58th Annual Meeting of the American Association for the Study of Liver Diseases Boston, MA November 2-6, 2007
Jan 12, 2016
58th Annual Meeting of the American Association for the
Study of Liver Diseases
Boston, MA
November 2-6, 2007
Epidemiology and Natural History of HBV Infection
Douglas Dieterich MD
Mount Sinai School of Medicine
New York, NY
How Old is HBV?
▬ HBV associated with humans for >1,000 years but no definitive evidence
▬ Recent evidence establishes ≥500 years
▬ Naturally mummified body of a Korean child found virtually intact
▬ Laparoscopy: Large organ in RUQ and biopsies sent for pathology and HBV DNA testing- HBV DNA genotype C isolated
from the liver- Pathology: Appeared to be normal liver
Klein A, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 925.
7 Taiwanese townships aged 30–65 years
(n=89,293)
Baseline HBsAg+(n=9800)
Baseline HBV DNA(n=3851)
Follow-up analysisfor cirrhosis/HCC
(n=3774)
Viral Load Predicts Disease Progression:The REVEAL Study
Risk Evaluation of Viremia Elevation & Associated Liver Disease
Prospective, multicenter, observational cohort study
Chen CJ. JAMA. 2006;295:65-73.
1991-19921991-1992RecruitmentRecruitment
June 2004: June 2004: 43,993 PYs follow-up43,993 PYs follow-up
• 24% PCR neg
• 85% HBeAg(-)
• 94% ALT<45 IU/L
• 98% non-cirrhotic
(on Ultrasound)
Effect of Chronic Elevations of HBV DNA Level on HCC Risk
▬ Impact of increasing HBV DNA levels was assessed - Subset with HBV DNA ≥104 c/mL, no cirrhosis, anti-HCV negative
▬ 71 new cases of HCC (n=1,289; 15,508 PY)- 69% males
▬ Risk of HCC was strongly associated with increasingHBV DNA level in a dose dependent fashion:
Chen C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 920.
REVEAL Study
HBV DNA (Copies/mL) Hazards Ratio (95% CI)
<300 Referrant*
300-9,999 6.1 (0.8 – 48.2)*
10,000 – 99,999 6.2 (0.8 – 48.4)*
100,000 – 999,999 7.7 (1 – 60.8)*
>1 million 13.1 (1.7 – 99.6)**P value for trend <0.001
Changes in HBV DNA Using a Trajectory Model Increased HCC Risk
Chen C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 906; Iloeje U, et al. Ibid. Poster 907.
Cumulative Incidence of HCC by HBV DNA Trajectory Classes
Cumulative Incidence of HCC by HBV DNA Trajectory Classes
Year of Follow-upYear of Follow-up
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0 1 2 3 4 5 6 7 8 9 10 11 12
0.09
13
Reference Group: HBV DNA < 104 at enrollment
Class I: Medium to Low
Class II: Medium to Medium
Class III: High to High
Class IV: Persistently Very High
Reference Group: HBV DNA < 104 at enrollment
Class I: Medium to Low
Class II: Medium to Medium
Class III: High to High
Class IV: Persistently Very High
Cu
mu
lativ
e I
nci
de
nce
of
HC
CC
um
ula
tive
In
cid
en
ce o
f H
CC
▬ Compared to HBsAg (-) patients:
▬ Increasing HBV from one level to another was also a risk for HCC
HBV DNA (c/mL)
HRHR
Trajectory
<300 3.0 --
300-9,999 3.3 0.7
10,000-99,999
14 2.6
100,000-999,999
32 8.5
>1 million 30.2 10
HBV DNA Levels Predict HCC Recurrence After RFA
▬ 66 pts with HBV and HCC were treated with RFA*▬ Recurrence rates on follow up (mean 3.2 year):
- One year 30%- Two year 60%- Three year 74.3%
▬ Multivariate Analysis for risk of recurrence
Risk Factor Risk ratio (95% CI, p value) Platelet count (<150,000/mm3) 3.74 (1.56-8.97, 0.003)
HBV DNA level (≥10,000 c/mL) 2.87 (1.16-7.09, 0.023)
Goto T, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 917.
*Radio-Frequency Ablation
Serial HBV Measurements Predict Disease Progression
▬ Study from Thrace, Greece evaluated risk factors for CHB disease progression▬ 257 CHB pts enrolled: 14 HBeAg(+), 243 HBeAg(-)
- F/U 12.5 years (mean)- Viral markers, liver biochemistry and PE every 6 mos.- Liver Bx and abdominal U/S every 2-4 years
▬ 27% of HBeAg(-) pts intermittently had HBV DNA <104
- Serial measurements are necessary to find real HBV DNA levels▬ Multivariate Odds Ratio (OR) of fibrosis risk:
Zacharakis G, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 898.
HR 95% CI P value
HBV DNA(>104 vs <104 c/mL
604.865 67.233-999.999 <0.0001
ALT(<40 vs >40 IU)
0.002 <0.001-0.015 <0.0001
Age(<40 vs >40 yrs)
0.057 0.006-0.519 0.011
Significant Liver Disease in Asymptomatic Patients
▬ 105 treatment-naïve patients with CHB- HBV DNA > 105 c/ml, ALT ≤ 2x ULN x 12 mos, mean age 37 years
▬ Significant fibrosis in 60% and histology in 66%▬ Compared to patients < 20 years of age:
▬ Conclusion: A large portion of patients with ALT< 2x ULN have significant fibrosis on liver biopsy
Park JY, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 942.
