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63rd Annual Meeting of the
American Association for the
Study of the Liver Disease
(63rd AASLD)
Boston, Massachusetts
November 9-13, 2012
Epidemiology and Natural
History of HBV Infection
Tram Tran, MD
Cedars Sinai Medical Center
Los Angeles, CA
HBV Discovered in Korean Mummy
Dated to the 16th Century
• Laparoscopic liver biopsies performed on
mummified Korean child dated to 16 A.D.
• Complete sequence of the oldest HBV isolate
and the most ancient full viral genome known
so far
• Genome (3,215 base-pairs) analysis of the
ancient HBV revealed a unique HBV genotype
C2 (HBV/C2) sequence commonly spread in
Southeast Asia
• Comparison of the ancient genome with
contemporary HBV/C2 DNA sequences
from various regions in East Asia showed
significant differences
• Sequence likely dates back to 3,000-100,000
years ago
Bar-Gal G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 927.
HBV DNA level: Most Important Predictor
of HBV DNA and HBsAg Seroclearance
HBV DNA Undetectable and HBsAg
Loss at 1-2 Years by HBV DNA Level
• Cumulative HBsAg clearance 3%
• Multivariate analysis showed HBV
DNA level and APRI* score
significantly associated (p<0.0001)
with HBsAg clearance
• Conclusion: HBV DNA level is the
strongest predictor of HBV DNA
and HBsAg seroclearance in HBV
inactive carriers (untreated
HBeAg-negative HBsAg carriers)
*APRI = AST-platelet ratio index
Knop V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 349.
Percent
• Study to prospectively analyze
factors for HBV DNA and HBsAg
clearance in HBeAg-negative
patients (N=163 pts; 2 year
follow-up)
Predictors of HBsAg
Seroclearance in CHB
• 3, 014 patients in multicenter U.S. cohort retrospectively enrolled from 2001-2011
• HBsAg clearance in 26 patients over 11,751 person-years
− 0.22% annual clearance and 0.86% overall rate
• Higher annual clearance associated with male gender, HBeAg-negative and HBV
DNA ≤ 10,000 IU/mL
Annual Incidence of HBsAg Seroclearance by Various Patient Characteristics
Among Treatment Naïve Patients
p=0.24
p=0.05
(n=1162) (n=1417)
(n=1480) (n=1099)
(n=612) (n=1967)
p=0.11
Percent
p=0.01
(n=2579)
Gender
Age
Baseline HBeAg
(n=1286) (n=1293)
Baseline HBV DNA
(IU/mL)
• Conclusion: HBsAg seroclearance rates may be lower than previously described,
with or without treatment
Nguyen LH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 328.
Long Term Follow-up of Inactive HBV
Carriers and Relation with HBsAg Levels
• HBeAg-negative, untreated, normal ALT level patients deemed “inactive
carriers” with HBV DNA <2,000 IU/ml (N=170) followed for mean of 4.3 years
• 1 year 13% became active 2 years 25%5 years 37%
• Baseline HBV DNA <2000 IU/ml and HBsAg level <100 IU/ml predictive of
remaining inactive
HBV DNA < 200 IU/ml
HBsAg<1000 IU/ml
HBsAg>1000 IU/ml
P<0.001
HBV DNA > 200-2000 IU/ml
P<0.001
• Conclusion: Combination of HBV DNA and HBsAg gave 100% prediction of
remaining inactive carrier
Hansen BE, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 338.
Lamivudine in pregnancy: Impact
on HBV Flares and HBeAg
Seroconversion Post Partum
• Antiviral therapy useful in pregnant CHB
patients to prevent flares and prevent mother
to child transmission of HBV, but risks of
therapy withdrawal unknown
• 64 pregnant CHB patients recruited 2007-2011
− LAM offered 32 weeks until 2-4 weeks postpartum
− Median age 29 years, f/u 11 months, baseline viral
load >108 logs
• 48 received LAM median treatment and 16
served as control
• First 3 months postpartum 29% LAM vs. 18%
control (p=NS) had flare (ALT >2XULN)
• Seroconversion occurred in 5 patients
− Postpartum flare not associated with
seroconversion
• Conclusion: Flares not higher after LAM use in
pregnancy and are usually mild
Tan PK, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 335.
Maximum ALT post partum
1000900800700600500-
(0-3 months
post partum)
(3-18 months
post partum)
300
200
100
Seroconversion by Genotype
Risk of HBV Vertical Transmission after
Amniocentesis in Mothers with CHB
Population Characteristics
• 63 infants born to mothers who had
amniocentesis compared to 198 matched
controls
− All infants had appropriate vaccinations
• Level of maternal viremia predicts risk of
transmission with amniocentesis:
Mothers
− No statistical difference in HBV transmission
when maternal viremia <6.99 log copies/ml
− Maternal viremia ≥107 log copies/ml: 50% amnio
vs. 4% controls (p=0.006)
• Amniocentesis performed on HBsAg-positive
mothers with HBV DNA ≥ 107 log c/mL
increased the risk of vertical transmission.
• Conclusion: HBsAg-positive women who plan
to have amniocentesis should be evaluated for
the risk of vertical transmission and stratified
by their HBV DNA levels
Pan C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 904.
Infants
Mean ±SD
(range)
Amniocentesis
Cases (n =63)
Controls (n=198)
P
Value
Age (years)
34±5.37 (20~42)
28 ±4.07 (18~41)
0.000
Primigravid
16/63
28 /198
0.052
Husband
HBsAg+
3 /63
8/198
0.804
Prior Infant
HBsAg+
3 /63
3 /I98
0.155
Log HBV DNA
(copies/mL)
3.78 ±1.80
(2.70~8.09)
5.05 ±2.24
(2.70~8.46)
0.000
Cesarean
Section
51 /63
129 /198
0.019
Gestation days
277.55 ±7.25
(255~292)
272.00±9.97
(215~291)
0.000
Mean ±SD
(range)
Amniocentesis
(n=63)
Controls
(n=198)
P
Value
Male
35 /63
103 /198
0.665
Weight (gm)
3384.13±505.5
2 (1200~4600)
3406.31±400.9
5 (2450~4500)
0.378
Length (cm)
49.86±3.08
(41~55)
50.18±0.88
(47~53)
0.419
Apgar at one
minute
9.95±0.22 (910)
9.93±0.30 (810)
0.366
Detectable
HBV DNA at
birth
3 /63
10 /198
1.000
HBsAg+ at
birth
10 /63
47 /198
0.222
Breast-fed
24 /63
63 /198
0.443
Hepatocellular carcinoma:
Incidence and Risk for CHB
patients on Antiviral therapy
• In a large US observational cohort
study, HBV antiviral therapy and HCC
relationship was studied using ICD9
codes/tumor registry and chart review
(2463 patients, follow-up 5 years)
Cox Multivariable Regression Model for Prediction of
Hepatocellular Carcinoma
− 779 received antiviral therapy
• 69 pts developed HCC
− 27% of these received antiviral therapy
• Factors associated with increased risk
of HCC included no antiviral therapy,
male gender, age >40 years at time of
CHB diagnosis and higher
comorbidity index.
