AASLD 2014 HBV Post Conference Update 11-21-14

Post Conference HBV Update
65th Annual Meeting of the

American Association for the Study of Liver Diseases
This activity is jointly provided by the

University of Nebraska Medical Center
and Practice Point Communications
Supported by an independent educational grant from

Gilead Sciences Medical Affairs
Simply Speaking Hepatitis Post Conference HBV Update: 65th Annual Meeting of the American Association for the Study of Liver Diseases is
Copyrighted 2014 by Practice Point Communications, unless otherwise noted. All rights reserved.
Created in collaboration with:

Robert G. Gish MD and the Practice Point Team at Simply Speaking
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
Program Overview
Epidemiology, diagnostics, and disease progression
Treatment
Clinical trials
Real-life settings
HBV reactivation and transplantation

Investigational HBV therapy
Serologic Testing Rates Among a National Cohort of

US Veterans With HBV
Retrospective cohort study of
Baseline Characteristics
regular recipients of VA care

(1999-2013; n=16,718,862)
HBsAg
Positive
Cohort
(n=21,828)
National database (claims, clinical
data, pharmacy records, death)

HBsAg tested (15%)
HBsAg positive (0.9%)
Outcomes
Rates of serologic testing, initiation
of anti-viral treatment, and HCC

screening
Prevalence and risk factors for
adverse clinical outcomes
Age
Median (years)
>50 years (%)
52
60
Male (%)
94
White/Black/Asian/AI-HP (%)
52/41/5/2
HCV coinfection (%)
17
HIV coinfection (%)
Cirrhosis (ICD-code x 2) (%)
Significant alcohol use (AUDIT-C) (%)
39
ALT >2x ULN (%)
32
Speciality care referral (GI/ID) (%)
31
AI-HP: American Indian-Hawaiian Pacific.

Serper M, et al. Hepatology. 2014;60(suppl 1):230A-231A. Abstract 68
Process Outcomes Among a National Cohort of US

Veterans With HBV by Speciality Care Referral
No speciality care (n=6744)
Speciality care (n=15,084)
99%
HBsAg Positive US Veterans (%)
100
80
73%
73%
65%
60
61%
59%
49%
44%
40
34%
33%
29%
27%
20
18%
15%
11%
10%
5%
ALT
HBV DNA
17%
HBeAg
Anti-HBe Anti-HAV Anti-HDV
Laboratory Testing
1.4% 3%
HCC
HAV
Vaccination Screening
If ALT
>2x ULN
Antiviral Therapy
Overall
*P<0.001 for speciality care versus no speciality care.

Clinical Outcomes and All-Cause Mortality Among a

National Cohort of US Veterans With HBV
Clinical outcomes (IRR speciality/
no speciality care)
Predictors of All-Cause Mortality

(Adjusted Hazard Ratio)
HCC: 0.52 (P<0.001)
2000-2010
(n=14,611)
2010-2013
(n=7217)
Age (1-year increase)
1.06*
1.06*
Significant EtOH use
5.18*
2.47*
Hepatic decompensation
3.60*
5.93*
Anti-viral therapy
0.96
0.83*
HCC screening (1x test)
0.80*
0.64*
HIV coinfection
1.60*
1.96*
HCV coinfection
1.10*
1.06
ALT 2x ULN
1.18*
1.09
Hepatic decompensation: 1.97
(P<0.0001)
Death rate: 1.05 (P=0.067)
Antiviral therapy (2010-2013) and
HCC screening were significantly

associated with a significantly lower
mortality
Adjusted for gender, age, speciality care referral, medical

comorbidities. *P<0.05.
IRR: incidence rate ratio (per 1000 person-years), unadjusted for anti-viral therapy.
Summary and Conclusions of Serologic Testing

Among 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 improve
guidelines adherence and clinical outcomes in HBV
Multiplex PCR Assay:

Simultaneous Detection of Hepatitis A, B, C, D, and E
TaqMan Array Card (TAC) technology
Sensitivity and Specificity
Real-time PCR assay
(Viral Hepatitis TAC)
Requires 20-46 L total nucleic acid

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
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
Impact of Race on the Risk of HCC Among US

