AASLD 2014 HBV Post Conference Update 11-21-14

8/10/2019 AASLD 2014 HBV Post Conference Update 11-21-14

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Post Conference HBV Update

65thAnnual Meeting of the

American Association for the Study of Liver Diseases

Simply SpeakingHepatitis Post Conference HBV Update: 65thAnnual Meeting of the American Association for the Study of Liver Diseases is

Copyrighted 2014 by Practice Point Communications, unless otherwise noted. All rights reserved.

Supported by an independent educational grant from

Gilead Sciences Medical Affairs

This activity is jointly provided by theUniversity of Nebraska Medical Centerand Practice Point Communications


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Created in collaboration with:

Robert G. Gish MD and the Practice Point Team at Simply Speaking


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Learning Objectives(CME/CNE/CPE)

Upon completion of this educational activity, participants should be able to:

Screen for hepatitis B virus (HBV) infection according to the recommendations

from the American Association for the Study of Liver Diseases (AASLD) and the

Centers for Disease Control and Prevention (CDC)

Appropriately select antiviral HBV treatment strategies for according to the

recommendations from the AASLD guidelines

Manage safety and tolerability problems with antiviral HBV agents, including

side effect, drug-drug interactions, and resistance

Evaluate new agents being investigated for HBV therapy to optimize

information-based decision making about therapy


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Program Overview

Epidemiology, diagnostics, and disease progression Treatment

Clinical trials

Real-life settings

HBV reactivation and transplantation

Investigational HBV therapy


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Process Outcomes Among a National Cohort of USVeterans With HBV by Speciality Care Referral

Serper M, et al. Hepatology. 2014;60(suppl 1):230A-231A. Abstract 68

0

20

40

60

80

100

HBsAgPositiveUSVete

rans(%)

61%

11%

99%

59%

ALT

No speciality care (n=6744)Speciality care (n=15,084)

HBV DNA HBeAg Anti-HBe Anti-HAV Anti-HDV HAVVaccination

HCCScreening

Overall If ALT>2x ULNLaboratory Testing

Antiviral Therapy

*P


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Clinical Outcomes and All-Cause Mortality Among aNational Cohort of US Veterans With HBV

Clinical outcomes (IRR speciality/no speciality care)

HCC: 0.52 (P


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Summary and Conclusions of Serologic TestingAmong a National Cohort of US Veterans With HBV

Low rates of Recommended serologic/virologic testing (DNA testing)

HAV vaccination

HCC screening

HDV testing

Conclusions

Significant gaps in recommended HBV care among this national cohort and in

the US

Need for implementation and testing of clinical decision support tools to improveguidelines adherence and clinical outcomes in HBV

Serper M, et al. Hepatology. 2014;60(suppl 1):230A-231A. Abstract 68


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Multiplex PCR Assay:Simultaneous Detection of Hepatitis A, B, C, D, and E

TaqMan Array Card (TAC) technology Real-time PCR assay

Requires 20-46 L total nucleic acid

extract from 200 L of serum

1 L/reaction

Detect up to 48 pathogens Can detect coinfections

Run-time: 4 hours

Limitations

Initial design and validation can be

cumbersome Lower analytical sensitivity

PCR product not available for sequencing

Kodani M, et al. Hepatology. 2014;60(suppl 1):230A. Abstract 67

Sensitivity and Specificity(Viral Hepatitis TAC)

Sensitivity

(%)

Specificity

(%)

Overall

Concordance

(%)

HAV 94 93 93

HBV 92 100 96

HCV 100 100 100

HDV 100 100 100

HEV 100 100 100

Total 96 (93-96) 98 (96-100) 97


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Impact of Race on the Risk of HCC Among USVeterans With Chronic HBV Infection

Retrospective cohort study

VA Corporate Data Warehouse

Diagnosed with HBV during 2001-2011 with >1 year of

follow-up

Positive HBsAg test confirmed by a subsequent HBV test

(HBsAg, HBeAg, or HBV DNA) >6 months apart

HCC defined by ICD-9 code 155.0 (malignant neoplasm

of liver) in the absence of code 155.1 (intrahepatic

cholangiocarcinoma)

HCC incidence rate: 32.3/1000 person-years

525 cases over 16,278 years of follow-up

HCC incidence rates by race (per 1000 person-years)

Asian: 93.2

White: 30.6

Black: 29.9

Mittal S, et al. Hepatology. 2014;60(suppl 1):972A. Abstract 1609.