Age (years) Odds Ratio (95% CI)
20-29 7.1 (1.4-36.9)
30-39 14.2 (2.1-94.2)
40-49 24.4 (4.2-141.3)
>50 38.8 (4.0-309.8)
R is k o f F ib ro s is b y A L T L evel
19.8
43.5
0
10
20
30
40
50
P ercent
0 - 0.75 x ULN 0.75 - 1 x ULN
Significant Histological Findings in Patients with Normal ALT
▬ Study comparing liver histology in CHB pts with persistently normal (n=139) and abnormal (n=135) ALT
▬ Normal ALT group: 24% significant fibrosis, 9.4% cirrhosis
▬ Within normal ALT range, fibrosis rate higher in pts with higher ALT
▬ Age >40 years significant risk for fibrosis
▬ No correlation with HBeAg status or HBV DNA level
Gui H, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 936.
Pat
ient
Per
cent
P=0.029
HBeAg Seroconversion is a Poor Clinical Endpoint
▬ 298 patients with documented HBeAg seroconversion- 116 treatment-induced, 182 spontaneous
▬ Reactivation in 71 patients (39%)- Older age, male gender and higher ALT at seroconversion were risks
for reactivation (all p<0.006)- No difference between IFN, ADV, LAM treatment
▬ Treatment induced seroconversion less durable than spontaneous- Remission of ALT shorter (14 vs 22 mos., p=0.037)- More likely to have HBeAg reactivation at 48 mos. (38% vs 25%,
p=0.048)
Lim, GL et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 937.
Longitudinal Study of HBsAg Seroclearance
▬ 298 patients with HBsAg clearance- 71% male, med. age 43.1
- Med. F/U 36 mos after HBsAg clearance
▬ 29 liver biopsies: 44% anti-HBs(+) - 100% detectable HBV DNA
- 79% cccDNA
▬ 7 pts with HCC and 9 with liver decompensation- ↑risk with age ≥50 at HBeAg
seroconversion for HCC and significant fibrosis (p=0.001)
Wong, D et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 900.
Cum
ulat
ive
Ris
k of
HC
C (
%)
Cum
ulat
ive
Ris
k of
HC
C (
%)
20
15
10
5
0
0 12 24 26 48 60 72 84 96 108 120
* p = 0.004
HBsAg seroclearance at age ≥ 50*
HBsAg seroclearance at age < 50*
Follow-up (month)Follow-up (month)Age of HBsAgseroclearanceAge of HBsAgseroclearance
No. ofpatients
at risk
No. ofpatients
at risk 147 120 86 63 51 46 38 31 24 18 12≥50
151 124 102 87 71 56 47 37 21 15 10<50
HBV and Gender
▬ Longitudinal study to assess gender and natural course of HBeAg(+) CHB (1977-1998)- 454 males, 110 females- Mean F/U 12 yrs
▬ No differences in:- Hepatitis B flares - Spontaneous HBeAg seroconversion
▬ ↑Risk persistent ALT elevation in males (47% vs. 15%, p<0.0001)- May be cause of faster progression to cirrhosis
Lin E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 928.
Liver Transplants for HBV Declining
▬ All LTx candidates newly registered to the Organ Procurement and Transplantation Network (UNOS) (1985-2006)
▬ Unique individual patient for primary LTx ▬ All diagnostic information used to identify patients
with HBV or HCV:- Diagnostic codes and written-in diagnosis - Laboratory data
- HBsAg, HBV-DNA, anti-HCV, HCV-RNA
Kim WR, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 12.
Therapeutic Strategies for HBV Treatment
Emmet Keeffe MD
Stanford University School of Medicine
Palo Alto, CA
Effect of Lamivudine and Adefovir on Development of HCC
▬ Evaluation of LAM and ADV effect on HCC in pts with HBV-related cirrhosis
▬ Retrospective study: 111 pts on oral antiviral and 111 untreated pts randomly selected and matched according to age, gender, Child-Pugh class A, and HBeAg(+)
Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.
LAM LAM
LAMContinued(n=590)
LAMswitched(n=284)
Treat(n=111)
Untreated
(n=1592)
Control (n=111)
Baseline Characteristics
Treated Group (n=111)
Control Group(n=111) p-values
Clinical Data
Age (years) 42.8 ± 8.4 43.1 ± 9.8 NS
Sex (M/F), n (%) 78/33 (70.3/29.7) 78/33 (66.1/33.9) NS*
Family history, yes (%) 63 (56.8) 64 (57.7) NS*
Interferon history, n (%) 20 (18.0) 20 (18.0) NS*
Laboratory data
AST (IU/L) 137 ± 145 103 ± 120 0.061
ALT (IU/L) 159 ± 176 127 ± 182 NS
Total bilirubin (mg/dL) 1.1 ± 0.6 1.1 ± 0.6 NS
Albumin (g/dL) 4.0 ± 0.4 3.8 ± 0.5 0.007
Platelet (x10³/mm³) 113 ± 28 104 ± 35 0.045
HBV DNA (pg/mL) 1183.1 ± 2473.3 346.3 ± 833.0 0.005
Follow-up period (years) 4.4 ± 2.2 5.4 ± 4.1 <0.001
HCC, n 5 36
Age at diagnosis 54.2 ± 6.4 53.8 ± 10.0 NS
Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.
Cumulative Incidence of HCC
Control (32.4%) (n=104)
40
0 5 10 15 20
Cum
ulat
ive
Inci
denc
e of
H
CC
(%
)
Years Elapsed
Log-rank, p<0.003
20
0
Treated (4.5%) (n=111)
Conclusion: Oral antiviral agents, such as LAM and ADV, may reduce the incidence of HCC in patients with HBV-related liver cirrhosis
Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.
Entecavir Therapy in HBeAg(+) CHB
ETVN=354
Responders [R]HBV DNA <0.7 MEq/mL by bDNA and HBeAg loss
Virologic Responders [VR]HBV DNA <0.7 MEq/mL by bDNA and HBeAg(+)
Non-responders [NR]HBV DNA ≥0.7 MEq/mL by bDNA
NR=19
VR=247
R=74
Week 48
21 Non-respondersAt Week 48 or who became non-responders during Year 2
151 Virologic RespondersAt Week 96
11 RespondersAt Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up
Week 144
ETV-022 ETV-901
Week 96 Week 192
NR=8
VR=198
R=37
243
Study DesignStudy Design
Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.