Veterans With Chronic HBV Infection
Retrospective cohort study
VA Corporate Data Warehouse
HBV
Cohort
(n=10,421)
Diagnosed with HBV during 2001-2011 with >1 year of
follow-up
Mean age (years)
51
Male (%)
96
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
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
Black: 29.9
Mittal S, et al. Hepatology. 2014;60(suppl 1):972A. Abstract 1609.
10
Impact of Race on the Risk of HCC Among US

Veterans With Chronic HBV Infection
Adjusted hazard ratio for risk of
Time to HCC
developing HCC (relative to white race)

50
Asian: 2.99 (P<0.05)
White
Black
Asian
Other
Other: 1.77 (P=NS)
Other factors significantly associated
with a higher risk of developing HCC

included
Baseline cirrhosis (versus no; P<0.05)
HCV coinfection (versus no; P<0.05)
HCC-Free Survival (%)
Black: 1.07 (P=NS)

40
30
20
10
HBeAg positive or unknown (versus
negative; P<0.05)
0
HBV DNA level unknown (versus
negative; P<0.05)
Mittal S, et al. Hepatology. 2014;60(suppl 1):972A. Abstract 1609.
10
Time (years)
11
Impact of Antiviral Therapy on HCC Incidence:

San Francisco Bay Cohort
Retrospective cohort study (1991-2014)
Consecutive HBV patients from 2
Not
Treated
(n=1983)
Treated
(n=1238)
Age (years)
46*
45
Male (%)
55*
66
Asian/White (%)
93/2
98/<1
Family history (%)

HBV
HCC
29*
12*
30
13
Alcohol history (%)
23*
32
Median follow-up (months)
44
53
Cirrhosis (%)
17*
40
3.59*
5.5
31*
55
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
HBeAg positive (%)

HBV DNA (log10 IU/mL)
ALT (U/L)
*P<0.0001 versus treated arm.
Lin D, et al. Hepatology. 2014;60(suppl 1):315A-316A. Abstract 232.
12
Predictors of HCC in a San Francisco Bay Cohort

HCC incidence
Predictors of Developing HCC

(Adjusted Hazard Ratio)
(cases per 1000 person-years)

Overall: 6.6
Adjusted HR
(95% CI)
P
Value
Male
2.8
(1.5-5.2)
0.001
>45 years of age

(versus <45 years)
2.8
(1.5-4.9)
0.001
Cirrhosis
(versus no cirrhosis)
17.3
(10.1-29.8)
<0.001
Treated
(versus not treated)
0.43
(0.23-0.79)
0.007
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.
Not associated with HCC development were: HBeAg positivity,

ALT >2x ULN, HBV DNA >20K IU/mL.
13
ALBATROS Study: Predictors of HBsAg

Seroclearance in Untreated, European HBV Cohort
European untreated HBeAg-negative HBsAg
HBsAg Seroclearance and

HBsAg and HBV DNA Levels
carriers (n=583)
Analyze dynamics parameters (HBsAg, HBV
DNA, ALT, liver stiffness) within the first and

second year of follow-up to predict HBsAg
seroclearance
normal limits for BMI, ALT/AST, GGT, lipids)

HBsAg: 5049 IU/mL; HBV DNA 2.3 log10 IU/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<0.001)
Among those with HBsAg seroclearance,
there was a more rapid log decay of

qHBsAg during the first year follow-up
versus those without HBsAg seroclearance
Knop V, et al. Hepatology. 2014;60(suppl 1):977A Abstract 1618.
4
Log Concentration
Not candidates for antiviral therapy (within
HBsAg seroclearance
No (n=174)
Yes (n=10)
3
2
1
0
-1
Baseline
1 Year
HBsAg
Baseline
1 Year
HBV DNA
14
HBsAg Seroclearance:
Analysis of a Large Multi-Center US Cohort
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)
HR: hazard ratio adjusted for age, sex, HBeAg, practice type, HBV DNA at baseline.
Nguyen LH, et al. Hepatology. 2014;60(suppl 1):1005A-1006A Abstract 1679.
15
Program Overview
Treatment
Clinical trials
Real-life settings