• Conclusion: Despite antiviral therapy,
HCC can still occur, especially in an
older, male CHB population
Gordon SC, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 318.
Variable
Antiviral HBV therapy (received
vs. not received)
Hazard Ratio (95% CI)
P
0.50 (0.36-0.71)
<.001
Age
<.001
40-<50 years vs. ≤40years
7.54 (2.07-27.7)
.002
50-<60 years vs. ≤40years
9.69 (2.73-33.76)
<.001
≥60 years vs. ≤40years
23.3 (6.59-81.7)
<.001
Charlson/Deyo comorbidity index
<.001
Score of 1 vs. 0
1.38 (0.87-2.19)
.174
Score 2 or 3 vs. 0
2.15 (1.46-3.16)
<.001
1.94 (1.30-2.87)
.001
Male vs. female
Hepatocellular Carcinoma: Risk
Factors in CHB
• 11-year retrospective analysis of 101
HCC patients and with viral
suppression compared to matched
cohort
− 30% non-cirrhotic
− Median follow-up 35 months
• Multivariate analysis: age> 60, male
gender, and LAM use associated
with increased HCC risk
• Conclusion: Association of
lamivudine exposure with HCC
raises the possibility of
drug-induced mutations increasing
HCC risk
Ghaly S, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 332.
Multivariate analysis for HCC development
Odds Ratio 95% Confidence Interval
Age 60+
1.84
0.79-4.26
Male gender
1.94
0.93-4.06
HBeAg Positive
0.50
0.25-0.96
Lamivudine Exposure
3.1
1.6 – 6.1
Hepatocellular Carcinoma:
Incidence and Risk for Patients
with Family History of HCC
• Study in Taiwan of 22,472 individuals
with 18 year f/u and linkage to
national cancer registry
• 374 cases of HCC identified during
362,000 person/yrs of follow-up
• Family history of HCC and HBsAgpositive had synergistic interaction
with the risk of HCC in multivariableadjusted analysis (age-sex-BMIalcohol-smoking-ALT-DM)
(HR: 32.33, 95% CI [20.8-50.3], pvalue <0.01)
• Conclusion: HBV patients with family
history of HCC should be considered
very high risk for HCC.
Loomba R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 598.
Family History of HCC, HBsAg and HBeAg
Serostatus, HBV DNA level, and Risk of Incident HCC
40.0%
19.1%
17.6%
10.3%
5.4%
2.5%
0.64%
0.62%
Progression to Cirrhosis and
Mortality with CHB
• Study examining natural history of untreated CHB
patients over 25 years of follow-up
• 105 untreated CHB patients enrolled
−
−
−
−
Cumulative survival probability according to
HBV replication during follow-up
100%
79%
76% male
Mean age 30 years
64% HBeAg-positive
No evidence of cirrhosis
• 43% became inactive carriers
− 47% of these cleared HBsAg
• 30% became HBeAg-negative
• 30% developed cirrhosis (incidence rate 13/1000
person/years)
− Older age, male sex, absence of sustained remission
and sustained HBV replication predicted cirrhosis
Patients at risk
Inactive Carriers
HBeAg-/HBV-DNA+ or
HBeAg persistence
45
44
42
41
41
39
22
45
37
35
29
20
11
9
Cumulative survival probability according
to HBV cirrhosis occurrence
99%
• Inactive Carriers and patients without cirrhosis
had improved survival probability
• Conclusion: In Caucasian patients with CHB
without cirrhosis at presentation, progression to
cirrhosis is relatively slow but cirrhosis occurrence
strongly predict disease-related mortality
79%
Patients at risk
No Cirrhosis
Cirrhosis at follow-up
Fattovich G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 319.
73
32
64
32
61
31
60
24
57
17
51
12
27
6
Epidemiology and Factors Related
to Chronicity of Acute HBV
• Study of 350 patients with acute HBV
− 155 with one year f/u
− Male 76%; mean age 38 years; 9 HIV+;
50% sexual risk factor
Comparative clinical and biochemical characteristics of
the non-chronic and chronic evolution group
• Results:
− 96.7% resolution vs. 3.3% CHB
− Median time from symptoms to clearance:
HBeAg 23 days and HBsAg 111 days
• Development of CHB following acute
infection associated with lower ALT and
bilirubin during acute HBV and HIV+
status at time of infection
• Conclusion: HIV patients appear to
evolve more frequently to CHB and lower
values of biochemical markers appear
related to the evolution of acute hepatitis
B infection to CHB
Dirchwolf M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 320.
Autolimited
HBV (n=150)
Chronic
Evolution
HBV (n=5)
P
Value
36 (±12)
38 (±9)
0.76
Sex (men)
77% (n=115)
60% (n=3)
0.39
ALT (U/L)
2068 (±1309)
789 (±323)
0.01
Bilirubin
(Mg/dL)
10.5 (±7.3)
1.6 (±0.7)
0.001
5% (n=7)
40% (n=2)
0.003
Age (years)
HIV+
Rheumatoid Factor in CHB Reflects
Disease Activity and Stage
• Study evaluating role of Rheumatoid Factor
(RF) as marker of disease activity in CHB
R=0.94
• RF available in 378 CHB pts
− 53% Caucasian, 71% male, mean age 41 years
• 35% had positive RF and more likely in:
Older (47 vs. 37 yrs)
Female
Lower platelet counts (183 vs. 214)
Higher AST/platelet ratio index
Increased histologic activity on biopsy
• In CHB, RF may reflect disease activity and
advanced fibrosis, and disappearance of RF
correlates with virological response to
therapy.
Hernaez R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 342.
R=0.98
HBV DNA (Log IU/mL)
• RF titers increased during flares and
decreased on antiviral therapy
RF (IU/mL)
−
−
−
−
−
Performance of Transient
Elastography for Staging
Liver Fibrosis in CHB
• Meta-analysis to assess
performance of transient
elastography for fibrosis in HBV
patients
• A total of 18 studies comprising 2,772
patients were analyzed
Meta-analysis results of LSM cutoff values for staging liver fibrosis
Fibrosis Weighted mean LSM value (kPa)
F≥2
7.9
F≥3
8.8
F=4
11.7
Range (kPa) Sensitivity (%) Specialty (%)
6.1-11.8
74.3
78.3
8.1-9.7
74.0
63.8
7.3-17.5
84.6
81.5
• AUROC for diagnosis:
− Significant fibrosis (F2): 0.859 (95% CI,
0.857–0.860)
− Severe fibrosis (F3): 0.887 (95% CI,
0.886–0.887)
− Cirrhosis (F4): 0.929 (95% CI, 0.928–
0.929)
• Conclusion: Transient elastography
can be performed with good
diagnostic accuracy for quantifying
liver fibrosis in patients with CHB.