Baseline Characteristics

HBV

Cohort

(n=10,421)

Mean age (years) 51

Male (%) 96

White/Black/Asian/other (%) 41/39/5/15

HCV coinfection (%) 14

HIV coinfection (%) 14

HBsAg (%)

Positive/negative/unknown 25/42/33

HBV DNA (%)

Positive/negative/unknown (%) 25/31/44

Cirrhosis (%) 17


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Impact of Race on the Risk of HCC Among USVeterans With Chronic HBV Infection

Adjusted hazard ratio for risk ofdeveloping HCC (relative to white race)

Asian: 2.99 (P


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Impact of Antiviral Therapy on HCC Incidence:San Francisco Bay Cohort

Retrospective cohort study (1991-2014)

Consecutive HBV patients from 2

medical centers and 2 speciality

community based clinics (n=3221)

Cirrhosis (liver biopsy, imaging, or

secondary clinical data) HCC (liver biopsy or radiographic

evidence per AASLD guidelines)

HBV therapy (pegIFN, antiviral agents)

Most patients did not receive antiviral

therapy (62%)

HBV DNA undetectable achieved in

87% of those treated

HCC: 102 cases

Lin D, et al. Hepatology. 2014;60(suppl 1):315A-316A. Abstract 232.


Not

Treated

(n=1983)

Treated

(n=1238)

Age (years) 46* 45

Male (%) 55* 66Asian/White (%) 93/2 98/


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Predictors of HCC in a San Francisco Bay Cohort

HCC incidence(cases per 1000 person-years)

Overall: 6.6

Cirrhotics: 53.9

Non-cirrhotics: 1.57

HCC incidence was significantly lower in

patients with anti-HBV therapy among both

non-cirrhotic and cirrhotic patients

Antiviral therapy was a significant

independent predictor for decreased HCC

risk in this mostly Asian cohort, regardless

of age, sex, or cirrhosis status

However, HCC still develops at a significantly

high rate in treated patients, underscoring the

need for vigilant HCC surveillance in patients

(regardless of treatment status)

Lin D, et al. Hepatology. 2014;60(suppl 1):315A-316A. Abstract 232.

Predictors of Developing HCC

(Adjusted Hazard Ratio)

Adjusted HR

(95% CI)

P

Value

Male 2.8

(1.5-5.2)

0.001

>45 years of age

(versus 20K IU/mL.


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ALBATROS Study: Predictors of HBsAgSeroclearance in Untreated, European HBV Cohort

European untreated HBeAg-negative HBsAgcarriers (n=583)

Analyze dynamics parameters (HBsAg, HBV

DNA, ALT, liver stiffness) within the first and

second year of follow-up to predict HBsAg

seroclearance

Not candidates for antiviral therapy (within

normal limits for BMI, ALT/AST, GGT, lipids)

HBsAg: 5049 IU/mL; HBV DNA 2.3 log10IU/mL;

Genotype A (9%), B/C (6%), D (22.1%), other (63%)

Low HBsAg and low HBV DNA levels at

baseline and during the first year were

strong predictors of HBsAg seroclearance

(P


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HBsAg Seroclearance:Analysis of a Large Multi-Center US Cohort

Retrospective cohort study (2001-2013) ICD-9 electronic query and chart review (n=3594)

2 community GI clinics, 3 community primary care clinics, 1 community multi-speciality medical

center, 1 university medical center

Primarily Asian cohort (95%)

