ (Study 103) CHB

Snow-Lampart A, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 480.

All patients:– At baseline– Yearly if HBV DNA ≥ 400 copies/mL

(≥ 69 IU/mL)– At discontinuation of TDF mono-therapy

if HBV DNA ≥ 400 copies/mL

Any patient post-baseline with:– Conserved site changes in pol/RT– Virologic breakthrough (VB)*

– Polymorphic site changes (> 1 patient)

Genotyping(HBV pol / RT)

Phenotyping(HBV pol / RT)

*Defined as a confirmed 1 log10 increase in HBV DNA from nadir and/or confirmed HBV DNA >400 copies/mL after having <400 copies/mL*Defined as a confirmed 1 log10 increase in HBV DNA from nadir and/or confirmed HBV DNA >400 copies/mL after having <400 copies/mL

Studies 102 and 103: No Relationship Between Virologic Breakthrough and Emergence of Genotypic

Changes

Snow-Lampart A, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 480.

TDF Monotherapy (n=6)

TDF Monotherapy (n=6)

No Change

Polymorphic Site Change

No Change

Polymorphic Site Change

Genotypic Changes in HBeAg- and HBeAg+ TDF-TDF Treated Patients During Year 3

Genotypic Changes in HBeAg- and HBeAg+ TDF-TDF Treated Patients During Year 3

• Conserved site changes observed in 3/13 subjects (rtR51k, rtL180M±rtM204V±rtA181T; rtR192H)

• None of the changes were associated with Virologic Breakthrough

• Conserved site changes observed in 2/9 subjects (rtG152E; rtN236T±rtR274Q)

• rtG152E observed during a transient Virologic Breakthrough

N=3

N=1

N=1N=1

N=1

N=2N=2

N=3

FTC+TDF Therapy (n=7)

FTC+TDF Therapy (n=7)

TDF Monotherapy (n=5)

TDF Monotherapy (n=5)

N=3N=2

N=1

N=3

FTC+TDF Therapy (n=4)

FTC+TDF Therapy (n=4)

Genotypic Changes in HBeAg- and HBeAg+ ADV-TDF Treated Patients During Year 3

Genotypic Changes in HBeAg- and HBeAg+ ADV-TDF Treated Patients During Year 3

Conserved Size Change

Unable to Genotype

Conserved Size Change

Unable to Genotype

Resistance Surveillance in CHB Patients Treated with TDF: No Reduction in HBV Susceptibility to TDF

● 5 conserved site changes

● No persistent virologic breakthrough and no in vitro reduced susceptibility to TDF

Snow-Lampart A, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 480.

Treatment Group Viral Isolate Change from BL in HBV pol/RT

Fold Change from BL

TDF Patient AWeek 144 pool rtR51K 1.4

TDF-FTC/TDF Patient BWeek144 pool 4tA181T 0.7

TDF-FTC/TDF Patient C Week144pool/clones rtR192H Replication Defective

ADV-TDF Patient EWeek144 pool

Week 144 clone 1Week 144 clone 2

rtN236N/T±rtR274R/QrtN236TrtR274Q

1.98.21.9

Treatment Group Laboratory Isolate Change from control in HBV pol/RT

Fold Change from control

TDF-FTC/TDF pCMVHBVrtR192H rtR192H Replication Defective

ADV-TDF pHY92rtG152E rtG152E 1.7

CHARM Study: Prevalence and Nature of Viral Mutations in CHB Patients on Oral Antiviral Therapy

● Multicenter, cross sectional study- 18 sites Australia- 778 patients receiving ≥6 months antiviral therapy- Direct sequencing analysis done on all patients with detectable

HBV DNA

● Current ATV regimen:- ETV 0.5 mg (25%) - ETV 1.0 mg (10%)- LAM (23%) - ADV (8%)- ADV + LAM (23%)

● 28% had detectable HBV DNA- 64% of these had ≥1 detectable drug resistance mutation

Roberts SK, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 389.

CHARM Study: Prevalence and Nature of Viral Mutations in CHB Patients on Oral Antiviral Therapy

● Drug resistant mutations most common in those with ≥4 AVT regimens

● Most common resistance mutations- L180M + M204V/I (15%)

- M204V/I (13%)

- A181V/T (7%)

● 49% NOT receiving therapy

● 8% receiving suboptimal AVT; 29% detectable HBV DNA

Roberts SK, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 389.