Characteristics of previous reported meta-analyses versus current study
AUROC
Cutoff values (kPa)
≥F2
≥F3
F4
≥F2
≥F3
F4
Talwalkar
0.870
N/A
0.957
N/A
N/A
N/A
Stebbing
0.84
0.89
0.94
7.81
N/A
15.56
Fredrich-rust et al
0.84
0.89
0.94
7.65
N/A
13.01
Tsochatzis et al
N/A
N/A
N/A
7.3
10.2
15.0
Chon et al (this study) 0.859
0.887
0.929
7.9
8.8
11.7
AUROC, area under the receiver operating characteristic curve; kPa, kilopascal.
Kim SU, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1376.
Staging Fibrosis in CHB Using
APRI and FIB-4
• Large observational cohort study (Chronic Hepatitis B and C Cohort Study) of
both treated and untreated CHB
• 277 with lab and biopsy data available (1997-2010)
− 64% male, 52% Asian
• Median biopsy age 45 years
− 25% F0, 25% F1, 21% F2, 15% F3, 14% F4
• AUC 0.84 APRI*, 0.82 FIB-4, 0.63 AST/ALT ratio
• Both APRI* and FIB4 are useful markers for distinguishing severe fibrosis (F3F4) from absent-to-moderate fibrosis (F0-F2).
Mean (95% CI) APRI, FIB-4, and AST/ALT values by liver biopsy fibrosis stage
APRI*
Liver biopsy fibrosis stage
No fibrosis (F0)
Fibrosis portal expansion (F1)
Few bridges or septa (F2)
Numerous bridges or septa (F3)
Cirrhosis (F4)
58
67
56
34
43
Mean (95% CI) P-value*
0.38 (0.32-0.45)
0.42 (0.36-0.50) <0.01
0.67 (0.55-0.82) <0.01
0.84 (0.67-1.05)
0.15
1.55 (1.17-2.05) <0.01
*APRI = AST-platelet ratio index
Lu M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 346.
FIB-4
58
67
56
34
43
Mean (95% CI) P-value*
0.97 (0.85-1.10)
0.90 (0.79-1.04) <0.01
1.48 (1.26-1.73) <0.01
1.65 (1.30-2.08)
0.41
3.55 (2.79-4.51) <0.01
AST/ALT ratio
78
88
69
43
47
Mean (95% CI) P-value*
0.80 (0.73-0.87)
0.74 (0.68-0.80) <0.01
0.72 (0.66-0.80)
0.79
0.75 (0.68-0.83)
0.65
0.90 (0.78-1.04)
0.44
Using Noninvasive Serum Markers
to Predict Survival in CHB
• Study of 600 patients who underwent FibroTest, APRI, biopsy, and FIB-4 on
same day
− Male 64%, age 42 years, 36% inactive carriers
• Overall survival was very high at 5 years and predicted by liver stiffness and
FibroTest:
− 97.1% with liver stiffness ≤9 kPa vs. 61.5% with liver stiffness >20 kPa (p<0.01)
− 96.8% with FibroTest ≤0.73 vs. 49.2% with FibroTest >0.85 (p<0.01)
Liver Stiffness and FibroTest and Survival
≤20kPa
>20kPa
P<0.001
≤0.85
>0.85
P<0.001
• Conclusion: Non-invasive diagnosis of liver fibrosis, either by liver stiffness
measurement or FibroTest, can predict survival in chronic hepatitis B.
de Ledinghen V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1321.
Cost-Effectiveness of
Universal HBV Vaccination in
Adults with Diabetes Mellitus
• Data show increased risk of HCC in diabetics and CDC recommends vaccinating adults with DM for
HBV
• Markov model of diabetic adults in US evaluated effect of HBV vaccine on morbidity and mortality
• One-time HBVac program of 50,000 diabetic adults would be expected to prevent 423 cases of
CHB and 4.7 cases of HCC death assuming annual progression rate of 0.33% in HBV liver disease
to HCC
• Model projected an estimated cost per Quality-adjusted life-year saved of $51,200 for diabetic
adults who received HBVac.
• Conclusion: This Markov model suggests that routine HBV vaccination in US adults with DM is cost
effective and may be associated with decreased risk of HCC mortality
Mortality by HBV Vaccine Status
1
11
21
Njei B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 343.
31
41
51
Durability of Antibody Response
Following HBV Vaccination in
Healthcare Workers (HCW)
• Study assessing durability of HBV vaccine in 159
Health care workers
− Assessed 10-14 years (group 1), 15-19 years (group 2),
and ≥20 years (group 3) after vaccination
− Mean age at vaccination 31-34 years
• Anti-HBs negativity was 16%, 26% and 25%
among groups 1, 2 and 3, respectively.
• HCWs without detectable anti-HBs were older
(51 vs. 47 years; p=0.04), vaccinated at a later age
(35 vs. 32 years; p=0.02) and non-smokers
(92% vs. 76%; p=0.04)
• Booster vaccination highly effective (94%) in
HCWs with negative anti-HBs titers.
• Conclusion: anti-HBs titers appear to wane
over time in HCWs vaccinated as adults. Older
age at vaccination was associated with negative
anti-HBs titer.
Gara N, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Oral Presentation.
Efficacy of Booster HBV Vaccination
Hepatitis B and C Association with
Non-Hodgkin’s Lymphoma (NHL)
• Analysis of risk of NHL with HBV or
HCV (2005-2009)
• 1,055,912 patient discharges included:
− HCV ICD-9: 45%
− HBV ICD-9: 5%
− No Hepatitis ICD-9: 50%
• In multivariate analysis, hepatitis status
was an independent risk factor for NHL
with HBV having the largest effect size
(OR=3.32, p<0.001)
• Conclusion: This study confirms
previous reports linking HBV and HCV
and further elucidation of the
mechanisms of the hepatitis and
lymphoma relationship is needed
Moehlen M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 907.
Multivariate analysis results of the
relationship between hepatitis status and NHL
Pre-Immunosuppressant HBV
Screening Practices
• Survey distributed to 523 specialists (overall response rate was 79%): hematology (131),
oncology (125), gastroenterology (102), rheumatology (68), dermatology (63), and other (34).
• Physicians were predominantly women (54%) of average age 41 years, and with 14 years of
professional experience.
• 74% stated they were aware of recommendations for management of HBV reactivation risk
− Trend stronger in gastroenterology and rheumatology (>80%) and weaker in oncology (56%), p<0.0001.
• 37% never or only sometimes asked about HBV risk factors and 35% never or only sometimes
requested HBsAg before starting treatment.