Baseline Characteristics
HBeAg(+) ETV 4-Yr Cohort
(N=146)
Age, mean (years) 36
Male (%) 80
Race:
Asian (%) 64
Non-Asian (%) 36
HBV DNA by PCR, mean (log10 copies/mL) 9.91
ALT, mean (U/L) 122
413
26
2730
Nucleoside-naïve HBeAg(+) ETV 4 year Treatment Cohort
Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.
ABCDOther
HBV Genotype (%)
ETV-022 and ETV-901
Outcomes and Conclusions
▬ 91% nucleoside-naïve HBeAg(+) on ETV for 4 years had undetectable HBV DNA
▬ 86% maintenance of normal ALT levels
▬ Additional patients in year 3 and 4 had HBeAg loss and HBeAg seroconversion
▬ Only one patient developed resistance
Endpoint Week 192*
HBV DNA <300 copies/mL 98/108 (91%)
ALT ≤ 1 x ULN 96/112 (86%)
HBeAg Loss** 39/96 (41%)
HBeAg seroconversion** 15/96 (16%)
Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.
* Denominator represent patients with available samples** Numbers/proportions represent additional patients achievingHBeAg loss or HBeAg seroconversion during treatment in ETV-901
ETV-022 and ETV-901
Long-term Follow-up on ETV Nonresponders
ETV
NR
VR
R
Week 48
Non-responders 30
Virologic Responders 225
Responders
397
ETV-022 [HBeAg(+)] and ETV-027 [HBeAg(-)] ETV-901
Week 96
NR
VR
R
Cumulative response outcomes
Patients who enrolled in ETV-901
Non-responders 21
Virologic Responders 166
Responders
105
Study DesignStudy Design
Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.
All Treated (N=354)
Nonresponders(N=146)
Age, mean (years) 35 35
Male (%) 77 81
Race:
Asian (%) 58 38
Non-Asian (%) 42 62
HBV DNA by PCR, mean
(log10 copies/mL)9.62 10.39
ALT, mean (U/L) 140 106
HBV Genotype (%)
Baseline Characteristics
Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.
Baseline Characteristics of All Treated Patients in ETV-022 vs. Protocol-Defined Nonresponders Who Subsequently Entered ETV-901
27
1931
1013A
B
C
D
Other
48
195
1414
ETV-901: ETV Nonresponders
Long-term Outcomes
EndpointAchieved endpoint in
ETV-901Maintained endpoint at
Last observation
HBV DNA <300 copies/mL 15/21 (71%) 12/21 (57%)
ALT Normalization 20/21 (95%) 13/21 (62%)
HBeAg seroconversion 7/21 (33%) 7/21 (33%)
▬ Four patients experienced a virologic breakthrough; none developed ETV resistance
▬ No patients discontinued due to adverse events
Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.
ETV-901: ETV Nonresponders
Conclusions
▬ Fewer than 5% of nucleoside-naïve patients treated with ETV in studies ETV-022 and ETV-027 met protocol-defined criteria of “Non-Response”
▬ Most “non-responders” who continued to receive ETV treatment in rollover study ETV-901 achieved HBV DNA <300 copies/mL and ALT normalization
▬ 4 patients experienced virologic breakthrough during treatment in ETV-901; however, genotypic and phenotypic analysis failed to show evidence of ETV resistance
▬ Treatment compliance should be evaluated in patientswith non-response
Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.
ETV-901: ETV Nonresponders
Telbivudine Therapy:Baseline Variables Predict Outcomes
Entry criteria: • Nucleos(t)ide-naïve patients, aged 16-70, with HBeAg(+) (n=921)
or HBeAg(-) (n=446) CHB and compensated liver disease
• Serum HBV DNA >6 log10 copies/mL
• Serum ALT ≥1.3-10 x ULN• Pretreatment liver biopsy consistent with CHB
Randomization 1:1
Lamivudine (n=687)
Telbivudine (n=680)
0 52 weeks(Primary Endpoint)
104 Weeks(Final Analysis)
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
Methods
▬ Baseline variables included in the model- age, body mass index (BMI), serum ALT, Ishak fibrosis
score, serum HBV DNA level, Knodell histologic activity index (HAI) score, gender, and HBV genotype
▬ For analysis of on-treatment predictive factors, patients were categorized according to- serum HBV DNA level at Weeks 12 and 24: PCR-negative; <3 log10
copies/mL; 3-4 log10 copies/mL, and ≥4 log10 copies/mL
- baseline ALT level: <2 x ULN, 2-5 x ULN, and >5 x ULN
▬ For stepwise multiple regression analyses, patients were categorized as HBV DNA PCR-negative or not PCR-negative at Weeks 12 and 24
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
GLOBE Substudy
GLOBE Substudy
Odds ratio ± 95% CI
ALT normalization BMI (P<0.001)
Week 24 PCR-negative (P<0.001)
Age (P=0.013)
2.69
2.49
1.93
HBeAgseroconversion
Week 24 PCR-negative (P<0.001)
Baseline ALT (P=0.001)
2.61
2.80
Serum HBV DNAPCR-negative
Week 24 PCR-negative (P<0.001)
5.66
Baseline HBV DNA (P=0.015)
Baseline ALT (P=0.005)
BMI (P=0.021)
2.00
2.00
1.73
Resistance
Week 24 PCR-negative (P<0.001)
Age (P<0.001)
Gender (P=0.028)
0.16
0.40
0.49
0 1 2 3 4 5 6 7 8 9 10 11
ALT normalization
Week 24 PCR-negative (P=0.002)
Age (P=0.004)
3.98
3.74
BMI (P=0.010)
Serum HBV DNAPCR-negative
Week 24 PCR-negative (P<0.001)9.76
3.79
24.4
Resistance
0.06
0.10
0.23
0.23
Week 24 PCR-negative (P<0.001)
Baseline Ishak fibrosis score (P=0.002)
BMI (P=0.039)
Age (P=0.047)
Odds ratio ± 95% CI
0 1 2 3 4 5 6 7 8 9 10 11
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
HBeAg(+) HBeAg(-)
Baseline Variables and On-Treatment (Week 24) Predictors of Week 104 Outcomes
71% of telbivudine treated patients achieved
PCR negativity at Week 24(n=57/80)
Baseline ALT ≥2 x ULN, HBV DNA <9 log10
(n=80)
89% PCR-negative
at Week 104(n=51/57)
52% Seroconversion
at Week 104(n=25/48)
1.8% Resistance at Week 104
(n=1/57)
81%ALT normalat Week 104
(n=46/57)
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
Globe SubstudyWeek 104 Outcomes With Telbivudine: HBeAg(+)
95% of telbivudine treated patients achieved
PCR negativity at Week 24(n=86/91)
Baseline HBV DNA <7 log10
(n=91)
91% PCR-negative
at Week 104(n=78/86)
2% Resistance at Week 104
(n=2/86)
83% ALT normalat Week 104
(n=57/69)
Week 104 Outcomes With Telbivudine: HBeAg(-)
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
Globe Substudy
Conclusions
▬ High rates of efficacy and low resistance occurred after 2 years telbivudine treatment in patients with:- HBeAg(+) and elevated ALT and HBV DNA <9 log10 c/mL
- HBeAg(-) and <7 log10 c/mL at baseline
- Optimal viral load reduction at week 24
▬ These parameters may contribute to on-treatment patient management strategies
Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.