16
Study 103 and 102: 8-Year Tenofovir DF Treatment

for Patients With Chronic HBV
Randomization
2:1
Study 103*
HBeAg-Positive
Treatment-Nave
48 Weeks
Double-Blind
8 Years
Open-Label
Tenofovir DF 300 mg
Tenofovir DF 300 mg
Adefovir 10 mg
Tenofovir DF 300 mg
Study 102*
HBeAg-Negative
Lamivudine nave or
experienced
Week 0
48
Liver
Biopsy
72
96
384
Current
Analysis
*Pretreatment liver biopsy. Other eligibility criteria: age 18-69 years, compensated liver disease, HBV DNA >106 copies/mL,
ALT >2 x ULN and <10 x ULN, Knodell necroinflammatory score >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.
Marcellin P, et al. Hepatology. 2014;60(suppl 1):313A-314A Abstract 229.
17
Study 103 and 102:

HBeAg Negative
(n=375)
HBeAg Positive
(n=266)
44
34
65/25/10
52/36/12
ALT (U/L)
140
147
HBV DNA (log10 copies/mL)
6.1
7.6
Cirrhosis (%)
24
24
Viral genotype (%)

A
B
C
D
Other
11
11
11
64
3
23
13
26
33
5
Age (years)
Race (%)
Caucasian/Asian/other
18
Tenofovir DF in Chronic HBV: HBeAg Negative

Patients Achieving HBV DNA <400 Copies/mL (ITT)
Double-Blind
100
93%
80
Patients (%)
Open-Label
(Study 102)
P<0.001
75%
60
(combined)
63%
40
TDF to TDF
ADV to TDF
20
Year 8 observed response: 99.6%
24
48
72
96
120
144
168
192
216
240
384
Weeks
Long-term evaluation (missing=failure; adding FTC=failure). 18% of patients were lamivudine experienced, of these
93% and 96% of TDF to TDF and ADV to TDF patients, respectively, had HBV DNA <400 copies/mL at week 96.
19
Tenofovir DF in Chronic HBV: HBeAg Positive Patients

Achieving HBV DNA <400 Copies/mL (ITT)
Double-Blind
100
80
Patients (%)
Open-Label
(Study 103)
76%
60
58%
P<0.001
(combined)
TDF to TDF
ADV to TDF
40
20
13%
Year 8 observed response: 98.0%
24
48
72
96
120
144
168
192
216
240
384
Weeks
Long-term evaluation (missing=failure; adding FTC=failure).
20
Tenofovir DF in Chronic HBV:

Cumulative Probability of HBsAg Loss
Double-Blind
Open-Label
(Study 103)
0.16
12.9% (n=28, ITT)
0.14
Probability
0.12
0.1
0.08
TDF to TDF
ADV to TDF
0.06
0.04
0.02
0
24
48
72
96
120
144
168
192
216
240
288
336
384
Weeks on Treatment
Baseline predictors for HBsAg loss (multivariate):
Caucasian race, genotype A or D, <4 years of HBV infection, HBsAg level.
21
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 (<1.0%)

Attributed to documented non-adherence in the majority of cases
Tenofovir DF was well tolerated

Discontinuations due to adverse events: 2.2%
Dose reduction, treatment interruption, or discontinuation for a renal event: 3.4%
Creatinine >0.5 mg/dL above baseline (2.2%)
Phosphate <2.0 mg/dL (1.7%)
Creatinine clearance <50 mL/min (1.0%)
No evident loss in bone mineral density (by DXA) during follow-up years 4 to 8
22
Durability of HBeAg Seroconversion With

Tenofovir DF or Entecavir for Chronic HBV Infection
Retrospective, chart review
Community (n=7) and academic (n=4)
Patients
(n=54)
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)

High-level virologic relapse
(reappearance of HBV DNA >2000 Iu/mL)
Median age (years)
43
Male (%)
63
Asian/foreign born (%)
94/85
Prior treatment (%)

Nave (ETV/TDF/both)
Experienced (ETV/TDF)
64/33/3
43/57
Time to (months)
Undetectable HBV DNA
HBeAg seroconversion
11
21
Consolidation period
(months)
Follow-up after treatment
discontinuation (months)
16.8
30.3
HBeAg seroconversion (reappearance of HBeAg)