HBsAg seroclearance: documented loss of HBsAg

Similar baseline mean age, HBeAg status, HBV DNA, ALT, or time of follow-up were

similar between those achieving HBsAg seroclearance compared with those who did not

HBsAg clearance: 1.4% overall (0.33% annual)

50 patients over 15,117 person-years of follow-up

Male (adjusted HR: 1.9; P=0.4) gender was significantly more likely to reach HBsAg

seroclearance

Trend suggesting non-Asian ethnicity as an independent predictor (adjusted HR: 2.0; P=0.08)

Nguyen LH, et al. Hepatology. 2014;60(suppl 1):1005A-1006A Abstract 1679.

HR: hazard ratio adjusted for age, sex, HBeAg, practice type, HBV DNA at baseline.


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Program Overview

Epidemiology, diagnostics, and disease progression

Treatment

Clinical trials

Real-life settings




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Study 103 and 102: 8-Year Tenofovir DF Treatmentfor Patients With Chronic HBV

Marcellin P, et al. Hepatology. 2014;60(suppl 1):313A-314A Abstract 229.

48 WeeksDouble-Blind

Study 103*HBeAg-PositiveTreatment-Nave

Study 102*HBeAg-Negative

Lamivudine nave orexperienced

Tenofovir DF 300 mg

Adefovir 10 mg

Week 0 48 72 96 384

Randomization2:1

8 YearsOpen-Label

Tenofovir DF 300 mg

Tenofovir DF 300 mg

LiverBiopsy

CurrentAnalysis

*Pretreatment liver biopsy. Other eligibility criteria: age 18-69 years, compensated liver disease, HBV DNA >106copies/mL,ALT >2 x ULN and 3, seronegative for HIV, HDV, and HCV.

If HBV DNA >400 copies/mL, option to add emtricitabine to tenofovir DF in a fixed-dose tablet.


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Study 103 and 102:Baseline Characteristics


HBeAg Negative

(n=375)

HBeAg Positive

(n=266)

Age (years) 44 34

Race (%)

Caucasian/Asian/other 65/25/10 52/36/12ALT (U/L) 140 147

HBV DNA (log10copies/mL) 6.1 7.6

Cirrhosis (%) 24 24

Viral genotype (%)

AB

C

D

Other

1111

11

64

3

2313

26

33

5


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Tenofovir DF in Chronic HBV: HBeAg NegativePatients Achieving HBV DNA


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Tenofovir DF in Chronic HBV: HBeAg Positive PatientsAchieving HBV DNA


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Tenofovir DF in Chronic HBV:Cumulative Probability of HBsAg Loss


Double-Blind(Study 103) Open-Label

TDF to TDF

ADV to TDF

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

Probabilit

y

Weeks on Treatment

12.9% (n=28, ITT)

Baseline predictors for HBsAg loss (multivariate):Caucasian race, genotype A or D,


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Tenofovir DF in Chronic HBV (Study 102 and 103):Resistance and Safety Data at Year 8

No resistance to tenofovir DF was detected Virologic breakthrough was rare (0.5 mg/dL above baseline (2.2%)

Phosphate


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Durability of HBeAg Seroconversion WithTenofovir DF or Entecavir for Chronic HBV Infection

Retrospective, chart review Community (n=7) and academic (n=4)

GI/hepatology practices

HBeAg-positive Asian patients treated with

entecavir or tenofovir DF

Achieved HBeAg seroconversion and consolidation

therapy

Treatment discontinued prior to loss of HBsAg

Outcome measures

Remission (persistently undetectable HBV DNA,

durable HBeAg seroconversion, normal ALT)

Low-level virologic relapse

(reappearance of HBV DNA 2000 Iu/mL)

HBeAg seroconversion (reappearance of HBeAg)

Fong T-L, et al. Hepatology. 2014;60(suppl 1):1121A-1122A Abstract 1912.