GLOBE Substudy
Brown C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 940.
1.00
0.75
0.50
0.25
0
0 100 200 300 400 500 600 700 800
Su
rviv
al D
istr
ibu
tion
Fu
nct
ion
* Grade 1–2 CK elevations are only counted for subjects who did not have Grade 3–4 CK elevation
LdT
LAM
Chronic Telbivudine Therapy: Creatine Kinase Elevations and Muscle Toxicity
▬ FDA review of the telbivudine approval database for CK elevations and adverse event patterns consistent with muscle toxicity- Data reviewed from trials that prospectively measured CK levels and recorded clinical adverse events, and
in which LdT was used in at least one arm- Time to onset and frequency of CK elevations from the pivotal phase 3 trial (52 week data) were assessed
Time-to-Onset (days) of New-Onset CK Elevations (Grade 1-4) in NV-02B-007*
Conclusions
▬ Emerging pattern of a myopathy with chronic telbudine therapy- Unknown if associated with mitochondrial toxicity
▬ Imperfect relationship between the timing and severity of CK elevations and myopathy and variable demography and symptom presentation- Further characterization of toxicity, including mechanism
and predisposing factors, warranted
▬ Myopathy may occur more frequently in the population treated longer-term with telbivudine
Brown C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 940.
LdT Myopathy
Model for Predicting Sustained HBeAg Loss with Peginterferon Alfa-2b
▬ 233 pts randomized to PEG-IFN α-2b 100 μg ± LAM100 mg for 52 weeks
▬ Univariate logistic regression analysis, followed by backward stepwise selection used to identify predictors of HBeAg loss at 26 weeks- Model based on HBV genotype, serum HBV DNA, ALT, GGT and previous IFN therapy provided an
adequate prediction of PEG-IFN induced HBeAg loss
▬ Nomogram was generated from the logistic regression formula
Buster E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1002.
Probability of sustained HBeAg loss:Calculated by drawing a vertical line to the top points axis through each variable. Sum points for each variable and locate on Total score axis. A vertical line is projected from Total score axis to the bottom scale to get predicted probability
Probability of sustained HBeAg loss:Calculated by drawing a vertical line to the top points axis through each variable. Sum points for each variable and locate on Total score axis. A vertical line is projected from Total score axis to the bottom scale to get predicted probability
log it (p) – 3.3861 -42854 *(geno-B) -26463 *(geno-C) -0.4907 * (geno-D) +1.4497 *log ALT -0.8043 * previous IFN -0.3849 *log HBV DNA +1.2644 * log GGT +6.8256 *log ALT *(geno-B) +2.3102 *log ALT *(geno-C) -0.3586 –log ALT *(geno-D).
Chance HBeAg Loss (%)Chance HBeAg Loss (%)
Total ScoreTotal Score
Previous IFNPrevious IFN
HBV DNA (log)HBV DNA (log)
GGT (x ULN)GGT (x ULN)
PointsPoints
ALT
(x
ULN
)by
Gen
otyp
eA
LT (
x U
LN)
by G
enot
ype A
B
C
D
A
B
C
D
55 1010 2020 3030 4040 50506060 7070 8080 9090 9595
00 44 66 222222 88 1212 14141010 1616 20201818
YesYes NoNo
1111 99 881010 77 5566
11 3322 55
n14n14
11 3322 44
11 33 44
11 44
00 22 33 101011 44 66 7755 9988
Cases Demonstrating Use of Nomogram
Point Per Variable:
Total Score
ChanceHBeAg Loss
ALT – Genotype
HBV DNA
GGTPrevious
IFN
Case ITurkish male with genotype D infection, ALT 1.2 x ULN, GVB DNA 8 log10 copies/mL, GGT 0.8 X ULN and previously treated with IFN.
8.3 2.6 0 0 10.9 27%
Case IIChinese female with genotype C infection, ALT 0.9 x ULN, HBV DNA 9.65 Log10 copies/mL, GGT 0.3 x ULN and no previous IFN.
3.6 1.25 0 1.8 6.65 <5%
Case IIIDutch male with genotype A infection, ALT 3.8 x ULN, HBV DNA 9.4 Log10 copies/mL, GGT 2.1 x ULN and no previous IFN.
9.9 1.4 0.9 1.8 14.0 61%
Buster E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1002.