Fong T-L, et al. Hepatology. 2014;60(suppl 1):1121A-1122A Abstract 1912.
23
Outcomes Following HBeAg Seroconversion With

Outcomes
High-Level Virologic Relapse
Remission: 7% (4/54)
HBsAg negative and anti-HBs positive (n=1)
(Cumulative Probability)
100
Low-level virologic relapse: 24% (13/54)

80
Became HBV DNA undetectable during

Maintained ALT <2x ULN (n=13)
None reverted to HBeAg positive
High-level virologic relapse: 69% (37/54)

ALT >2x ULN (n=18)
HBV DNA levels were similar between those with

normal and abnormal ALT
Relapse (%)
follow-up (n=10)
60
40
20
HBeAg negative/anti-HBe positive (n=23)

HBeAg positive (n=12, 9 were anti-HBe
negative)
HBeAg and anti-HBe negative (n=3)
0
0
12
24
36
Time to Relapse (months)
48
24
Durability of HBeAg Seroconversion With

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

Age <45 years: 81.3% versus 47.4% (P=0.02)
No prior treatment: 81.3% versus 52.6% (P=0.003)
Prior entecavir treatment: 87.5% versus 42.1% (P=0.009)
Time to relapse: 8.3 versus 4.4 months (P=0.026)
Conclusions
Durability of HBeAg seroconversion with entecavir and tenofovir was not superior to
patients treated with older nucleoside analogues

HBeAg seroconversion should not be considered as a treatment end-point for HBeAg-
positive HBV patients

Therapy with nucleoside analogues should be continued indefinitely until achievement of
HBsAg seroconversion
25
Tenofovir DF + Entecavir in Entecavir-Resistant

Chronic HBV Infection
Open-Label
HBV DNA >60 IU/mL
Entecavir resistance mutations
(T184A/C/F/G/I/L/S, S202G, M250L/V)
No adefovir resistance
No previous tenofovir DF use
Compensated liver disease
(Child-Pugh A)
No HCV, HIV, or malignancy
Serum creatinine <1.5 mg/dL
Week 0
Tenofovir DF 300 mg qd
(n=45)
Tenofovir DF 300 mg qd + Entecavir 1 mg qd
(n=45)
24
48
Primary endpoint: HBV DNA <15 IU/mL.

Baseline demographics:
Male: 76%.
Mean age: 51 years.
HBeAg positive: 89%.
HBV DNA: 4.02 log10 IU/mL.
Cirrhosis: 23%.
ALT: 33 IU/L.
Serum albumin: 4.4 g/dL.
Serum creatinine: 0.9 mg/dL.
Duration of prior NRTI treatment: 78 months.
Lim Y-S, et al. Hepatology. 2014;60(suppl 1):315A Abstract 231.
26
Treatment Outcomes With Tenofovir DF + Entecavir in

Entecavir-Resistant Chronic HBV Infection
No significant difference between
tenofovir DF versus tenofovir DF +

entecavir in achieving complete
virologic response and reduction in
HBV DNA levels
Treatment Outcomes (Week 48)

Tenofovir DF
(n=45)
Tenofovir DF
+ Entecavir
(n=45)
71
73
-3.65
-3.74
-4.72 (n=15)
-5.32 (n=10)
100
7
100
4
No additional mutations
Treatment-emergent
resistance (%)
Both regimens were well tolerated
Discontinuations due to
adverse events (%)
Predictors of virologic response at
week 48
Prior adefovir exposure (OR: 0.14;
P=0.02)
HBV DNA level (OR: 0.33; P<0.001)
Marked decrease in pre-existing
resistance mutations
HBV DNA <15 IU/mL (%)

Change in HBV DNA
(log10 IU/mL)
Overall
Baseline HBV DNA
>5 log10 IU/mL
Detectable HBV
resistance mutations (%)
Baseline
Week 48
OR: odds ratio (multivariate analysis).

