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Post Conference Update: Highlights from the American Association of the Study of Liver Diseases
MARK SULKOWSKI, MDMARK SULKOWSKI, MD
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Medical Director, Viral Hepatitis Center
Johns Hopkins Medical Institution
Baltimore, Maryland
2
Learning Objectives (CME, CE, CPE)
● At the completion of this educational activity, participants should be able to:
- Discuss significant developments in the diagnosis and management of hepatitis B
- Summarize new drugs and treatment strategies for hepatitis B
- Describe toxicity of recent hepatitis therapies, drug side effects, and strategies for management
- Identify new therapeutic strategies to avoid or overcome antiviral resistance
- Highlight diagnosis and management approaches for hepatitis B in individuals co-infected with HIV
Epidemiology and Natural History of HBV Infection
4
Estimated Prevalence of Chronic Hepatitis B in Foreign-Born Persons Living in the United States
Centers for Disease Control and Prevention (CDC) estimates that <0.5% of the US population (800,000-1.4 million) are living with CHB
— Published estimates of CHB in foreign-born (FB) populations in the United States vary and are limited
— Recent studies taking into account all FB persons estimate prevalence of CHB in United States at ~2.0 million persons
Study to determine estimated prevalence of CHB in FB persons in the United States
— Census data used to estimate number of FB persons in the United States from 93 countries/regions
— Published CHB prevalence rates by countries/regions used to model low, mid, and high rates of CHB each
— Number of FB persons with CHB estimated by multiplying each FB population by its prevalence rate
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
5
Total and Foreign-Born US Population, 1970-2008
FB persons living in the United States increased from 20 million in 1990 to 41 million in 2008
050
100150200250300
350400450
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
1998
2000
2002
2004
2006
2008
FB
US
Pop
ulat
ion
(mill
ions
)
OtherAsiaLatin AmericaEuropeTotal US Population
OtherAsiaLatin AmericaEuropeTotal US Population
Tot
al U
S P
opul
atio
n (m
illio
ns)
5
1015202530
354045
0
4.7% FB 7.9% FB 13.6% FB
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
6
Published CHB Prevalence Rates and Low, Mid, and High CHB Rate Assumptions: China
Low, Mid, and High Rate Estimate Assumptions
Published CHB Rate From Review or Model
Published CHB Rate in Immigrants
Published CHB Rate From Population Study
Number in parentheses= sample size
CHB prevalence rates, China
0%
5%
10%
15%
20%
25%
Blood d
onors
, Sing
apor
e, 19
87
(662
)
Popula
tion,
six ci
ties
Pregn
an
t wom
en, N
ative
toHon
gKon
g (1
,2
20)
Pro
fe
ss
ion
al, te
chnic
al, a
dmin
worke
rs(1
,23
2)
Wom
en, J
ilin P
rovin
ce, N
E Chin
a (1
00)
Dep
artm
ent s
tore
emplo
ye
es, B
eijing
(361
)
Low
estim
ate
Pregn
ant w
omen
, Main
land
m
igran
ts to
HK(9
85)
Gen
eral
hosp
ital p
at
ients,
Hon
g Kon
g
(300
)
Pregn
ant w
omen
, Hon
gKon
g(7
07)
Agricu
lture
& fa
ctory
worke
rs(2
,277
)
Chines
e-bo
rnpe
rsons
in S
F Bay ar
ea
(1,0
16)
Pregn
ant w
omen
(14,
575)
Wom
en o
f child
bear
ingag
e(G
olds
tein
MODEL)
Chines
ear
m
y vete
rans
(100
)
Main
landbo
rnChin
ese
adole
scen
tsin
HK
Chines
e-
born
perso
nsin
UK(1
17
)
Gener
alpo
pulat
ion(O
ster M
ODEL)
Mid
estim
ate
Villa
ges in
sout
hern
Taiw
an
(6
,0
95)
Wom
enin
rura
l are
as(1
,1
80)
Govt e
mplo
ye
es, M
ainlan
d
migr
ants
toHK
(2
2,70
7)
Ran
do
msa
mple
of
gene
ral
popu
lat
ion (6
,5
00)
Gen
eral
popu
lation
, J
iangs
upr
ovinc
e(1
01)
Barbe
rs, B
eijing
(316
)
Highes
timate
Gen
eral
popu
lation
, Fuji
an(3
,809
)
Contro
l pop
ulatio
n, Y
angtz
e
River r
egion
(114
)
Steel
worke
rs,Sha
ngha
i (69
0)
Chin
ese-
born
perso