Effect of Lamivudine ± Adefovir on Esophageal Varices (EV)
▬ Open-label, prospective cohort study- 123 HBeAg(-), cirrhotic pts on LAM (100 mg/d) ADV
(10 mg/d)
▬ Intensive F/U- LFTs and HBV DNA every 2 mos.- Drug-resistance test, AFP and US scan every 6 mos.- Upper GI endoscopy at baseline and every other year
for pts without EV and every year for pts with EV
▬ Multiple Endpoints Assessed
Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.
*median (range)
Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.
Age, mean (years) 54 (34-72)
Male, No. 106 (86%)
ALT, IU/L* 56 (19-840)
HBV DNA, log10 cps/mL* 6.0 (3.5-9.3)
Child-Pugh’s Score A 100 (81%)
Esophageal Varics
F0 84 (68%)
F1 32 (26%)
F2 6 (5%)
F3 1 (1%)
CRS 2 ( 2%)
PHG 34 (28%)
Baseline Characteristics
Follow-up*
Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.
F0N=84
Unchanged75 (89%)
Worsened9 (11%)
Development Rate2.0% X year
Due to decompensation, HCC
F0N=32
Improved16 (50%)
Worsened3 (9%)
Progression Rate2.0% X year
Due to thrombosis, HCC
Unchanged13 (41%)
*Median of 76 mos. (range 11-126 mos.)
EV During 76 Months of LAM±ADV
Changes in Size of EV with LAM±ADV
▬ EV worsened in 3% with long-term HBV suppression with LAM±ADV vs. 25% with LAM+ADV after clinical resistance (p=0.0003)
▬ Overall, yearly rates of development and progression of EV were 2.0 and 2.0, respectively, both lower than expected in cohort of untreated virologic cirrhosis
*HBV-DNA persistently < 3.3 log10 copies/ml on therapy with LAM or LAM+ADV for virological resistance**HBV DNA10 > 6 log and ALT > ULN, confirmed by molecular analysis.
Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.
0
20
40
60
80
100RegressionStableProgression (p=0.0003)
Response*N=81
Resistance**N=42
10
30
50
70
90
New Therapies for HBV Treatment
Mark Sulkowski MD
Johns Hopkins School of Medicine
Baltimore, MD
Novel HBV Therapy
▬ HBV replication is closely linked to the life-time risk of disease outcomes (HCC, ESLD)
▬ New treatment paradigm = long-term suppression of HBV replication:- ↓ hepatic inflammation and fibrosis - ↓ risk of hepatic decompensation and/or HCC
▬ Increasing recognition of resistant HBV variants in previously treated persons
▬ Role of new anti-HBV therapies - Tenofovir- Clevudine- α-glalactosylceramide - Combination antiviral therapy
Tenofovir DF is a Nucleotide Analogue Inhibitor of HBV DNA Polymerase
▬ TDF is a nucleotide analogue- Inhibits HIV-1 RNA transcriptase and HBV DNA
polymerase- Obligate chain terminator
▬ TDF shown to have activity in patients mono-infected with HBV and co-infected with HIV/HBV
▬ TDF is approved for the treatment of HIV-1 infection - 1.3 million patient years safety exposure in HIV and 6
years clinical safety data
▬ Two pivotal HBV trials
Study GS-US-174-0103:TDF vs. ADV in HBeAg(+) Pts
Randomized, Double-Blind, Comparison of Tenofovir vs. Adefovir for HBeAg(+) Chronic Hepatitis B▬ Treatment naïve, HBeAg(+),18-69 years of age with compensated liver disease▬ HBV DNA >106 c/mL and ALT ≥ 2x and < 10xULN▬ Knodell Necroinflammatory score ≥ 3▬ HIV, HDV, HCV negative
RA
ND
OM
IZA
TIO
N 2
:1
Tenofovir 300 mg (n =176)
Adefovir 10 mg (n = 90)
Open-label5 Years
Week 240Liver Biopsy
Week 48Liver Biopsy
Pre-treatment Liver Biopsy
Double Blind
Tenofovir 300 mg
Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.
Primary Endpoint of Complete Response:HBV DNA <400 copies/mL AND Histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)
Primary Endpoint of Complete Response:HBV DNA <400 copies/mL AND Histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)
Baseline Characteristics
TDF(N=176)
ADV(N=90)
Mean Age 34 34
Race White Asian
52%36%
51%36%
Male 68% 71%
Mean HBV (log10 c/mL) 8.64 8.88
Mean ALT (U/mL) 142 155
Mean Knodell Necroinflammatory Score 8.3 8.5
Mean Knodell Fibrosis Score 2.1 2.3
Knodell Fibrosis (Score = 4) 20% 21%
Genotype A B C D
24%15%25%32%
21%11%30%35%
Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.
GS-US-174-0103
Primary and Secondary Endpoints (ITT)
P<0.001P>0.05 P<0.001
% P
atie
nts
Complete Response Histological Improvement
HBV DNA<400 copies/mL
6774 76
12
68
13
0
10
20
30
40
50
60
70
80
90
100
TDF
ADV
Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.
GS-US-174-0103
Mean HBV DNA Change
Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.
GS-US-174-0103
P<0.001
Treatment
TDFADV
Me
an
(9
5%
CI)
HB
V D
NA
(L
og
10 C
op
ies/
mL
)
1
2
3
4
5
6
7
8
9
10
Weeks on Study0 4 8 12 16 20 24 28 32 36 40 44 48
176TDF N=176176 173173173 165165165 166166166 160160160 90ADV N= 90 90 88 88 88 85 85 85 84 84 84 84 84 84
LLOQ
Study GS-US-174-0102:TDF vs. ADV in HBeAg(-) Pts
Randomized, Double-Blind, Comparison of Tenofovir vs. Adefovir for HBeAg(-) Chronic Hepatitis B▬ HBeAg(+),18-69 years of age with compensated liver disease▬ HBV DNA >105 c/mL and ALT ≥ 2x and < 10xULN▬ Knodell Necroinflammatory score ≥ 3▬ HIV, HDV, HCV negative▬ LAM Experienced or Naïve
RA
ND
OM
IZA
TIO
N 2
:1
Tenofovir 300 mg (n =250)
Adefovir 10 mg (n = 125)
Open-label5 Years
Week 240Liver Biopsy
Week 48Liver Biopsy
Pre-treatment Liver Biopsy
Double Blind
Tenofovir 300 mg
Marcellin P, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB2.