Lim Y-S, et al. Hepatology. 2014;60(suppl 1):315A Abstract 231.
27
ESTEEM Study: Tenofovir DF + Entecavir for MultiDrug Resistant Chronic HBV

Open-Label, Prospective,
Multicenter Study
Genotypic resistance from 2 different
classes of nucleoside analogues
Class A (lamivudine, clevudine,
telbivudine, entecavir)
Class B (adefovir, tenofovir DF)
HBV DNA >60 IU/mL on any rescue
HBV regimen (>24 weeks)
Compensated liver disease
(Child-Pugh A)
Tenofovir DF 300 mg qd + Entecavir 1.0 mg qd

(n=64)
Week 0
24
48
Primary endpoint: HBV DNA <60 IU/mL.

Baseline demographics:
Male: 81%.
Mean age: 47 years.
HBV DNA: 4.29 log10 IU/mL.
Cirrhosis (medical history): 12.5%.
ALT: 29 IU/L.
Previous courses of antiviral therapy: 3.
Creatinine clearance: 105.8 mL/min.
Park JY, et al. Hepatology. 2014;60(suppl 1):1096A Abstract 1865.
28
ESTEEM Study: Outcomes With Tenofovir DF +

Entecavir for Multi-Drug Resistant Chronic HBV
High virologic response among
patients with multi-drug resistant

chronic HBV
Treatment Outcomes (Week 48)

Tenofovir DF +
Entecavir
(n=64)
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
HBV DNA (%)

<60 IU/mL
<12 IU/mL
Change in HBV DNA (log10 IU/mL)
86
63
-2.39
ALT normalization (%)
26
HBeAg loss (%)
3.5
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.
HBeAg seroconversion (%)
HBsAg loss
29
C-TEAM Study: Long-Term Entecavir and Incidence of

HCC in Chronic HBV Infection
Multi-center observational cohort
(24 Taiwanese academic centers)
Entecavir
(n=1123)
Controls
(n=503)
Age (years)
55*
51
Male (%)
74
77
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 (%)
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
Hepatic encephalopathy (%)
<1%
<1%
HCC cases: 121
Liver decompensation (%)
<1%
*P<0.001 versus controls.

EV/GV: esophageal varices/gastric varices.
Su T, et al. Hepatology. 2014;60(suppl 1). Abstract LB-30.
30
C-TEAM Study: Long-Term Entecavir and Incidence of

HCC in Chronic HBV Infection
Long-term entecavir therapy
Life Time HCC Incidence
significantly reduced the development

of HCC and spontaneous bacterial
peritonitis compared with controls
Entecavir (versus no entecavir): 0.40
(P<0.001)
Male (versus female): 1.89 (P=0.003)
No difference between the entecavir
and historical control arms
Adjusted HR: 0.40

P<0.001
0.8
Failure Estimate
Hazard ratios for lifetime risk of HCC
No
Treatment
0.6
0.4
0.2
Entecavir
Variceal bleeding, hepatic
encephalopathy, liver transplantation
20
30
40
50
60
70
80
Age (years)
Su T, et al. Hepatology. 2014;60(suppl 1). Abstract LB-30.
31
HERMES Study (Interim Analysis): PegIFN Add-On

Therapy in HBV Genotype D Patients
Phase 3b Study
Open-label, multicenter (13 sites)
HBV (genotype D)
HBeAg negative
On nucleoside analogue therapy
HBV DNA <20 IU/mL for >12 months
and HBsAg >100 IU/mL
PegIFN
Add-On Period
Observation
Period
Week -12
Follow-Up
Nucleoside Analogue Therapy
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 years
BMI: 25.4 kg/m2.
ALT: 20 U/L
HBsAg at screening/start of pegIFN: 1163/1160 IU/mL
Lampertico P, et al. Hepatology. 2014;60(suppl 1). Abstract LB-31.
32
HERMES Study (Interim Analysis): PegIFN Add-On

Therapy in HBV Genotype D Patients
At week 24 of add-on therapy
>50% decrease in HBsAg achieved in 27% of
patients
Treatment Outcomes
With PegIFN Add-On
Weeks on
PegIFN Add-On
Lack of response (discontinued study): 16%

Increase in the proportion of patients with
HBsAg <500 or <1000 IU/mL compared with

baseline
Safety
Discontinuation due to adverse events: 4.3%
PegIFN dose adjustment due to adverse
events: 8.6%
Mean change from

baseline in HBsAg
(IU/mL)
Proportion of patients
with HBsAg (%)
<1000 IU/mL
<500 IU/mL
Baseline
12
24
(n=70)
(n=67)
(n=66)
--
-213.8*
-533.9*
33
16
32
20
39
26
Serious adverse events: 2.9% (one case of
hemoptysis judged related to pegIFN)

