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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.
Baseline Characteristics
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
HBV reactivation and transplantation
Investigational HBV therapy
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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
Marcellin P, et al. Hepatology. 2014;60(suppl 1):313A-314A Abstract 229.
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
Marcellin P, et al. Hepatology. 2014;60(suppl 1):313A-314A Abstract 229.
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.
Baseline Characteristics
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
43/57
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.
Baseline Characteristics
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
HBV reactivation and transplantation
Investigational HBV therapy
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.
Baseline Characteristics
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
Epidemiology, diagnostics, and disease progression Treatment
Clinical trials
Real-life settings
HBV reactivation and transplantation
Investigational HBV therapy
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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.
Baseline Characteristics
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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46
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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4848
Program Overview
Epidemiology, diagnostics, and disease progression Treatment
Clinical trials
Real-life settings
HBV reactivation and transplantation
Investigational HBV therapy
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.)