Specialty
ALL
Hematology
Oncology
Gastroenterology
Rheumatology
Dermatology
Others
NEVER Investigates
risk factors for
HBV infection
40 (8%)
5 (4%)
28 (22%)
2 (2%)
4 (6%)
1 (2%)
0 (0%)
NEVER requests
HBsAg
NEVER requests
anti-HBc
22 (4%)
0 (0%)
18 (15%)
0 (0%)
2 (3%)
2 (3%)
0 (0%)
34 (7%)
0 (0%)
23 (19%)
0 (0%)
5 (7%)
3 (5%)
3 (10%)
• Conclusion: HBV screening practices vary among the medical specialties and depend on familiarity
with the guidelines, particularly in high risk specialties such as oncology
García-Bengoechea, M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 915.
Therapeutic Strategies for
HBV Treatment
S. Martin Cohen, MD
Case Western Reserve University
Cleveland, OH
Continuing ETV with Partial
Virologic Response is Beneficial
• Naïve HBV patients receiving ETV 0.5 mg
daily
− Partial Virologic Response (PVR) >1 log IU/ml
decrease in HBV-DNA but still > 20 IU/ml at 48
weeks
− Complete virologic response (CVR) < 20 IU/ml
at 48 weeks
• Viral Breakthrough:
− Week 96: 1.6% CVR vs. 0% PVR (NS)
− Week 144: 1.6% CVR vs. 5.9% PVR (p=0.092)
• Cumulative Resistance:
− 0% CVR vs. 5.9% PVR (p=0.067)
• Conclusion: Long-term continuous ETV
monotherapy in naïve patients with PVR at
48 weeks can achieve additional virologic
response without significantly increasing
antiviral resistance
Kim IH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 376.
Virologic Response for
Patients Continued on ETV
P <0.001
PEG-IFN Lambda for HBV is
More Effective than PEG-IFN 2a
• Phase 2B study of PEG-IFN Lambda vs. PEG-IFN alfa-2a n HBeAg-positive CHB
patients
− Baseline: IFN naïve, HBV-DNA > 105 copies/ml
− 75% males, 90% Asians, 5% cirrhotics, 85% genotype B or C
• 24 week interim data of planned 48 week treatment course
−
−
−
−
HBV-DNA dropped more at 12 and 24 weeks with Lambda
HBsAg dropped more with Lambda
HBeAg loss was equivalent
ALT normalized more with alfa-2a
Serum HBV DNA Change From Baseline
P=<0.0001
0.0018
0.0272
0.1203
-1.78
-2.28
-2.58
-2.77
80
77
78
32
75
74
75=N
83
78
81
35
75
74
72=N
Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.
PEG-IFN Lambda has Fewer
Adverse Events than PEG-IFN 2a
• Adverse events
− PEG-IFN alfa had more fever, headache, alopecia, myalgia, dizziness, rash, arthralgia, and
dose-modifications due to hematologic AE’s
− Lambda had more ALT flares
Patients, n (%)
Any AE
Lambda 180 µg
N = 80
Alfa 180 µg
N = 83
72 (90)
75 (90)
Serious AEs
4 (5)
6 (7)
AEs leading to discontinuation of therapy
4 (5)
7 (8)
Dose reductions due to AE
Neutropenia
Thrombocytopenia
ALT increase
6 (8)
0
0
4 (5)
21 (25)
12 (15)
1 (1)
2 (2)
12 (15)
27 (34)
6 (7)
13 (16)
ALT flares
>2 x baseline and >10 x ULN
>2 x baseline and >5 x ULN
• Conclusions:
− PEG-Lambda had significantly better decrease in HBV-DNA at week 12, as well as better
decreases in HBsAg levels
− HBeAg seroconversion was equivalent between the 2
− PEG-alfa had better normalization of ALT at week 24
− PEG-Lambda had less flu-like symptoms and required less dose-modifications for
hematologic side effects.
Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.
Tenofovir is Effective Salvage
Therapy for NA-resistant HBV
• Single center, retrospective, cohort study of TDF vs. TDF + nucleoside
analog in NA-resistant CHB patients (N=148)
• Study population
− M204 – 62%
− A181T or N236T – 2%
− Viral breakthrough – 36%
• 95.5% became HBV-DNA negative (mean 5.8 months)
− 58 TDF monotherapy
− 90 TDF + nucleoside analogue
Virologic Response
TDF
TDF + NA
p value
4.44 log
4.65 log
p=0.53
5.2 months
6.2 months
p=0.34
Mean Baseline viral load
Mean Duration to HBV DNA<60 IU/mL
Conclusions:
− TDF is effective salvage therapy for those who have failed other NA’s
− No resistance was seen in this study
− No advantage in adding a nucleoside analogue to TDF alone
So J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 364.
PEG-IFN is Effective and Safe in
Patients with HBV and Advanced
Fibrosis/Compensated Cirrhosis
• To evaluate efficacy and safety of PEG-IFN 2a in
HBV patients with advanced fibrosis (Ishak 4-6)
compared to Ishak 0-3
• PEG-2a X 48 weeks with 24 week follow-up
• 13% of HBeAg+ and 21% of HBeAg- had Ishak
4-6
• For HBeAg+, the presence of advanced fibrosis
had significantly better HBeAg seroconversion
and DNA < 2,000, sAg loss, and ≥ 1 point
decrease in Ishak fibrosis score
• For HBeAg-, Overall response rates were similar
• Safety
− Overall no difference in med discontinuation rates
− Advanced fibrosis HBeAg+ pts had more hematologic
AE’s requiring dose reductions
Efficacy rates 24 weeks post-treatment according to baseline disease status in
HbeAg-positive patients
HBeAg-positive
Response variable
24 weeks post-treatment, n(%)
Fibrosis score
0-3
N=184
Fibrosis score
4-6
N=27
p-value
HBeAg seroconversion
63 (34.2)
13 (48.1)
0.1980
HBeAg seroconversion
+ HBV DNA <2000 IU/mL
39 (21.2)
11 (40.7)
0.0494
HBeAg loss +
HBV DNA <2000 IU/mL
42 (22.8)
11 (40.7)
0.0572
HBV DNA <2000 IU/mL
44 (23.9)
11 (40.7)
0.0975
2 (1.1)
5 (18.5)
0.0004
≥1-point decrease in Ishak score
57 (31.0)
14 (51.9)
0.0484
HBsAg <1000 IU/mL
40 (21.7)
9 (33.3)
0.2214
HBsAg clearance
Efficacy rates 24 weeks post-treatment according to baseline disease status in
HBeAg-negative patients
HBeAg-negative
Response variable
24 weeks post-treatment, n(%)
Fibrosis score
0-3
N=113
Fibrosis score
4-6
N=30
p-value
HBV DNA <2000 IU/mL
+ ALT normalization
41 (36.3)
9 (30.0)
0.6673
HBV DNA <2000 IU/mL
48 (42.5)
11 (36.7)
0.6778
5 (4.4)
2 (6.7)
0.6373
≥1-point decrease in Ishak score
41 (36.3)
15 (50.0)
0.2081
HBsAg <1000 IU/mL
46 (40.7)
7 (23.3)
0.0920
• Conclusions:
− PEG-2a can be effectively and safely used in patients
with compensated cirrhosis.