Primary Endpoint of Complete Response:HBV DNA <400 copies/mL AND Histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)
Primary Endpoint of Complete Response:HBV DNA <400 copies/mL AND Histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)
Baseline Characteristics
TDF(N=250)
ADV(N=125)
Mean Age (years) 44 43
Race White Asian
64%25%
65%24%
Male 77% 78%
Mean HBV DNA (log10 c/mL) 6.86 6.98
Mean ALT (U/L) 128 164
Mean Knodell Necroinflammatory Score Mean Knodell Fibrosis Score
7.82.3
7.82.4
Knodell Fibrosis Score = 4 (Cirrhosis) 19% 20%
Genotype A B C D
12%9%12%64%
11%14%10%63%
Marcellin P, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB2.
GS-US-174-0102
Primary and Secondary Endpoints
P<0.001P>0.05
P<0.001
% P
atie
nts
(IT
T)
Complete Response
Histological Improvement
HBV DNA<400 copies/mL
71 72
93
49
6963
0
10
20
30
40
50
60
70
80
90
100TDF
ADV
Marcellin P, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB2.
GS-US-174-0102
Mean HBV DNA Change
Marcellin P, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB2.
GS-US-174-0102
P<0.001
LLOQ
Treatment
TDFADV
Me
an
(9
5%
CI)
HB
V D
NA
(L
og
10
Co
pie
s/m
L)
1
2
3
4
5
6
7
8
Weeks on Study
0 4 8 12 16 20 24 28 32 36 40 44 48
250TDF N= 250250 242242242 239239239 242242242 241241241125ADV N= 125125 123123123 121121121 117117117 117117117
Safety and Resistance
▬ Grade 2-4 AEs: No significant differences▬ AEs leading to discontinuation: None drug-related▬ No TDF or ADV subject had a confirmed 0.5 mg
increase in serum creatinine or creatinine clearance < 50 ml/min
▬ Incidence of ALT flare (>10 x ULN and 2 x baseline) was low and similar in the two treatment groups (1.2% vs. 0.8%)
▬ No subject developed mutations associated with TDF resistance
Marcellin P, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB2.
GS-US-174-0102
Tenofovir in Treatment-Experienced Patients
▬ Retrospective Cohort (n=108)- TDF 300 mg/d
▬ Inclusion criteria- Chronic HBV infection,
HBeAg(+) or (-)- Rx naive or experienced
(nucleos(t)ide analogs or interferon-α)
▬ Pts with genotypic resistance to ADV excluded
Baseline Characteristics
Age (mean years) 42
Male sex 78%
Cirrhosis 19%
HBeAg(+) 69%
HBV DNA (mean log10 copies/mL) 6.6 (4 - 9.7)
ALT (mean U/L) 154 (10 – 1597)
LAM Experienced 86%
YMDD Mutations 59%
ADV Experienced 77%
Treatment Naive 5.5%
Van Bömmel F, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 83.
TDF in ADV-resistant HBV
▬ In vitro, ADV resistance mutations confer partial resistance to TDF- rtN236T ~ 5-fold decrease and
rtA181T/V ~ 1-fold decrease
▬ 10 HBV monoinfected pts with ADV resistance treated with TDF 300 mg/day
▬ Significant HBV DNA responses:- End of follow-up (17.4 months,
12 – 24), 6 pts < 1000 c/mL and 5 pts < 400 c/mL
- 2 pts added LAM: Both < 400 c/mL
▬ Persistence of ADV resistance variants but no new mutations identified
Van Bömmel F, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 960.
-3.3
-4.4
6 Months 12 months
Median HBV DNA Decline on TDF (log10c/mL)
Clevudine Decreases HBsAg titer
▬ Oral, once daily pyrimidine nucleoside analog (marketed in Korea)- Published reports indicate significant activity against
HBeAg(+) and (-)
▬ 50 Rx naïve patients- Clevudine 30mg/day x 24 weeks followed by 10 mg/day
for 24 weeks- HBsAg and HBV DNA (LOD = 300 copies/mL) followed
Byun KS, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 985.
Clevudine Outcomes
▬ HBV suppression was associated with a significant decrease in HBsAg titer
▬ Clinical significance of reductions in HBsAg is not known- Potential for increased
HBsAg clearance - Limited clinical utility
Byun KS, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 985.
HBV DNA and HBsAg change in pts with HBsAg > 40,000 IU/mL
HBV DNA and HBsAg change in pts with HBsAg > 40,000 IU/mL
-
20,000
40,000
60,000
80,000
100,000
D1 W12 W24 W36 W48
HB
sAg(
IU/m
L)
0
2
4
6
8
HB
V D
NA
(lo
g 10)
HBsAg HBV DNA
α-Galactosylceramide:Ineffective in HBV infection
▬ α-Galactosylceramide (α–GalCer)- Actives NK cells - Immunomodulatory activity via proinflammatory cytokines
(e.g., IL-6)- Inhibits HBV replication in transgenic mice
▬ Randomized controlled trial, 27 patients with CHB- α–GalCer 0.1, 1, 10 µg/kg or placebo via SC injection at
0, 4, 8 weeks
▬ No effect on HBV DNA or serum ALT level▬ Poorly tolerated
ter Borg M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1004.
▬ In vitro anti-HBV activity alone or in combination in human hepatoma cell line▬ Additive antiviral effect observed with LdT + TDF and weak synergistic effect with
LdT + ETV
▬ Mutation at position M204 confers resistance to both LdT and ETV ▬ Conclusion: “The use of LdT in combination with ETV is not recommended in the clinic”
In vitro Activity of Telbivudine Plus Tenofovir or Entecavir
Patty A, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 958.