Most common adverse events: mild or
moderate musculoskeletal pain/myalgia,

pyrexia, asthenia
Lampertico P, et al. Hepatology. 2014;60(suppl 1). Abstract LB-31.
33
ENTEBE Study: Entecavir + Tenofovir DF in HBV

Patients Who Were Previous NRTI Treatment Failures
European, open-label, phase 3b
study (n=92)
Patients
(n=9752)
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 <50 IU/mL at week 48
Zoulim F, et al. Hepatology. 2014;60(suppl 1):314A-315A Abstract 230.
Median age (years)
42
Male (%)
75
White (%)
76
3.7
HBeAg positive (%)
62
Anti-Hbe positive (%)
36
HBV genotype (%)

A/D
Resistance mutations (%)
(Sequence available [n=78])
Any mutation
Lamivudine
Entecavir
Adefovir
32/54
58
52
26
7
34
ENTEBE Study: Treatment Outcomes With Entecavir

+ Tenofovir DF in Previous NRTI Treatment Failures
Low baseline HBV DNA level was a
predictor of virologic response
Treatment Outcomes
Week 96
Response
(%)
Of the patients not achieving HBV DNA
<50 IU/mL (n=14)

HBV DNA detectable (n=6)
Discontinued (n=6)
Missing (n=2)
Resistance
No treatment-emergent resistance through
week 96 (n=6 with evaluable samples)
Regimen was well tolerated
HBV DNA <50 IU/mL

Overall (n=92)
By prior NRTI regimen
Entecavir (n=48)
Tenofovir DF (n=11)
Adefovir (n=4)
Lamivudine (n=20)
Adefovir + lamivudine (n=4)
Other (n=4)
85
88
82
100
80
75
100
HBeAg loss (n=56)
Discontinuations due to adverse events (n=1)
HBeAg seroconversion (n=56)
Most common adverse events:
HBsAg loss (n=92)
HBsAg seroconversion (n=92)
nasopharyngitis, fatigue, nausea, dyspepsia
Zoulim F, et al. Hepatology. 2014;60(suppl 1):314A-315A Abstract 230.
35
Program Overview
Treatment
Clinical trials
Real-life settings
36
ENUMERATE Study: Long-Term Entecavir and

Incidence of HCC in Chronic HBV Infection
Retrospective, observational study (n=745)
US national cohort of community (n=10) and
Patients
(n=745)
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, ALT
normalization, HBeAg seroconversion

Secondary: HCC, cirrhosis, hepatic
decompensation, liver transplantation, death,

adverse events
Ahn J, et al. Hepatology. 2014;60(suppl 1):1099A Abstract 1870.
Age (years)
47.0
Male (%)
63.1
Asian/Black/White/other (%)
84/4/8/4
Family history of HCC (%)
10.5
HBeAg negative/positive (%)
46/26
Cirrhosis (%)
9.3
Hepatic decompensation (%)
1.2
5.7
ALT/AST (U/L)
58/41
Albumin (g/dL)
4.3
Total bilirubin (mg/dL)
0.7
INR
1.1
37
ENUMERATE Study: Long-Term Entecavir and

Incidence of HCC in Chronic HBV Infection
Development of HCC after 5 years
Time to Incident HCC
Overall: 3.5%
25
Non-cirrhotic: 2.0%
Cirrhotic: 14%
20
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 HBeAg
status
HCC surveillance remains warranted in
patients on antiviral therapy for HBV

Ahn J, et al. Hepatology. 2014;60(suppl 1):1099A Abstract 1870.
HCC (%)
Patients who developed HCC were

15
Cirrhotic
10
P<0.001
5
Non-Cirrhotic
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 5.0

Time to HCC (years)
38
Program Overview
Treatment
Clinical trials
Real-life settings

39
HBV Reactivation in Patients Treated With Anti-Tumor

Necrosis Factor Agents
Retrospective study (2001-2012)
Kaiser Permanente Northern California
Patients
(n=8887)
Patients on anti-TNF (n=8887)