Patients

(n=54)

Median age (years) 43

Male (%) 63

Asian/foreign born (%) 94/85

Prior treatment (%)

Nave (ETV/TDF/both)

Experienced (ETV/TDF)

64/33/3

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Time to (months)

Undetectable HBV DNA

HBeAg seroconversion

11

21

Consolidation period

(months)

16.8

Follow-up after treatment

discontinuation (months) 30.3


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Outcomes Following HBeAg Seroconversion WithTenofovir DF or Entecavir for Chronic HBV Infection

Outcomes Remission: 7% (4/54)

HBsAg negative and anti-HBs positive (n=1)

Low-level virologic relapse: 24% (13/54)

Became HBV DNA undetectable during

follow-up (n=10)

Maintained ALT 2x ULN (n=18)

HBV DNA levels were similar between those with

normal and abnormal ALT

HBeAg negative/anti-HBe positive (n=23)

HBeAg positive (n=12, 9 were anti-HBe

negative)

HBeAg and anti-HBe negative (n=3)

Fong T-L, et al. Hepatology. 2014;60(suppl 1):1121A-1122A Abstract 1912.

High-Level Virologic Relapse(Cumulative Probability)

0

20

40

60

80

100

Relapse(%)

0 12 24 36 48

Time to Relapse (months)


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Durability of HBeAg Seroconversion WithTenofovir DF or Entecavir for Chronic HBV Infection

Factors associated with low or high level of virologic relapse after discontinuationof therapy (comparisons are low verus high virologic relapse rates)

Age


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Tenofovir DF + Entecavir in Entecavir-ResistantChronic HBV Infection

Lim Y-S, et al. Hepatology. 2014;60(suppl 1):315A Abstract 231.

Tenofovir DF 300 mg qd(n=45)

Tenofovir DF 300 mg qd + Entecavir 1 mg qd(n=45)

Open-LabelHBV DNA >60 IU/mLEntecavir resistance mutations

(T184A/C/F/G/I/L/S, S202G, M250L/V)No adefovir resistanceNo previous tenofovir DF useCompensated liver disease

(Child-Pugh A)

No HCV, HIV, or malignancySerum creatinine


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Treatment Outcomes With Tenofovir DF + Entecavir inEntecavir-Resistant Chronic HBV Infection

No significant difference betweentenofovir DF versus tenofovir DF +

entecavir in achieving complete

virologic response and reduction in

HBV DNA levels

Predictors of virologic response at

week 48

Prior adefovir exposure (OR: 0.14;

P=0.02)

HBV DNA level (OR: 0.33; P


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ESTEEM Study: Tenofovir DF + Entecavir for Multi-Drug Resistant Chronic HBV

Park JY, et al. Hepatology. 2014;60(suppl 1):1096A Abstract 1865.

Tenofovir DF 300 mg qd + Entecavir 1.0 mg qd(n=64)

Open-Label, Prospective,Multicenter Study

Genotypic resistance from 2 differentclasses of nucleoside analogues

Class A (lamivudine, clevudine,telbivudine, entecavir)

Class B (adefovir, tenofovir DF)HBV DNA >60 IU/mL on any rescueHBV regimen (>24 weeks)

Compensated liver disease(Child-Pugh A)

Week 0 24 48

Primary endpoint: HBV DNA


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ESTEEM Study: Outcomes With Tenofovir DF +Entecavir for Multi-Drug Resistant Chronic HBV

High virologic response amongpatients with multi-drug resistant

chronic HBV

Baseline presence of resistance

mutations did not impact treatment

response Virologic breakthrough in 5 patients

was transient and not associated

with additional or novel mutations

Tenofovir DF + entecavir was well

tolerated

No clinically significant adverse

events were noted during the study

Park JY, et al. Hepatology. 2014;60(suppl 1):1096A Abstract 1865.