HBsAg clearance
Piratvisuth T, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 397.
No Difference in Renal Toxicity with
2 years of Entecavir or Tenofovir
• Single center, retrospective study of patients treated for at
least 2 years with TDF, ETV, or nothing
Baseline Characteristics
Mean eGFR Over 24 Month Period
Untreated
(N=73)
ETV
(N=74)
TDF ± LAM
(N=50)
p-value
Age
40.8 ± 11.12
46.69 ± 11.29
41.75 ±
11.44
0.0043
Sex, male
40 (54.79%)
50 (67.57%)
32 (64%)
0.264
Cirrhosis
0
32 (43.24%)
19 (38%)
<0.0001
HCC
0
4 (5.41%)
2 (4%)
0.146
HTN
10 (13.70%)
12 (16.22%)
4 (8%)
0.410
DM
4 (5.48%)
7 (9.46%)
2 (4%)
0.432
100.93 ± 22.45
96.73 ± 28.64
98.92 ±
28.85
0.30
eGFR
(ml/min) MDRD
• Conclusions:
− There was a slight decrease in GFR on TDF or ETV after 2 yrs
(compared to controls)
− There was no difference between ETV and TDF
Le ST, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 443.
Long-term Entecavir Decreases
Liver Stiffness Measurements
• Liver stiffness measurements by transient elastography represent a
non-invasive measure of liver fibrosis
• 46 patients on ETV had a baseline and annual TE on Rx
P=0.037
(n=46)
P=0.002
(n=42)
(n=35)
P=0.007
(n=28)
P=0.461
(n=12)
Conclusion: Long-term ETV improved liver stiffness beginning in year 1 and
continuing through at least year 3
Papatheodoridia G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 384.
Tenofovir is Safe and Effective
in Real-life Practice
• 400 TDF-naïve patients treated with TDF, 2 year data
− 46% were treated with TDF as 1st-line treatment
− 54% were switched from another agent
• 70% males, 76% white, 70% eAg-, 37% fibrosis score ≥2
HBV-DNA
(IU/mL)
Viremia in Treatment Naïve Patients
HBV-DNA
(IU/mL)
≥200 Mio
≥ 200 Mio
<200 Mio-20 Mio
<200 Mio- 20 Mio
<20 Mio- 2 Mio
<20 Mio- 2 Mio
<2 Mio-200,000
<2 Mio-200,000
<200,000-20,000
<200,000-20,000
<20,000-2000
<20,000-2000
<2000-200
<2000-200
<200-20
<200-20
<20
<20
Baseline
•
•
•
•
Month 6
Month 12
Month 18
Month 24
Viremia in Treatment Experienced
Baseline
Month 6
Month 12
Naïve patients: 81% of HBeAg+ were HBV DNA negative, 88% for HBeAgExperienced: 84% of HBeAg+ were HBV DNA negative, 90% for HBeAgHBeAg loss and seroconversion was seen in 23% and 19% of HBeAg+ pts
HBsAg loss occurred in 5.1% of HBeAg+ and 1% of HBeAg-
Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.
Month 18
Month 24
Tenofovir is Safe and Effective
in Real-life Practice
Serum Phosphorus
BL
(n=34)
Month 6
(n=63)
Month 12
(n=59)
Creatinine Clearance
Month 24
(n=42)
Estimated CrCl
(CockcroftGault)
Mean
[ml/min] (SD)
Mean
[mmol/L] (SD)
1.11
(0.21)
1.07
(0.23)
1.10
(0.35)
1.07
(0.19)
Mean change
[ml/min] (SD)
BL
(n=361)
Month 6
(n=299)
Month 12
(n=289)
Month 24
(n=255)
106.9
(31.6)
105.9
(33.8)
104.7
(31.7)
102.2
(31.3)
-1.4
(16.1)
-3.2
(16.2)
-3.4
(15.4)
• No significant issues were seen at 96 weeks regarding
phosphorus levels or CrCl
• Conclusions:
− TDF suppressed HBV DNA through 2 years in the majority of
patients regardless of pre-treatment status
− HBeAg loss/seroconversion was seen in 23%/19% of HBeAg+
patients
− 5.1% of HBeAg+ patients lost HBsAg
− Safety (including renal) was favorable in this real-life study
Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.
HBIG-free Post-liver Transplant Regimen
Using Oral Antiviral Therapy Alone
Effectively Suppresses HBV-DNA
• Retrospective review of 363 HBV OLT patients in Hong Kong
• Non-randomized study
− LAM (176), ETV (142), or LAM + ADV (44)
• Mean follow-up 53 months
Long Term HBsAg Seronegativity &
HBV DNA Undetectability
Pre-OLT Characteristics
Parameters
Lamivudine
(n=176)
Entecavir
(n=142)
Age
Gender, Male
MELD score
51 (24-67)
84%
26 (6-40)
52 (23-67)
85%
25 (6-40)
55 (30-66)
84%
17 (6-36)
0.141
0.972
0.002
34%
66%
44%
56%
45%
55%
0.117
98%
57%
3.0 (0.9-8.0)
<0.001
<0.001
0.011
74%
0.413
Transplant type
Deceased donor
Living donor
Pre-transplant
Antiviral therapy
HBeAg positivity
HBV DNA (IU/ml)
Donor anti-HBs
Positivity
30%
58%
29%
25%
3.6 (0.9-9.1) 2.7 (0.9-8.1)
63%
67%
Combination
P value
(n=44)
Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.
•
•
98% HBV DNA negative at 8 years
88% HBsAg negative at 8 years
LAM Alone Without HBIG Should
Probably be Avoided as Post-OLT HBV
Treatment
• Overall 8 year survival was 83%,with no difference between
the 3 treatment groups (p=0.98)
Cumulative Rate of
Virological Rebound
Virological Rebound
(≥1 log IU/mL Increase)
42 Patients with VR
Lamivudine
17%
Combination
9%
P<0.001
7%
5%
0%
0%
Virologic rebound was significantly
higher in the LAM group
(36 total of which 25 had YMDD)
The RR for viral rebound was
15.21 for the LAM group
Entecavir
Conclusions:
1. Oral NA’s after OLT are associated with excellent HBV suppression
and long-term survival
2. Agents with less resistance potential should be used to prevent development
of virological rebound
Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.
Adding PEG-IFN Alfa-2a to
ETV Increases HBsAg Decline and
HBeAg Clearance
• PEG-IFN alfa-2a add-on strategy at weeks 24-48 to ETV in HBeAg+ pts
− 48 weeks ETV (n=83) vs. 24 wks ETV + 24 wks ETV + PEG-IFN (n=77)
• PEG-IFN 2a add-on group had significantly better HBV-DNA, HBeAg,
and HBsAg responses
ETV
ETV
ETV
P<0.001
P<0.001
P<0.001
ETV+Peg-IFN
ETV+Peg-IFN
HBV DNA
ETV+Peg-IFN
HBeAg
HBsAg
24
• HBeAg loss at 48 weeks was 18% vs. 8%
• 2 PEG add-on patients had grade 4 neutropenia
• Conclusions:
− Adding PEG-IFN 2a to ETV improves HBV-DNA, HBeAg, and HBsAg responses
− PEG was reasonably well-tolerated
− This might allow a more finite course of NA therapy for chronic HBV.