Clinical and Virologic Characteristics

HBV DNA detectableHBV DNA

Undetectable (n=533)All (n=208

Drug-resistance mutation(s)

(n=134)

No drug-resistance mutation(s)

(n=74)

HBeAg + 63% 60% 69% 20%

Mean ALT ± SD (IU/L) 42 ± 45 44 ± 45 37 ± 22 31 ± 16

≥ 4 prior AVT Regimen 18% 34% 9% 14%

Prior oral AVT 61% 81% 58% 57%

Mean duration of cumulative oral AVT (months) 54 ± 31 64 ± 26 35 ± 30 50 ± 31

TDF Effective in LAM-Resistant CHB Patients who Harbor A194T at Baseline

● Resistance to TDF not yet characterized- A194T (alanine to threonine) has been detected in

HIV/HBV co-infected patients treated with TDF and in vitro

● Study to determine virologic response to TDF in pts with rtL180M + rtM204V/I and rtA194T- 12/950 patients harboring A194T (10/12 with L180M

+M204V/I) enrolled- All previously treated with LAM (11/12) or ETV (1/12)- Salvage treatment with TDF, TDF + FTC, or TDF + LAM

Fung S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 399.

rtA194T

0123456789

0 3 6 9 12 15 18 21 24 27

TDF Effective in LAM-Resistant CHB Patients who Harbor A194T at Baseline

● 7/8 treated pts had undetectable HBV DNA (18.3 months f/u)Fung S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 399.

ALT

HBV DNA

ALT

HBV DNA

0

1

2

3

4

5

6

7

0 3 6 9 12 15 18 21 24 27

1009080706050403020100

Time on TDF+LAM (months)

HB

V D

NA

(lo

g 1

0/m

L)

TDF 300mg daily + LAM 100mg dailyPatient: HBeAg-, anti-HBe+, genotype D

rtA194T

AL

T (

IU/L

)

Time on TDF+LAM (months)

1009080706050403020100H

BV

DN

A (

log

10

/mL

)

TDF 300mg daily + FTC 200mg dailyPatient: HBeAg-, anti-HBe+, genotype B

AL

T (

IU/L

)

Long-term ADV in LAM-resistant CHB

● 320 patients LAM resistance SWITCHED to ADV monotherapy- 81 HBeAg-positive

● 5 year virologic response = 47%- More likely to be HBeAg-negative- Initial HBV DNA<8log10- <4log10 at 24 weeks therapy

Lee J , et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 421.

Long-term ADV in LAM-resistant CHB

● 320 Korean patients (81 HBeAg+) with LAM resistance switched to ADV monotherapy

● At 5 years of Tx, 47.3% cumulative virologic response - Higher response with baseline HBeAg-

negative (60.6% vs. 44.2%, p=0.01), baseline HBV DNA ≤8 log10 copies/mL, and HBV DNA <4 log10 copies/mL after 6 months of Tx

● At 5 years of Tx, 47.4% had virological breakthrough (VB) with ADV genotypic resistance (GR)

● Conclusion: ADV monotherapy not optimal therapy for LAM resistance

Lee J , et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 421.

Cumulative probability of VB, GR, and VB+GR

ADV duration 12 mo 24 mo 36 mo 48 mo 60 mo

Patients at risk 320 279 164 66 25

GR, total 4.4% 18.4% 34.3% 52.3% 65.6%

HBeAg + 5.4% 21.1% 35.5% 55.8% 71.4%

HBeAg - 0.0% 8.9% 28.2% 37.8% 45.6%

VB, total 1.6% 20.7% 39.5% 51.6% 61.8%

HBeAg + 1.9% 21.7% 41.5% 53.9% 66.7%

HBeAg - 0.0% 16.9% 31.4% 42.4% 42.4%

VB+GR, total 0.9% 13.5% 30.4% 43.5% 47.4%

HBeAg + 1.2% 13.5% 38.5% 45.0% 50.4%

HBeAg - 0.0% 13.6% 26.1% 37.9% 37.9%

Prevalence of LAM Resistance Mutations Among Treatment-Naïve CHB Patients

● Previous reports of treatment naïve patients harboring significant lamivudine resistant mutations

● 175 naïve patients tested by InnoLipa HBVDRv2/3● 17 (10%) tested positive for drug resistant mutants

● True LAM resistance in 1 patient: M204V/I● Other LAM-R mutations: 3.6%

Ng KA, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 429.

Number of MutationsRelated to Each Antiviral:

Number of MutationsRelated to Each Antiviral:

0 2 4

Number of Samples with Mutation0 2 4

Number of Samples with Mutation

L80VL80V

L180M L180ML180M L180M

A181T* A181T* A181T* A181T* A181T* A181T*

A194TA194T

S202CS202C

M204I M204IM204I M204I

M204VM204V

I233V*I233V*

LAM LdT ETV ADV TDFLAM LdT ETV ADV TDFn=13 n=10 n=5 n=9 n=3n=13 n=10 n=5 n=9 n=3

D E

CB

AG

F

HB

V R

ev

ers

e T

ran

sc

rip

tas

e

Switching Therapy to Lamivudine in Entecavir-treated Patients

● 2 year prospective, randomized study of ETV LAM sequential therapy (N=50)- All pts on ETV 0.5mg with normal ALT

and undetectable HBV DNA (<12 IU/ml)

- If HBV DNA rebound >20 IU/mL x 3, switched back to ETV

● All pts in ETV arm remained undetectable with normal ALT

● 3 pts in LAM arm with viral rebound- Pts switched back to ETV and

undetectable at week 48 with normal ALT and no resistance

Fung J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 433.