Anti-HEV in vitro activity of (a) LdT and ETV alone and in combination and (b) LdT and TDF alone and in combination
Anti-HEV in vitro activity of (a) LdT and ETV alone and in combination and (b) LdT and TDF alone and in combination
HB
V D
NA
, %
HB
V D
NA
, %
a)a)
Increasing Drug Concentration Increasing Drug Concentration
8080
6060
4040
2020
00
LdT aloneLdT aloneETV aloneETV aloneLdT + ETV 1.25 nMLdT + ETV 1.25 nM100100
b)b)
Increasing Drug Concentration Increasing Drug Concentration
8080
6060
4040
2020
00
LdT aloneLdT aloneTDF aloneTDF aloneLdT + TDF 0.16 µMLdT + TDF 0.16 µM100100
Resistance Issues with HBV Treatment
Yves Benhamou MD
Groupe Hospitalier Pitie-Salpetriere
Paris, France
HBV Resistance Mutations
845 a.a.
Terminalprotein
Spacer Pol/RT RNaseH
A B C ED
YMDDGVGLSPFLLA
I(G) II(F)
LAM Resistance rtL80V/I rtV173L rtM204V/I/SrtL180M
ADV Resistance rtA181T/V rtN236T
rtI233V ??
ETV Resistance rtL180M rtM204V/I
rtT184S/A/I/L rtS202G/C rtM250I/V
LdT Resistance rtL80V/I rtL180M rtM204I L229W/V
Locarnini S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1003.
HBV Polymerase Mutations by Treatment
V1
73L
A1
81V
L1
80M
A1
84G
I16
9T
LAM
ETV
LdT
ADV
Resistance Mutations Associated with Viral Breakthrough in Patients on Treatment L
80I
/V
Primary Mutation Compensatory Mutation
A1
81T
S2
02I
M2
04
I
M2
04
V
L2
29W
/V
N2
36T
M2
05
V
Cross resistance
Locarnini S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1003.
Cross-resistance To Multiple Antiviral Agents
▬ NRTI have revolutionized the treatment of CHB
▬ Sequential NRTIs can promote the emergence of multi-drug resistant mutants
▬ Case report of HBeAg(-) patient - Poor response to sequential ADV, LAM and ETV- Polymerase substitutions: rtA181T, rtI233V, rtN236T and rtM250L- Cloning established that these encoded on single genome- Multi-drug resistance on phenotype were determined
▬ Mutant HBV clones encoding rtI233V, rtM250L, rtA181T/N236T/M250L and rtA181T/I233V/N236T/M250L were generated by site directed mutagenesis
▬ Virus replication and its inhibition were monitored
Shaw T, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 986.
In Vitro Assessment of Effect of Resistance Mutations
▬ rtA181T/I233V/N236T/M250L- High level resistance to all L-nucleosides: LAM, LdT, Clevudine
and Emtricitabine
- Lower level resistance to ADV and TDF
▬ rtI233V and M250L no significant drug resistance▬ Conclusions:
- Sequential treatment with NRTI promotes multi-drug resistance.
- Combination therapy optimized to individual viral phenotypes could reduce multi-drug resistance.
Relative Sensitivity to L-nucleosides
Relative Sensitivity to Deoxyguanosine Analogs
Relative Sensitivity to Acyclic PurineNucleotide Analogs
Shaw T, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 986.
Ra
tio (
ML
/Wt)
WT
-0.10
1.00
10.00
rtQ33V
LdTLFMAULMVFTC
rtM250L Triple Quad
Ra
tio (
ML
/Wt)
WT
-0.10
1.00
10.00
rtQ33V
ETVFLGDAPDABV
rtM250L Triple Quad
Ra
tio (
ML
/Wt)
WT
-0.10
1.00
10.00
rtQ33V
ADV
TDFANA
rtM250L Triple Quad
HBV Quasispecies From Naïve to Viral Breakthrough
▬ HBV polymerase gene (rt1-rt280) was cloned before and at breakthrough during LAM therapy in 5 CHB patients with LAM failure
▬ Before treatment mutations at the LAM and ADV resistance sites were found▬ At the time of viral breakthrough, LAM resistant mutations were identified in 94%▬ No mutations at rt169, rt181, rt184, rt202, or rt236 were identified▬ Mutations in the polymerase gene of HBV preexist▬ Early detection of drug-resistant mutants before antiviral therapy may prevent treatment failure
Ahn SH, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 912.
L80 V/I T125N W153Q I169T V173L L180M A151V/T M204V/I Q215S
P1 7% 8% 2% 1% 1%
P2 1% 1% 2% 1% 1%
P3 1% 1% 1%
P4 2%
P5 1% 1% ?? / 1% 0% / 2%
P6 2% / 1%
P7 1% 1%
Pre-existing LMV Resistance Mutations at PretreatmentPre-existing LMV Resistance Mutations at Pretreatment
Restores replication in presence of LMV (J Viral Hepat 2006, 13 427)
Increased Resistance to ADV and ETV Over Time
▬ Number of available anti-HBV drugs is increasing ▬ Increasing use of antivirals can affect the frequency of
resistance mutations in the treated population.▬ Emergence of resistance may compromise efficacy of
drugs in the future▬ Large clinical database of HBV polymerase gene sequences
(n=10,800 clinical samples) to assess changes in the prevalence of resistance-associated mutations for LAM, ADV and ETV over a 5-year period (2002-2007)
Kagan RM, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 954.
ADV and ETV Resistance Tracks Prescription Utilization
Kagan RM, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 954.