Age (years)
49
Male (%)
38
Time on anti-TNF (months)
41
Treated by (%)
Dermatology
Rheumatology
Gastroenterology
More than 1
24
53
13
10
1 log increase in HBV DNA from baseline
Steroids + immunosuppressants (%)
41
HBV DNA >2000 IU/mL (if no baseline)
Anti-TNF agent (%)

Infliximab
Adalimumab
Etanercept
More than 1
24
12
33
32
Followed until death, liver transplant, or end
of membership
Electronic medical review

All cases of grade 3/4 hepatotoxicity
AST/ALT >5x ULN or 5x baseline
HBV reactivation
HBV DNA positive when previously negative

HBsAg positive when previously negative
Pauly MP, et al. Hepatology. 2014;60(suppl 1):232A-233A Abstract 72.
40
HBV Testing Status and Reactivation in Patients

Treated With Anti-Tumor Necrosis Factor Agents
HBV testing at baseline increased from 37%
HBV Status at Baseline
(2001) to 72% (2010)

HBV testing status of overall cohort at baseline
100
Tested/never tested/others: 52%/27%/21%
HBV reactivation (n=9)
80
Percent of
Total cohort (n=8887)
Tested for HBV (n=4621)
95.7%
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)
Patients (%)
HBsAg positive (n=7, none received
60
49.7%
40
20
Clinical approach to reactivation

Discontinued anti-TNF therapy (n=3)
HBV antiviral therapy, all responded (n=6)
0.3% 0.5%
HBsAg
Positive
2.0% 3.9%
HBcAb Positive HBsAg Negative
HBsAg Negative HBcAb Negative
No hospitalizations, liver failure, or death

41
HBV Reactivation in Patients Treated With Anti-Tumor

Necrosis 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 performed
if grade 3/4 hepatotoxicity develops

Further studies are needed to identify best HBV screening strategies among patients
taking anti-TNF therapy
42
PREBLIN Study:
Prophylaxis of HBV Reactivation With Tenofovir DF
Ongoing, prospective, open-label study
(n=69)
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-Hodgkin
lymphoma (%)
77.8
83.3
Chronic lymphatic
leukemia (%)
16.7
16.7
HBeAg-positive and -negative patients
HBV DNA undetectable before starting
rituximab for hematologic malignancies

HBV reactivation
HBV DNA elevation >1 log10 IU/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.
43
PREBLIN Study: Preliminary Results of Tenofovir DF

as Prophylaxis of HBV Reactivation
Preliminary analysis showed tenofovir
HBV Reactivation
(12-Month Preliminary Analysis)
DF prophylaxis prevented HBV

reactivation
No statistically significant difference in
20
liver and renal function between the 2

arms
arm (n=2)
Elderly man (anti-HBs positive) and
women (anti-HBs negative)

HBV DNA elevation >1 log10 IU/mL from
baseline at 4 month visit
15
Patients (%)
HBV reactivation in the observation
16.7%
P=0.152
10
ALT <40 U/L
Rescue therapy
Tenofovir DF, both patients HBV DNA
undetectable at 6-month visit

Buti M, et al. Hepatology. 2014;60(suppl 1):997A Abstract 1661.
0%
Tenofovir DF
(n=18)
Observation
(n=12)
44
Differences in Wait-Listing Trends for Liver

Transplantation Between Patients With HBV and HCV
All liver transplant wait-listed candidates
HCV
HBV
NASH
(n=31,530)
(n=3390)
(n=7935)
Age (years)
55
54
60
Recipients (n=124,289)
Male (%)
75
80
54
HBV, HCV, and NASH: 34.5%
White (%)
67
33
79
Diabetes (%)
18
18
55
BMI (kg/m2)
28
26
32
MELD indication at
wait listing
17
16
19
60
40
52
48
82
18
in the US
Scientific Registry of Transplant
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)
Indications for wait

listing (%)
ESLD
HCC
HCC (received HCC MELD exception
<180 days of listing)

Flemming JA, et al. Hepatology. 2014;60(suppl 1):208A Abstract 22.
45
Liver Transplant Wait-Listing Trends by Indication