Results at 48 weeks

Parameters ETV/ETV(n=25)

ETV/LAM(n=25) P

Follow-up period

(weeks)48 48 NS

ALT elevation 0% 0% NS

HBV DNA rebound 0 (0%) 3 (12%) NS

Evolution of HBV Quasispecies in CHB Patient Sequentially Treated with Different Nucleos(t)ides

● Ultra-deep pyrosequencing detects minor variants (~1%) in complex viral quasispecies

● Analysis by ultra-deep pyrosequencing of HBV quasispecies in consecutive serum samples from heavily-treated CHB patient- Sequential viral therapy: LAMADVETV- Multidrug resistance by standard direct sequencing

Rodriguez-Frias F, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 447.

Evolution of HBV Quasispecies in CHB Patient Sequentially Treated with Different Nucleos(t)ides

● Total of 100,390 sequences analyzed● Low levels LAM-r mutations and ADV-r mutations found at baseline ● After virologic breakthrough LAMA181T main variant (64.1%)● After ADV A181T(56.5%)● After ETV L180M+S202G+M204V+V207I (72.4%)

Rodriguez-Frias F, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 447.

HBV-DNA (log10 copies/mL)

ALT (IU/mL)

HBV-DNA (log10 copies/mL)

ALT (IU/mL) ETV + TenofovirETVADVLAM

32 Year Old Male, Genotype A, HBeAg+

HB

V D

NA

(lo

g10

co

pie

s/m

L) 140

120

100

80

60

40

20

0

AL

T (

IU/m

L)

12

34

5V173, L180, A181, T184, A194, S202, M204, N236

V173, L180, A181, T184, A194, S202, M204, V207, N236

V173, L180, A181AT,

M204, V207, N236

V173, L180LM, A181T, T184, A194,

S202, M204MIV, V207, N236

V173, L180, A181AT,

M204, V207, N236

I169, V173VL, L180LM, A181, T184, S202SG, M204MV, V207,

N236

V173, L180M, A181, T184, A194,

S202SG, M204V, I233, N236, M250

0

2

4

6

8

10

12

Jan'98

Jan'99

Jan'00

Jan'01

Jan'02

Jan'03

Jan'04

Jan'05

Jan'06

Jan'07

Jan'08

Jan'09

TDF in CHB Patients with Previous LAM and ADV Failure

● Open-label, prospective study

● CHB patients with pre-existing LAM-failure and HBV viremia after ≥24 weeks of ADV switched to TDF or TDF + LAM for ≥48 weeks (N=61)- Median duration of LAM 37.5 mos

and ADV 22 mos

- Baseline DNA 6.12 log10 c/ml

- Significant baseline resistance present

● Primary analysis: HBV DNA decline from baseline

Patterson S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 484.

Baseline Mutations N

LAM-R

rtM204I/V 20

Other 8

ADV-R

rtA181T/V 14

4

rtN236T 7

Pre-core (rtG1896A) 3

BCP (rtA1762A & G1764A 2

Envelope (rtG145R / P120T) 4

TDF in CHB Patients with Previous LAM and ADV Failure

● Median HBV DNA decline on TDF at week 48: 4.24 log10 c/ml● 20% at 48 weeks had HBV DNA >3 log10 c/ml

- 2 new mutations: N236T and A181T

- Associated with baseline N236T (p=0.024)

- Higher baseline VL (p=0.04)

Patterson S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 484.

Months Months

% P

atie

nts

<2

00

0 c

/mL

% P

atie

nts

<2

00

0 c

/mL

0

20

40

60

80

100

0 6 12 18

rtM204I/V

rtA181T/V

rtN236T

0

20

40

60

80

100

0 6 12 18

Low VL

All

High VL

TDF for CHB Patients with Suboptimal Response to ADV or ADV + LAM Treatment

● CHB pts with HBV viremia switched from ADVTDF (15%) or ADV + LAMTDF + LAM (85%) (N=85)- Median duration of ADV 29.2 mos.

- 46% with ADV-R mutations

● No virologic breakthrough on TDF between weeks 24 and 48

● Slightly reduced probability of achieving HBV DNA <12 IU/ml with ADV-R

Levrero M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 489.

N = 25 21 20 10

N= 36 31 29 13

Weeks on StudyP

erc

en

tag

e w

ith U

nd

ete

cta

ble

e

HB

V D

NA

(%

)

0

10

20

30

40

50

60

0 12 24 . 48

ADV-Resistant

Suboptimal Responders