Sonneveld M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 19.
Sequential Therapy of ETV
Followed by PEG-IFN 2a Showed No
Difference vs. ETV Alone
• HBeAg+ patients (n=146) received PEG-IFN for 48 weeks (conventional arm,
n=74) or ETV for 12 weeks with a 48-week course of PEG-IFN starting at
week 5 (sequential arm, n=74)
• No differences of HBeAg seroclearance, normalization of aminotransferase,
or HBV-DNA levels at EOT (6 month post-treatment data not yet available)
Biochemical and Virological Response at 48 Weeks
P=0.215
P=0.174
P=0.99
Conclusion: PEG-IFN add-on to ETV therapy did not provide EOT benefit
regarding HBV-DNA, eAg, or sAg levels
Jun DW, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 377.
5 Year ETV Effectively Suppresses
HBV-DNA in Naïve HBV Patients
• 418 consecutive naïve patients treated with ETV 0.5 mg for 52 months
• Mean age 58 years; 76% males, 83% HBeAg-negative, HBV DNA 6.0 log
IU/ml, 85% with elevated ALT, 49% cirrhotics
Rate of Viral Suppression through 5 years was 100%
in HBeAg-positive and negative
Virological response by HBeAg Status (Undetectable HBV DNA)
Months
67
66
48
42
32
11
Patients on f-up
Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.
338
327
296
265
227
86
HBsAg Loss Occurred in 33% of
HBeAg+ Pts Treated With 5 Years of ETV
HBsAg Loss in HBeAg-positive Patients
33%
Months
Patients
at risk
72
70
65
54
48
41
35
28
19
8
3
• HCC developed at an yearly rate of 2.5% despite good viral suppression
Conclusions:
• Long-term ETV monotherapy efficiently suppressed HBV replication in
naïve HBV patients
• High rates of HBsAg loss can also be seen with this therapy
Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.
Long-term De Novo
LAM and ADV Combination
Long-term Treatment is Effective
• Retrospective study of naïve patients with CHB
− HBeAg-positive (N=54), CHB-related cirrhosis (N=67)
− 5 year data
• No resistance was seen
• No safety issues were reported
Conclusion: De novo combination long-term therapy of LAM and ADV has a high virological and
biochemical response rate without drug resistance emergence.
Zhu B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 437.
Quantitative HBsAg Levels May be
an Effective Indicator for Cessation
of HBV Therapy
• The usefulness of quantitative HBsAg (qHBsAg) level as an indicator for cessation
of antiviral therapy.
• 97 patients (with qHBsAg levels available) who had stopped HBV therapy
− 47 relapsed, 50 non-relapsers
Patients with CHB who have stopped antivirals with
measurement of qHBsAg level at the time of cessation from
January 2008 to December 2011 (n = 306)
Exclusion (n = 209)
Analyzed (n = 97)
Relapse:
HBV DNA > 100IU.mL
Non-Relapser (n = 50)
1) F/U loss or F/U < 6month
2) Stopped NAs arbitrarily (HBV DNA (+) or
abnormal ALT at the time of cessation)
3) Acute hepatitis
4) Patients with liver cirrhosis
5) Patients with other comorbid medical conditions
Relapser (n = 47)
• Only significant variable predicting relapse was qHBsAg levels
− qHBsAg < 567 IU/ml at treatment cessation had an 81% sensitivity and 70% specificity of
predicting no relapse
Conclusion: qHBsAg level might be a useful indicator of predicting relapse, and thus could provide
a guide to determining if/when HBV therapy can be stopped.
Park UG, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 353.
Viral Resistance Issues
Kris Kowdley, MD
Virginia Mason Medical Center
Seattle, WA
TDF/FTC vs. TDF Monotherapy
for CHB Patients with LAM-R
• Randomized, double-blind, phase IIIb trial
• Chronic HBV with documented LAM-R (INNO-LiPA HBV)
• N= 280 patients
Randomization
1:1
Dosing x 96 weeks
TDF 300 mg once daily
(N=141)
TDF 300 mg + FTC 200 mg once daily
(N=139)
Baseline
Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20.
Further anti-HBV
therapy at discretion
of investigator – up to
24 weeks follow-up
Week 96
Primary Endpoint
Baseline Characteristics
TDF (N=141)
Age, mean years (range)
Male, n (%)
FTC + TDF (N=139)
47 (18-73)
104 (74)
46 (18-72)
107 (77)
Race, n (%)
Asian
White
83 (59)
52 (37)
89 (64)
42 (30)
HBeAg (+), n (%)
65 (46)
68(49)
6.4 (1.83)
6.5 (1.97)
84 (60)
50 (35)
7 (5)
85 (61
45 (32)
10 (7)
71 (91)
62 (44)
210 (34-648)
87 (147)
56 (40)
189 (7-832)
HBV DNA, mean log10 IU/mL (SE)
Region, n (%)
Europe
North America
Asia
ALT, mean U/L (SE)
Normal ALT, n (%)
Mean duration of LAM, weeks (range)
Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20
Results at Week 96:
Primary Endpoint: HBV DNA <69 IU/mL
TDF (N=141)
HBV DNA <400 cp/mL, n (%)
Normal ALT, n (%)
Serology, n (%)
HBsAg loss
HBeAg loss
HBeAg seroconversion
TDF Resistance
Adverse Events (AE) resulting in
study drug discontinuation
Deaths, n (%)
SAE, n (%)
SCr ≥ 0.5 mg/dL above baseline
PO4 < 2 mg/dL, n (%)
CrCL <50 mL/min, n (%)
Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20
FTC + TDF (N=139)
P-value
126 (89)
99 (70)
120 (86)
97 (07)
ns
ns
0 (0)
10/65 (15)
7/65 (11)
0 (0)
1 (<1)
9/68 (13)
7/68 (10)
0 (0)
1 (0.7)
2 (1.4)
ns
1 (0.7)
0 (0)
0
2 (1.4%)
5 (3.5%)
2 (1.4)
1 (0.7)
0
0
4 (2.9%)
ns
ns
ns
ns
ns
ns
ns
TDF vs. FTC/TDF Conclusions
• Nearly 90% of subjects with documented LAM-R
achieved suppression to HBV DNA <400 cp/mL
at week 96 with both TDF and FTC/TDF
• No significant differences in efficacy were
observed between monotherapy and combination
therapy regimens
• No detectable TDF resistance was observed
with TDF or FTC/TDF through 96 weeks
• TDF demonstrated favorable safety and
tolerability with a low rate of renal events
and no evidence of clinically relevant bone loss
Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20
TDF vs. FTC/TDF Resistance
• Analysis of amino acid changes within HBV polymerase /reverse
transcriptase (pol/RT) after 96 weeks of TDF or FTC/TDF in 280 subjects
with LAM-R mutations
• Viremia at Week 96:
− TDF arm = 7/133 subjects (5.3%) – 6 without virologic breakthrough
− 2 had reversions toward consensus (rtM180L/M, rtV204M/V, rtI204M) or changes
(rtV173L/V) at conserved sites
− 2 had unique polymorphic site changes
− 1 had no change
− 2 had no genotype
− FTC/TDF = 8/132 subjects (6.1%) – 4 without virologic breakthrough
− 1 had unique polymorphic site change
− 1 had no change
− 1 was unable to genotype
• 12/15 viremic subjects had genotype data at week 96
− 10/12 maintained baseline LAM-R mutations
• Conclusions: no virologic resistance to TDF identified through 96 weeks in
patients with LAM-R at baseline
Croso AC, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 389
DEFINE Trial: ETV/ADV vs. LAM/ADV
vs. ETV for LAM-R HBeAg+ CHB
• Randomized, open-label, comparative phase IIIb trial
• Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa)
• N= 415 patients
Dosing x 96 weeks
Randomization
1:1:1
ETV (1.0 mg) + ADV (10 mg) QD
(N=138)
LAM (100 mg) + ADV (10 mg) QD
(N=137)
ETV (1.0 mg) QD
(N=139)
Baseline
Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.