An
nu
al P
resc
riptio
ns
x 1
00
1,000
800
600
400
200
0
0.8%
0.7%
0.6%
0.5%
0.4%
0.3%
0.2%
0.1%
0.0%Y2005 Y2006 Y2007*
Year
ETV prescriptions Predicted ETV resistance
Pre
dicte
d R
esista
nce
1,600
1,200
800
400
0
4%
3%
2%
1%
0%Y2003 Y2005 Y2007*
Year
ADV prescriptions Predicted ADV resistance
Y2004 Y2006
Frequencies of LAM and ADV Associated Mutations Vary by HBV Genotype
Genotype A
(N=1726)
Genotype B
(n=2898)
Genotype C
(n=3191)
Genotype D
(n=791)P*
LAM
M204V 11% 2.6% 3.7% 3.9% <0.001
M204I 2.5% 2.7% 4.8% 3.4% <0.001
L181M 12% 2.8% 5.8% 5.8% <0.001
ADVA181T 0.8% 0.4% 2.5% 1.1% <0.001
A181V 0.5% 0.4% 1.8% 1.5% <0.001
N236T 0.5% 1.6% 1.2% 1.3% NS
* Chi-square test with 3 d.f. and a Bonferroni correction for 6 comparisons* Chi-square test with 3 d.f. and a Bonferroni correction for 6 comparisons
Kagan RM, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 954.
Conclusions
▬ Prevalence of LAM resistance has declined▬ Prevalence of ADV and ETV resistance has
increased with their utilization▬ Resistance to:
- LAM higher in HBV genotype A- ADV higher in HBV genotype C
Kagan RM, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 954.
Double-Blind Study
Nucleoside Therapy
ETV-047
Naïve
ETV-053
Naïve
ETV-052
LAM refractory
HBV DNA (copies/mL) ≥107,8 ≥105 ≥105
ObjectiveDose-response,
bridgingSafety and efficacy Safety and efficacy
Treatment Group0.01, 0.1, 0.5mg ETV
100mg LAM0.1, 0.5mg ETV 0.5, 1mg ETV
Duration (Weeks) 24 52 52
No. of Patients 137 66 84
Rollover Study (ETV-060)
Open Study ETV-080
Treatment Group 0.5mg 0.5mg 1mg
No. of Patients 134 66 82
Long-Term Emergence of Entecavir Resistance in HBeAg(+) Patients
▬ Study Design: Cumulative resistance assessed in patients from three phase 2 dose ranging studies (n=284) prior to entering an open-label rollover study of ETV (ETV-060)
Kobashi H, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 963.
Genotypic Resistance of ETV in Nucleoside Naïve Patients
▬ 5/167 patients had evidence of genotypic ETVr over 3 year period of treatment
▬ 1/66 patients who received continuous treatment for 3 years of ETV 0.5 mg daily had evidence of ETVr
Kobashi H, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 963.
ETV-047Naïve 103 pts
1 Year(ETV-060)
-2 Year(100w)
-3 Year(148w)
0.01mg: 35pts 0 pts 0 pts 2 pts35 pts
24 weeks
0.01mg: 34pts 0 pts 0 pts 1 pts34 pts
0.05mg: 34pts 0 pts 0 pts 0 pts32 pts
ETV-053Naïve 86 pts
0.1mg: 32pts 0 pts 0 pts 1 pts32 pts
52 weeks
0.5mg: 34pts 0 pts 0 pts 1 pts34 pts
At Approved
Dose0.5mg: 66pts 66 pts 1/66 pts (1.5%)
▬ 29/82 LAM resistant pts had evidence of genotypic ETV resistance over 3 year period of treatment and 21 of them experienced breakthrough
Genotypic Resistance of ETV in LAM Refractory Patients
Kobashi H, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 963.
1 Year(ETV-060)
-2 Year(100w)
-3 Year(148w)
ETV-052LAMr 84 pts
0.5mg* 0 pts 11 pts 6 pts32 pts
52 weeks
1.0mg 0 pts 8 pts 4 pts42 pts
At Approved
DoseCumulative ETVr substitutions
12/42 pts (29%)
0 pts 8 pts 12 pts
1 Year(ETV-060)
~2 Year(100w)
~3 Year(148w)
Total 82 pts
* Approved dose to LAMr patients is 1.0mg daily
LAMr before ETV Emerged ETVr
L180M+M204I/V
(n=15)
T184A (n=9)
S202G (n=3)
T184A+S202G (n=3)M204V
(n=6)
L180M+T184A (n=4)
L180M+S202G (n=2)
ADV in LAM-resistant CHB
▬ Evaluation of ADV in LAM-resistant CHB- 146 HBeAg(+) CHB with
LAM-resistance- Treated with ADV mean
of 25 mos. (12-42)
▬ Response rates and role of primary non-response in prediction of virologic response and resistance evaluated
Park NH, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 983.
Primary non-response: Decrease in HBV DNA < 2 log copies/mL from baseline at week 24 of ADV
100
80
60
40
20
0
0
(%)
P < 0.05
Primary Responder
Primary Non-responder
12 24 36 48Months
Cu
mu
lati
ve R
ate
of
Vir
olo
gic
Res
po
nse
Month %
12 9.9
24 26.6
36 48.3
Primary Responder
Month %
12 2.9
24 7.5
36 12.2
Primary Non-responder
Cumulative rates of virologic response
ADV in LAM-resistant CHB
*Breakthrough: > 1 log10 c/mL increase in HBV DNA from nadir †Primary non-response: Decrease in HBV DNA < 2 log copies/mL from baseline at week 24 of ADV
Park NH, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 983.
Month %
12 2.7
24 11.2
36 24.9
Month %
12 13.2
24 25.1
36 62.4
100
80
60
40
20
0
0
(%)
P < 0.05
Primary Responder
Primary Non-responder
12 24 36 48Months
Cum
ulat
ive
Rat
e of
Viro
logi
c B
reak
thro
ugh Primary Responder Primary Non-responder
Breakthrough* in Primary Non-responders and Responders† During ADV Therapy
58th Annual Meeting of the American Association for the
Study of Liver Diseases
Boston, MA
November 2-6, 2007