Treatment Outcomes (Week 48)

Tenofovir DF +

Entecavir

(n=64)

HBV DNA (%)


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C-TEAM Study: Long-Term Entecavir and Incidence ofHCC in Chronic HBV Infection

Multi-center observational cohort(24 Taiwanese academic centers)

HBsAg positive, anti-HCV negative

Treatment-nave, no HCC development

in first year

HBV DNA >2000 IU/mL

Child A cirrhosis (METAVIR F4, Ishak >5)

Study arms

Entecavir 0.5 mg (2006-2014; n=1023)

Follow-up: 3.6 years

HCC cases: 85

Historical controls (1993-2008; n=503)

Untreated

Follow-up: 6.8 years

HCC cases: 121

Su T, et al. Hepatology. 2014;60(suppl 1). Abstract LB-30.


Entecavir

(n=1123)

Controls

(n=503)

Age (years) 55* 51

Male (%) 74 77

HBV DNA (log10IU/mL) 5.6 5.5

HBeAg negative (%) 71 70

ALT (IU/L) 115* 59

Albumin (g/dL) 3.9* 4.2

Total bilirubin (mg/dL) 1.4* 1.0

AFP (ng/mL) 23 48

EV/GV bleeding (%) 3 3

Hepatic encephalopathy (%)


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C-TEAM Study: Long-Term Entecavir and Incidence ofHCC in Chronic HBV Infection

Long-term entecavir therapysignificantly reduced the development

of HCC and spontaneous bacterial

peritonitis compared with controls

Hazard ratios for lifetime risk of HCC

Entecavir (versus no entecavir): 0.40(P


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HERMES Study (Interim Analysis): PegIFN Add-OnTherapy in HBV Genotype D Patients

Lampertico P, et al. Hepatology. 2014;60(suppl 1). Abstract LB-31.

Nucleoside Analogue Therapy

Phase 3b StudyOpen-label, multicenter (13 sites)HBV (genotype D)HBeAg negativeOn nucleoside analogue therapyHBV DNA 12 months

and HBsAg >100 IU/mL

Week -12 0 48 96

Study status: 97 enrolled, 70 started pegIFN, data available for 66 patients at week 24.Primary endpoint: decline in serum HBsAg levels.Peginterferon 180 g sc once weekly.Baseline demographics (n=70):

Male: 81%.Median age: 51 years.Age at HBV diagnosis: 32 yearsBMI: 25.4 kg/m2.ALT: 20 U/LHBeAg positive: 89%.HBsAg at screening/start of pegIFN: 1163/1160 IU/mL

ObservationPeriod

PegIFNAdd-On Period Follow-Up


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HERMES Study (Interim Analysis): PegIFN Add-OnTherapy in HBV Genotype D Patients

At week 24 of add-on therapy >50% decrease in HBsAg achieved in 27% of

patients

Lack of response (discontinued study): 16%

Increase in the proportion of patients with

HBsAg


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ENTEBE Study: Entecavir + Tenofovir DF in HBVPatients Who Were Previous NRTI Treatment Failures

European, open-label, phase 3bstudy (n=92)

HBeAg positive or negative

Prior treatment failure (HBV DNA

>50 IU/mL) on NRTIs

Compensated liver function

Entecavir 1.0 mg + tenofovir DF

300 mg qd for 96 weeks

Primary efficacy endpoint

HBV DNA


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ENTEBE Study: Treatment Outcomes With Entecavir+ Tenofovir DF in Previous NRTI Treatment Failures

Low baseline HBV DNA level was apredictor of virologic response

Of the patients not achieving HBV DNA


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Program Overview

Epidemiology, diagnostics, and disease progression

Treatment

Clinical trials

Real-life settings



ENUMERATE St d L T E t i d


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ENUMERATE Study: Long-Term Entecavir andIncidence of HCC in Chronic HBV Infection

Retrospective, observational study (n=745) US national cohort of community (n=10) and

university (n=16) practices

Entecavir therapy >12 months

>2 sets of laboratory tests for HBV DNA and

ALT after starting entecavir therapy

Excluded: HCV, HDV, or HIV coinfection;combination therapy with another nucleoside

analogue or pegIFN; solid organ

transplantation

Median follow-up: 4.0 years

Endpoints

Primary: HBV DNA suppression, ALTnormalization, HBeAg seroconversion

Secondary: HCC, cirrhosis, hepatic

decompensation, liver transplantation, death,

adverse events

Ahn J, et al. Hepatology. 2014;60(suppl 1):1099A Abstract 1870.