Week 96
Primary Endpoint
Baseline Characteristics
Age, mean years (range)
Male, n (%)
Race, n (%)
Asian
White
Time on prior LAM, yrs
HBV DNA, mean log10
IU/mL (SE)
HB V genotype, n (%)
A
B
C
D
Other/missing
ALT, mean U/L (range)
BMI, mean (range)
ETV+ADV
(N=138)
45 (18-69)
91 (66)
LAM+ADV
(n=137)
44 (16-74)
97 (71)
132 (96)
6 (4)
126 (92)
11 (8)
389 (94)
26 (6)
3.2
3.0
3.5
6.7 (0.08)
7.5 (0.09)
7.4 (0.09)
6 (4)
3 (2)
124 (90)
3 (2)
2 (2)
71 (10-480)
24 (16-36)
11 (8)
6 (4)
113 (93)
5 (4)
2 (2)
89 (14-1300)
24 (18-33)
27 (7)
16 (4)
356 (86)
11 (3)
5 (1)
69 (12-367)
24 (16-33)
Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.
ETV (n=140)
44 (19-71)
88 (63)
Results at Week 96:
Primary Endpoint: HBV DNA <50 IU/mL
ETV/ADV
(N=138)
HBV DNA <50 IU/mL at week
48, n (%)
HBV DNA <50 IU/mL at week
96, n (%)
Normal ALT, n (%)
Serology, n (%)
HBsAg loss
HBeAg loss
HBeAg seroconversion
Adverse Events (AE)
resulting in study drug
discontinuation
Deaths, n (%)
SAE, n (%)
SCr ≥ 0.5 mg/dL above
baseline
ETV-R (%)
ADV-R (%)
LAM/ADV (N=137)
P-value
ETV (n=140)
25
20
16
44
29
n/a
77
80
74
0 (0)
17/138 (12)
10/138 (7)
0 (0)
17/135 (13)
7/135 (5)
0 (0)
15/139 (11)
5/139 (4)
1 (0.7)
2 (1.5)
3 (2.1)
ns
1 (0.7)
14 (10.1)
0 (0)
13 (9.5)
1 (0.7)
21 (15.0)
ns
ns
1 (0.7)
2 (1.5)
1 (0.7)
ns
0.8
0.7
1.5
2.2
9.8
1.5
ns
ns
Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.
ns
0.01
ns
ns
DEFINE Trial: Conclusions
• Although the efficacy of ETV+ADV was comparable to
that of LAM+ADV and ETV monotherapy at week 48,
ETV+ADV was superior to LAM+ADV at week 96
• ALT normalization rates were comparable across all 3
treatment groups
• Serologic responses were low with all 3 treatments,
similar to previous reports with LAM+ADV or ETV in
LAM-R CHB patients
• Treatment with either ETV+ADV or LAM+ADV was
associated with low rates of resistance development
• Overall, ETV+ADV was well-tolerated and more effective
than LAM+ADV for the treatment of LAM-R CHB over 96
weeks of treatment
Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.
Korean Study: ETV/ADV vs. ETV
for ADV-refractory LAM-R CHB
• Retrospective analysis of long-term efficacy of ETV/ADV or ETV at
weeks 48 and 96 at one university liver center in Korea
• Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa)
• N= 91 patients
Retrospective
Observational
Dosing x 48-96
weeks
ETV (1.0 mg) QD
(N=46)
ETV (1.0 mg) + ADV (10 mg) QD
(N=45)
Baseline
Kim IH, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.
Week 96
Baseline Characteristics
ETV+ADV (N=45)
Age, mean years (range)
Male, n (%)
LAM-R Mutations
Overall
rtM204I/V
rtL+rtM204I/V
ADV-R Mutations
rtN236T
rtA181T/V
rtN236T+rtA181T/V
HBV DNA, mean log10
IU/mL
HBeAg positive, n (%)
ALT, mean U/L
Duration of ETV, months
Cirrhosis, n (%)
Kim IH, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.
ETV (n=46)
P-value
46
35 (78)
48
38 (83)
43 (96)
16 (36)
25 (56)
44 (96)
7 (15)
31 (67)
2 (4)
1 (2)
5.1
5.7
0.067
40 (89)
56
33
14 (31)
40 (87)
82
30
14 (30)
ns
0.016
ns
ns
ns
ns
ns
ns
Results at Weeks 48 and 96:
HBV DNA <20 IU/mL, n (%)
Week 48
Week 96
Serum HBV DNA, mean reduction from
baseline, log10 IU/mL
Week 48
Week 96
Normal ALT, n (%)
Week 48
Week 96
HBeAg loss/seroconversion,n (%)
Week 48
Week 96
Virologic breakthrough, n (%)
Week 48
Week 96
ETV/ADV (N=45)
ETV alone (N=46)
14 (31)
17 (45)
11 (24)
10 (35)
-3.0
3.3
-2.0
-3.0
27 (60)
23 (61)
28 (61)
18 (62)
ns
ns
3/40 (8)
5/34 (15)
5/40 (13)
5/26 (19)
ns
ns
0/45 (0)
1/38 (3)
8/46 (17)
13/29 (45)
0.006
<0.001
Factors Associated with Virologic Breakthrough (multivariate analysis):
only ETV monotherapy vs. ETV+ADV was associated (OR 5.89, p=0.015)
Kim IH, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.