nsin
NYC(5
66
)
IVdr
ug
user
s
Ethnic
Yao
Prison
er
s
Ethnic
Tibe
tan
Fam
ily
mem
bers
of H
BsA
g
+
carri
ers
Per
cent
HB
sAg-
posi
tive
wer RiskGroups
Higher RiskGroups
Chinese-bornpersonsin UK
Chinese-bornpersonsin NYC
Chinese-bornpersons in
San Francisco
LowEstimate10.0%
MidEstimate13.6%
HighEstimate17.0%
CHB Prevalence Rates: China
0%
5%
10%
15%
20%
25% Low Estimate10.0%
Low Estimate10.0%
Chinese-BornPersons in
San Francisco
Chinese-BornPersons in
San Francisco
Chinese-BornPersons in
UK
Chinese-BornPersons in
UK
Mid Estimate13.6%
Mid Estimate13.6%
High Estimate17.0%
High Estimate17.0%
Chinese-BornPersons in
NYC
Chinese-BornPersons in
NYCP
erce
nt
HB
sAg
Po
siti
ve
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
7
Published CHB Prevalence Rates and Low, Mid, and High CHB Rate Assumptions: IndiaCHB prevalence rates, India
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
11%
12%
Per
cent
HB
sAg-
posi
tive
Lower RiskGroups
Higher RiskGroups
LowEstimate
0.2%
MidEstimate
1.0%
HighEstimate
2.0%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
11%
12%
CHB Prevalence Rates: IndiaLower RiskGroups
Lower RiskGroups
Low Estimate0.2%
Low Estimate0.2%
Mid Estimate1.0%
Mid Estimate1.0% High Estimate
20.%High Estimate
20.%
Higher RiskGroups
Higher RiskGroups
Per
cen
t H
BsA
g P
osi
tive
Low, Mid, and High Rate Estimate Assumptions
Published CHB Rate From Review or Model
Published CHB Rate From Population Study
Number in parentheses= sample size
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
8
Percent of FB Population and FB With CHB by Place of Birth
Asia
South/Latin America
Africa
Europe/Oceania
North America
0% 5% 10% 15% 20% 25% 30% 35%
China
Vietnam
Philippines
Korea
India
Other Asia
Mexico
El Salvador
Caribbean
South America
Other Latin America
Western Africa
Eastern Africa
Other Africa
Eastern Europe
Southern Europe
Other Europe
Oceania
North America
Total FB Population (%)
FB With CHB (%, mid estimate)
Pla
ce o
f B
irth
Percent in United States
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
9
Study Results
Number of FB persons with CHB in the United States ranges from 850,000 to 2,240,000 persons
— 52%-62% from Asia— 13%-15% from Africa— 9%-18% from Central America
Average CHB prevalence rate among the FB population is 2.0%-5.4%
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
10
New CDC Recommendations:HBV Screening for FB Persons From Countries With
Intermediate HBV Prevalence Rates (≥2%)*
CDC List of Countries With Hepatitis B Prevalence ≥2%
Region HBsAg prevalence ≥2%
Africa All countries
Asia All countries
Australia and South Pacific All countries except Australia and New Zealand
Middle East All countries except Cyprus and Israel
Eastern Europe All countries except Hungary
Western Europe Malta, Spain, and indigenous populations in Greenland
North America Alaska Natives and indigenous populations in Northern Canada
Mexico and Central America Guatemala and Honduras
South America Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas of Bolivia, Brazil, Columbia, and Peru
Caribbean Antigua-Barbuda, Dominica, Grenada, Haiti, Jamaica, St. Kitts-Nevis, St. Lucia, and Turks and Caicos Islands
*September, 2008; change from ≥8%
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
11
Study of FB Persons in the United States With CHB: Conclusions
Number of FB persons with CHB in the United States may be higher than previously thought
High CHB prevalence rate and related morbidity and mortality argue for building surveillance systems
— Will help develop programs for prevention, earlier diagnosis, and linkage to care
New CDC recommendations extending screening to FB persons from countries with intermediate HBV prevalence could identify more than 250,000 additional FB persons with CHB
Welch S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 853.