(2003-2013)
Hepatocellular Carcinoma
End-Stage Liver Disease

7
10
4.55
6
HCV
5
5.20
4.49
4
3
2.76
NASH
2
1
0.80
0.63
HBV
SIR per 100,000 Population
SIR per 100,000 Population
HCV
2.25
NASH
1.0
0.38
HBV
0.64
0.50
0.1
0.08
0.35
03 04 05 06 07 08 09 10 11 12 13
Calendar Years
0.01
03 04 05 06 07 08 09 10 11 12 13
Calendar Years
SIR: standardized incidence rates.
46
Liver Transplant Wait-Listing Trends by Indication

(2003-2013)
HBV
Average Annual Change

per Wait Listing Year
Dramatic decrease in the rate of wait
listing for ESLD with stabilization of the

rate for HCC
20
Likely reflects the success of effective
HCV
Slight decrease in wait listing for ESLD
Rate of wait listing for HCC continues to
rise
NASH
Rates of wait listing continue to
15
Incidence Rate Ratio (%)
all-oral antiviral therapy
Wait Listing
Overall
ESLD
HCC
14.5%
11.0%
10%
10
9.3%
5
+2.8%
0.1
0
-1.0%
-5
-1.1%
-4.2%
increase for ESLD and HCC

-10
HCV*
HBV*
NASH*
*P<0.05 for all annual changes except for HCC under HBV.
47
Program Overview
Treatment
Clinical trials
Real-life settings
48
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 log10 decline: 75%
ALT normalization: 55%
No significant changes in HBsAg levels
Cohort B (HDV): HDV RNA >1 log10 decline: 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.
49
ARC-520 (siRNA-Based Therapeutic) in Patients With

Chronic 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.
50
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.
51
Evaluation and Outcomes Measurement Process

You will receive an electronic initial evaluation to the email address
provided 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 your

area
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 this
CME/CNE/CPE sponsored educational activity
(Please note: If you attended multiple Simply Speaking lectures throughout the year, a separate
initial and long-term evaluation will be sent to you for each lecture.)
52

AASLD 2014 HBV Post Conference Update 11-21-14

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AASLD 2014 HBV Post Conference Update 11-21-14

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Post Conference HBV Update

65th Annual Meeting of the

This activity is jointly provided by the

Supported by an independent educational grant from

Created in collaboration with:

recommendations from the AASLD guidelines

side effect, drug-drug interactions, and resistance

information-based decision making about therapy

HBV reactivation and transplantation

Serologic Testing Rates Among a National Cohort of

regular recipients of VA care

National database (claims, clinical

data, pharmacy records, death)

of anti-viral treatment, and HCC

adverse clinical outcomes

HCV coinfection (%)

HIV coinfection (%)

Cirrhosis (ICD-code x 2) (%)

Significant alcohol use (AUDIT-C) (%)

ALT >2x ULN (%)

Speciality care referral (GI/ID) (%)

AI-HP: American Indian-Hawaiian Pacific.

Process Outcomes Among a National Cohort of US

HBsAg Positive US Veterans (%)

Anti-HBe Anti-HAV Anti-HDV

*P<0.001 for speciality care versus no speciality care.

Clinical Outcomes and All-Cause Mortality Among a

Predictors of All-Cause Mortality

HCC: 0.52 (P<0.001)

Age (1-year increase)

Significant EtOH use

HCC screening (1x test)

Hepatic decompensation: 1.97

Antiviral therapy (2010-2013) and

HCC screening were significantly

Adjusted for gender, age, speciality care referral, medical

Summary and Conclusions of Serologic Testing

guidelines adherence and clinical outcomes in HBV

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

Multiplex PCR Assay:

Sensitivity and Specificity

Real-time PCR assay

(Viral Hepatitis TAC)

Requires 20-46 L total nucleic acid

extract from 200 L of serum

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

Impact of Race on the Risk of HCC Among US

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

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

HCC incidence rate: 32.3/1000 person-years

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

HCV coinfection (%)

HIV coinfection (%)

HBV DNA (%)

Impact of Race on the Risk of HCC Among US

developing HCC (relative to white race)

Asian: 2.99 (P<0.05)

Other: 1.77 (P=NS)

Other factors significantly associated

with a higher risk of developing HCC

HCC-Free Survival (%)