P-value
ns
ns
0.022
ns
Korean Study: Conclusions
• In a cohort of 91 Korean patients with
adefovir-refractory LAM-R CHB, ETV+ADV trended
towards stronger efficacy than ETV monotherapy in
suppressing HBV DNA to undetectable levels at
week 96, but this was not statistically significant
• Only ETV monotherapy was associated with a
higher rate of virologic breakthrough in multivariate
analysis (OR 5.89, p=0.015)
• Other biochemical and serologic outcomes
(normalization of ALT, HBeAg loss/seroconversion)
not significantly improved with ETV+ADV than ETV
monotherapy
Kim, IH et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.
ALTER Study:
ADV/LAM Therapy for ETV-R CHB
• Prospective, open-label single arm roll-over study at 9 Korean
hospitals with 20 patients with prior LAM-R who were randomized to
ETV in one of 2 arms of the ACE Trial (RCT) and developed ETV-R,
and then retreated with open-label ADV/LAM for 12 months
• Documented ETV-R by MALDI-TOF
Randomized
1:1
ACE TRIAL: 104 weeks
ADV (10 mg)/LAM (100 mg) QD
(N=110)
ALTER STUDY: 12 mo
ETV-R
ADV (10 mg)/LAM
(100 mg) QD
(N=20)
ETV (1.0 mg) QD
(N=109)
Baseline
Yim HJ, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 409.
Week 104
Baseline Characteristics
ADV/LAM (N=20)
Age, mean years (range)
Male, n (%)
Baseline LAM-R Mutations
M204V + L180M
M204V/I + L180M
M204I
Baseline ETV-R Mutations
T184L/I/A/F
S202G
T184I + S202G
T184L + I169T
T184L + I169T + M250V
HBV DNA, mean log10 IU/mL (range)
HBeAg positive, n (%)
ALT, mean U/L
Duration of ETV, months (range)
Cirrhosis, n (%)
Yim HJ, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 409.
47 (29-74)
15 (75)
17 (95)
1 (5)
2 (10)
11 (50)
5 (25)
3 (15)
1 (5)
1 (5)
5.66 (3.36-7.45)
17 (85)
39 (11-185)
31 (12-39)
7 (35)
Results at Months 3, 6, 9, and 12:
ADV/LAM (N=20)
HBV DNA <20 IU/mL, n (%)
Month 3
Month 6
Month 9
Month 12
Serum HBV DNA, mean decrease from baseline, log 10 IU/mL
Month 3
Month 6
Month 9
Month 12
Normal ALT, n (%)
Month 3
Month 6
Month 9
Month 12
HBeAg loss,n (%)
Month 3
Month 6
Month 9
Month 12
Yim HJ, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 409.
4/19 (21)
5/19 (26)
5/18 (28)
4/17 (24)
-2.08
-2.24
-2.27
-2.35
14/19 (74)
16/19 (84)
17/18 (94)
14/17 (82)
4/12 (33)
5/16 (32)
5/14 (36)
3/14 (21)
ALTER Study: Conclusions
• In a cohort of 20 Korean patients with LAM-R treated with
ETV who developed ETV-R, ADV/LAM significantly
reduced serum HBV DNA levels at 12 months, but only
approximately ¼ achieved undetectable HBV DNA at 1
year of salvage therapy
• Of 16 patients with available ETV mutant data at 12
months, 1 (6%) showed disappearance of ETV-R
mutants, 9 (56%) had reduction in proportion of ETV-R
mutants – 1 patient developed ADV-R without VR
• Further long-term studies evaluating the role of ADV/LAM
in ETV-R CHB in a larger cohort are needed to clarify the
safety and efficacy of this treatment strategy
Yim HJ, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 409.
GS-102 and GS-103:
No Detectable Resistance at 6 Years
Randomized, Double-Blind, Comparison of TDF vs. ADV for CHB
RANDOMIZATION
2:1
1 Year
Pre-treatment
Liver Biopsy
2 Years
5 Years
Double Blind
Open-label
Tenofovir 300 mg
TDF 300 mg
Adefovir 10 mg
TDF 300 mg
Week 48
Liver Biopsy
Week 96
Week 72 HBV DNA ≥400 copies/mL:
Option to add FTC to TDF in a fixed dose tablet
Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 374
Week 240
Liver Biopsy
8 Years
End of Study
GS-102 and GS-103:
Resistance Patterns in HBeAg(-) and
HBeAg(+) During Year 6
• 73% (466/641) of enrolled patients remain on study at Year 6
• 80% (466/585) of patients entering the open-label phase remain on study at Year 6
• HBV DNA <400 cp/mL on-treatment at Year 6: 99.6% Study 102 and 99.0% Study 103
• 1.2 % (8/641) Qualified for Resistance Surveillance During Year 6
Patients on TDF Who Qualified for Genotypic Analysis (n=8)
Conserved site change
N=3
No change
N=4
N=1
Polymorphic site change
Unable to genotype
Conclusion: No resistance to TDF was detected through 6 years
Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 374.
Predictors of LAM-R in
Long-Term LAM Treatment
• Retrospective analysis of 227 German patients treated at 3 German
liver centers with LAM 100 mg/day (130 patients) or 150 mg/day (97
patients) for a mean duration of 35 months (6-146 months)
• 77/227 patients (34%) developed LAM-R
− 7% (Year 1), 24% (Year 2), 35% (Year 3), 41% (Year 4), 46% (Year 5),
52% (Year 6), 55% (Year 7), only 2 additional cases at months 139 (11
yrs) and 146 (12 yrs)
• LAM-R in HBeAg positive patients was correlated with HBeAg loss:
− LAM-R in 7/27 patients with HBeAg loss (26%) versus 18/41 patients
without HBeAg loss (44%), p= 0.01
• Predictors of LAM-R: baseline HBV DNA >105 copies/mL (p=0.03)
• Conclusion: Lamivudine resistance is common with long-term LAM
treatment but occurs uncommonly after 6 years of virologic response,
and is less frequent in patients with baseline HBV DNA < 105
copies/mL
Brodzinski A, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 418
Frequency of HBV Resistance
Mutations in Treatment-Naïve CHB
• Presence of viral variants with drug-resistance mutations in
untreated CHB arising from transmission of resistant HBV
strains may compromise response to nucleos(t)ide analogues
• Retrospective analysis of 557 treatment-naïve Brazilian CHB
patients who underwent population-based sequencing
• Results: 10/557 patients (1.8%) harbored HBV variants with
primary resistance mutations, four of which harbored
secondary mutations
• An additional 18 patients (3.2%) demonstrated variants with
novel amino acid substitutions at positions reported to be
associated with adefovir resistance
• Conclusion: The prevalence of clinically significant resistant
variants in a population of treatment-naïve Brazilian patients is
relatively low, but may explain some early treatment failures.
Gomes-Gouvea MS et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 916
63rd Annual Meeting of the
American Association for the
Study of the Liver Disease
(63rd AASLD)
Boston, Massachusetts
November 9-13, 2012