12
Evaluation of ALT Determination for Assessing Chronic Hepatitis B (CHB)
Study of 1,335 CHB patients enrolled into registration trials of TDF and ADV to evaluate:
— Concordance between ≥2 ALT values ≤60 days apart
— Liver histology with a single normal range ALT (NRALT)
— Risk factors for significant liver disease
— Association of established (men ≤43 U/L; women ≤34 U/L) and new (men ≤30 U/L; women ≤19 U/L) ALT ULN values with liver disease severity
Pretreatment ALT measured on ≥2 occasions (screening, baseline)— All patients had ≥1 screening ALT >ULN
— Intermittent ALT elevation, ≥1 NRALT (IE ALT)
— Persistent ALT elevation, all ALT values >ULN (PE ALT)
All patients had a liver biopsy between screening and baseline visits
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
13
IE ALT*(n=60)
PE ALT†
(n=275) P value
Age (yrs)Mean±SDRange≥40 yrs old
39.4±11.520-65
32 (53.3%)
38.8±12.016-69
607 (47.6%)
0.658
Gender (% men) 63% 76% 0.031
Race (% Asian) 42% 41% 0.930
HBeAg positive 17 (28%) 748 (58.8%) <0.001
Baseline HBV DNA (log10 copies/mL)Mean±SD Range
6.3±1.33.6-9.0
7.8±1.22.2-10.9
<0.001
Baseline ALT‡ (U/L)Mean±SD Range
44.6±31.66-223
144.2±127.036-1459
<0.001
Patient Demographics andDisease Characteristics
*Intermittent ALT elevation, ≥ 1 NRALT ; †Persistent ALT elevation, all ALT values > ULN; ‡ALT ULN: men ≥43 U/L; women ≥34 U/L
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
14
Liver Histology in Patients With Intermittently Versus Persistently Elevated ALT*
*ALT ULN: men ≤43 U/L; women ≤34 U/L
19/5919/5919/5919/59
581/1246581/1246581/1246581/1246
33/5933/5933/5933/59
993/1247993/1247993/1247993/1247
0
20
40
60
80
100
0
20
40
60
80
100
P=0.030
80%
56%
Knodell Fibrosis Score 3 Knodell Necroinflammatory Score 6
P<0.001
IE ALT PE ALT
32%
47%
IE ALT PE ALT
% o
f P
atie
nts
% o
f P
atie
nts
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
15
Normal ALT at Baseline in IE ALT* Patients With Significant Liver Disease
*ALT ULN: men ≤43 U/L; women ≤34 U/L
0
20
40
60
80
100
Knodell Fibrosis Knodell Necroinflammatory
17/1917/19
89%
79%
% o
f P
atie
nts
Wit
h N
RA
LT
at B
asel
ine
% o
f P
atie
nts
Wit
h N
RA
LT
at B
asel
ine 26/3326/33
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
16
Results Using Established ALT ULN
No demographic or disease characteristics associated with significant liver disease
In patients with IE ALT using established ALT, none of the following associated with Knodell fibrosis score ≥3 or Knodell necroinflammatory score ≥6:
— Age (below/above 40 years)— Gender— Asian/non-Asian ethnicity— HBeAg status— HBV viral genotype— Baseline ALT — Baseline HBV DNA
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
17
Patients With Elevated ALT:Liver Fibrosis and Eligibility for CHB Tx
*ALT ULN: men ≤43 U/L; women ≤34 U/L†ALT ULN: men ≤30 U/L; women ≤19 U/L
Per
cen
t W
ith
Bas
eli
ne
AL
T >
2x U
LN
72%65%
90% 88%
0102030405060708090
100
Knodell Fibrosis Score ≥3 Eligibility for Tx
Est ALT ULN* New ALT ULN†
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
18
Study of ALT in CHB: Conclusions
Patients with IE ALT with established ALT ULN often have significant liver disease, which cannot be excluded by a single normal ALT test
Early repeat testing of normal ALT (eg, ≤2 months interval) in CHB patients may
— Reveal elevated ALT— Identify patients with underlying liver disease
Using New ALT ULN — Most patients with significant underlying liver disease
have ALT >2 x ULN— 34% more patients are eligible for treatment
Heathcote EJ, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 850.
19
Age-Specific Prognosis AfterHBeAg Seroconversion
Cohort study of CHB prognosis in different age groups following spontaneous HBeAg seroconversion
441 with HBeAg seroconversion followed ≥1 year— At seroconversion:
• 388 <40 years of age• 53 ≥40 years of age
Annual incidence of CHB-related complications for entire population:— 1.9% with hepatitis relapse— 0.2% developed cirrhosis— 0.6% developed hepatocellular carcinoma
All significantly higher among HBeAg seroconverters ≥40 years of age:— Hepatitis relapse (P=0.005)— Development of cirrhosis (P<0.0001)— Development of hepatocellular carcinoma (P=0.024)
Conclusion: after HBeAg seroconversion, patients remain at risk for CHB-related complications, especially if ≥40 years of age at seroconversion
Chen Y-C, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 815.