Patients

(n=745)

Age (years) 47.0

Male (%) 63.1

Asian/Black/White/other (%) 84/4/8/4Family history of HCC (%) 10.5

HBeAg negative/positive (%) 46/26

Cirrhosis (%) 9.3

Hepatic decompensation (%) 1.2

HBV DNA (log10

IU/mL) 5.7

ALT/AST (U/L) 58/41

Albumin (g/dL) 4.3

Total bilirubin (mg/dL) 0.7

INR 1.1

ENUMERATE St d L T E t i d


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ENUMERATE Study: Long-Term Entecavir andIncidence of HCC in Chronic HBV Infection

Development of HCC after 5 years Overall: 3.5%

Non-cirrhotic: 2.0%

Cirrhotic: 14%

Patients who developed HCC were

Older (age 53.4 years versus 46.8 years)

Cirrhotic (39% versus 8%)

No statistically significant differences in

HCC incidence by gender, ethnicity,

baseline HBV DNA, ALT, or HBeAgstatus

HCC surveillance remains warranted in

patients on antiviral therapy for HBV

Ahn J, et al. Hepatology. 2014;60(suppl 1):1099A Abstract 1870.

Time to Incident HCC

0

5

10

15

20

25

HCC(%)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 5.0

Time to HCC (years)

Cirrhotic

Non-Cirrhotic

P


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Program Overview


Clinical trials

Real-life settings




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HBV T ti St t d R ti ti i P ti t


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HBV Testing Status and Reactivation in PatientsTreated With Anti-Tumor Necrosis Factor Agents

HBV testing at baseline increased from 37%(2001) to 72% (2010)

HBV testing status of overall cohort at baseline

Tested/never tested/others: 52%/27%/21%

HBV reactivation (n=9)

HBsAg positive (n=7, none received

prophylactic antiviral therapy)

Silent reactivation (n=5)

Grade 3/4 hepatotoxicity (n=2)

HBsAg negative, HBcAb negative (n=1; silent

reactivation)

Other (n=1, not tested at baseline, grade 3/4

hepatoxicity)

Clinical approach to reactivation

Discontinued anti-TNF therapy (n=3)

HBV antiviral therapy, all responded (n=6)

No hospitalizations, liver failure, or death

Pauly MP, et al. Hepatology. 2014;60(suppl 1):232A-233A Abstract 72.

HBV Status at Baseline

0

20

40

60

80

100

Patients(%)

0.3% 2.0%3.9%

49.7%

HBsAgPositive

HBcAb PositiveHBsAg Negative

Percent of

Total cohort (n=8887)

Tested for HBV (n=4621)

HBsAg NegativeHBcAb Negative

95.7%

0.5%

HBV Reacti ation in Patients Treated With Anti T mor


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HBV Reactivation in Patients Treated With Anti-TumorNecrosis Factor Agents

Grade 3/4 hepatotoxicity (2.7%; 243/8887) HBV (n=3; no hospitalizations or deaths)

Indeterminate (n=100)

Other (n=140)

Rate of HBV reactivation and grade 3/4 hepatoxicity was low, but both were higher

among those who were HBsAg positive at baseline HBV reactivation in this cohort did not result in serious complications

Conclusions

HBsAg positive patients should be evaluated for prophylactic antiviral therapy or be

monitored closely for HBV reactivation

HBsAg negative/HBcAb positive patients should be monitored and HBV testing performedif grade 3/4 hepatotoxicity develops

Further studies are needed to identify best HBV screening strategies among patients

taking anti-TNF therapy

Pauly MP, et al. Hepatology. 2014;60(suppl 1):232A-233A Abstract 72.

PREBLIN Study:


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PREBLIN Study:Prophylaxis of HBV Reactivation With Tenofovir DF

Ongoing, prospective, open-label study(n=69)

HBeAg-positive and -negative patients

HBV DNA undetectable before starting

rituximab for hematologic malignancies

HBV reactivation

HBV DNA elevation >1 log10IU/mL above

baseline and/or HBsAg reappearance

Preliminary analysis of first 12 months

in 30 of 69 patients enrolled

Prophylaxis arms (18 months)

Tenofovir DF

Observation

Buti M, et al. Hepatology. 2014;60(suppl 1):997A Abstract 1661.


Tenofovir DF

(n=18)

Observation

(n=12)

Age (years) 66 73

Male (%) 61 58

Weight (kg) 71.7 75.4

BMI (kg/m2) 26.1 28.5

Anti-HBs positive

(%)

55.6 50.0

Non-Hodgkinlymphoma (%)

77.8 83.3

Chronic lymphatic

leukemia (%)

16.7 16.7

PREBLIN Study: Preliminary Results of Tenofovir DF


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PREBLIN Study: Preliminary Results of Tenofovir DFas Prophylaxis of HBV Reactivation

Preliminary analysis showed tenofovirDF prophylaxis prevented HBV

reactivation

No statistically significant difference in

liver and renal function between the 2

arms

HBV reactivation in the observation

arm (n=2)

Elderly man (anti-HBs positive) and

women (anti-HBs negative)

HBV DNA elevation >1 log10IU/mL from

baseline at 4 month visit

ALT


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Differences in Wait-Listing Trends for LiverTransplantation Between Patients With HBV and HCV

Retrospective cohort study (2003-2013) All liver transplant wait-listed candidates

in the US

Scientific Registry of Transplant

Recipients (n=124,289)

HBV, HCV, and NASH: 34.5%

Standardized incidence rates of liver

transplant wait listing based on the total

US population

Listing definitions

End-stage liver disease (biochemical

MELD >15 at listing)

HCC (received HCC MELD exception


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Liver Transplant Wait-Listing Trends by Indication(2003-2013)

Flemming JA, et al. Hepatology. 2014;60(suppl 1):208A Abstract 22.

0

1

2

3

4

5

6

7

03 04 05 06 07 08 09 10 11 12 13

End-Stage Liver Disease

SIRper100,000Po

pulation

Calendar Years

NASH

HCV

4.49

HBV

5.20

2.76

0.80

0.350.63

03 04 05 06 07 08 09 10 11 12 13

Hepatocellular Carcinoma

SIRper100,000Po

pulation

Calendar Years

NASH

HCV4.55

HBV

2.25

0.64

0.38

0.50

0.08

10

1.0

0.1

0.01

SIR: standardized incidence rates.

Liver Transplant Wait Listing Trends by Indication


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Liver Transplant Wait-Listing Trends by Indication(2003-2013)

HBV Dramatic decrease in the rate of wait

listing for ESLD with stabilization of the

rate for HCC

Likely reflects the success of effective

all-oral antiviral therapy

HCV

Slight decrease in wait listing for ESLD

Rate of wait listing for HCC continues to

rise

NASH

Rates of wait listing continue to

increase for ESLD and HCC

Flemming JA, et al. Hepatology. 2014;60(suppl 1):208A Abstract 22.

Average Annual Changeper Wait Listing Year

-10

-5

0

5

10

15

20

IncidenceRateRatio(%

)

-4.2%

+2.8%

-1.0%

0.1

HCV*

-1.1%

14.5%

Wait Listing

Overall

ESLD

HCC

HBV* NASH*

11.0%10%

9.3%

*P


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Program Overview


Clinical trials

Real-life settings



Proof of Concept Study:


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Proof of Concept Study:HBV/HDV Entry Inhibitor

2 cohorts receiving the HBV/HDV entry inhibitor Cohort A (n=40): HBV (HBeAg negative, HBV DNA >2000 IU/mL)

0.5, 1, 2, 5, and 10 mg sc once daily for 12 weeks (n=8/dose group)

10 mg arm extended to 24 weeks

Cohort B (n=24): HDV (compensated liver disease, 12.5% cirrhosis) patients scheduled for 48 weeks of

pegIFN therapy

Pre-treatment 2 mg (n=8), then pegIFN + HBV/HDV entry inhibitor for 24 weeks (n=8 in each arm)

Result

Cohort A (HBV): 10-mg arm showed best response and generally well tolerated

HBV DNA >1 log10decline: 75%

ALT normalization: 55%

No significant changes in HBsAg levels

Cohort B (HDV): HDV RNA >1 log10decline: 93% at week 24

HDV RNA negative and normal ALT at week 24 (n=1)

Treatment induced preS-specific antibodies and bile acid elevation at doses >1 mg

Urban S, et al. Hepatology. 2014;60(suppl 1). Abstract LB-20.

ARC-520 (siRNA-Based Therapeutic) in Patients With


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ARC-520 (siRNA-Based Therapeutic) in Patients WithChronic HBV Infection

Double-blind, placebo-controlled, single-dose escalation phase 2 study

HBeAg negative

Chronic HBV and ongoing entecavir therapy (continued throughout study)

Randomized arms (3:1)

ARC-520 1, 2, 3 mg/kg, single intravenous dose (pretreated with oral histamine)

Placebo (n=4)

Results

A single, 2 mg dose of ARC-520 administered intravenously significantly reduced HBsAg from day 3

through 83 compared with baseline

Day 85: 22% reduction from baseline

Nadir HBsAg at day 33 (51% reduction)

Safety (2-mg dose arm)

Mild severity (n=2; CK elevation, injection extravasation)

Moderate severity (n=2; near syncope, malaise)

Yuen M, et al. Hepatology. 2014;60(suppl 1). Abstract LB-21.

NVR 3 778 (HBV Core Inhibitor):


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NVR 3-778 (HBV Core Inhibitor):Phase 1a Safety and Pharmacokinetics

Healthy, adult volunteers (n=40; 8 subjects per cohort) 4 single-dose arms (50, 150, 400, 800 mg)

Multiple-dose arm (200 mg qd for 14 days)

Safety

No serious or severe clinical adverse events

Adverse events were generally mild or moderate

Laboratory abnormalities were infrequent, transient, mild, and considered unrelated to

study drug.

Pharmacokinetics

Dose-related systemic exposure

Doses >200 mg produced peak and 24-hour trough concentrations that were multifold

above the 50% and 90% HBV inhibitory concentrations in cell culture. Conclusions:

NVR 3-778 is undergoing phase 1b testing in HBV patients

Gane EJ, et al. Hepatology. 2014;60(suppl 1). Abstract LB-19.


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Evaluation and Outcomes Measurement Process

You will receive an electronic initial evaluation to the email addressprovided within 1 business day

Reminder email communications will be sent up to 5 days post lecture until

the evaluation is completed

Incomplete evaluations may preclude attendees from receiving their

CME/CNE/CPE certificate & future communications about lectures in yourarea

In addition, you will receive a long-term evaluation via email 8 to 12 weeks

after completing this course to measure competence, performance, and/or

patient outcomes achieved as a result of your participation in thisCME/CNE/CPE sponsored educational activity

(Please note: If you attended mult ip le Simp ly Speakinglectures thro ugh out the year, a separate

in i t ia l and long-term evaluat ion w il l be sent to you for each lecture.)

AASLD 2014 HBV Post Conference Update 11-21-14

Documents

Transcript of AASLD 2014 HBV Post Conference Update 11-21-14