20
Perinatal Transmission of HBV:Effect of Viral Load and HBeAg Status
Study to evaluate the rate of and maternal virologic factors associated with perinatal HBV transmission
— HBsAg+ pregnant women identified during antenatal screening
— 87 HBeAg+; 202 HBV DNA positive— All infants routinely offered HBIG and HBV vaccination
124 infants tested for HBV at 9 months of age— HBV transmission in 3 infants (2.4%)
• All had mothers with HBV DNA >8 log10 c/mL and HBeAg+• Transmission rate 7.2% HBV DNA >8 log10 c/mL and 5.5% HBeAg+
— All uninfected infants were anti-HBs positive and HBsAg negative
Perinatal transmission can occur despite prophylactic measures, primarily in HBeAg+ women with HBV DNA >8 log10 c/mL
Wiseman E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 827.
21
High Prevalence of Hepatic Steatosis and Impact on Fibrosis in HBV
Retrospective study to evaluate effect of hepatic steatosis on HBV progression
— 220 CHB pts (63% male; 68% Asian; 51% HBeAg+) Overall, 34% with hepatic steatosis
— Hepatic steatosis associated with:• Male gender (40% vs 24%; P=0.034)• Older age (44 vs 36 yrs; P<0.0001)• Higher BMI (27 vs 24; P<0.00057)
— Pts with hepatic steatosis more likely to have• Hepatic fibrosis (70% vs 56%; P=0.005)• Bridging fibrosis/cirrhosis (29% vs 16%; P=0.022)
— Similar trends for HBeAg-positive and HBeAg-negative CHB No differences regarding hepatic inflammation, iron deposition,
elevated ALT, or HBV DNA Conclusion: hepatic steatosis is a significant factor in CHB-related
disease
Bleibel W, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 831.
22
Predictors of Liver-Related Morbidity and Mortality in CHB
Retrospective study of HBsAg-positive pts referred to hepatology department of French hospital since 1980 (N=1300)
— Pts co-infected with HIV, HDV, and HCV excluded (n=207)
Cox regression analysis used to determine predictors of liver-related mortality and morbidity
Factors assessed:— Age— Sex— Ethnic origin— Alcohol consumption— Baseline HBeAg status— ALT— Serum HBV DNA
HBeAg- HBeAg+ P value
Median follow-up (years) 5.0 6.7 <0.0001
Mean age (years) 39.6 35.0 <0.0001
Male (%) 69.0 68.5 0.89
Caucasian/African/Asian (%) 22.1/52.4/25.5 30.0/20.5/49.5 <0.0001
Alcohol 0/≤50/>50 g/day (%) 83.2/11.5/5.3 80.6/15.3/4.1 0.27
HBV DNA <4/4-<6/≥6 log10 c/mL (%)
47.8/20.9/19.0 3.0/7.0/84.5 <0.0001
Median ALT (IU/L) 32 62.5 0.09
Anti-HBV Tx (%) 46.7 81.0 <0.0001
Liver decompensation (%) 8.0 11.0 0.16
HCC (%) 3.8 3.5 0.84
Liver-related death (%) 3.2 3.5 0.86
Liver transplantation (%) 0.3 1.0 0.21
Baseline Characteristics (n=1093)
Ngo Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 1944.
23
Factors Associated WithComplications of HBV
Ngo Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 1944.
Follow-Up (Months)Follow-Up (Months)
667 8005334002671330.00
0.25
0.50
0.75
1.00
0
Follow-Up (Months)Follow-Up (Months)
667 8005334002671330.00
0.25
0.50
0.75
1.00
0
667 8005334002671330.00
0.25
0.50
0.75
1.00
0 667 8005334002671330.00
0.25
0.50
0.75
1.00
0
Su
rviv
al
Wit
ho
ut
Co
mp
lic
ati
on
s (
%)
Female
Male
HBV DNA <4 log
HBV DNA ≥4 log
ALT <2x ULN
ALT ≥2x ULN
<35 years of age
≥35 years of age
HBV DNA Level
Gender
Elevated ALT
Age
24
Multivariate Analysis of Factors Associated With Liver-Related Morbidity and Mortality
Factor Risk Ratio 95% CI P value
Age ≥35 years 1.06 1.04-1.07 <0.0001
Male gender 1.95 1.07-3.55 0.03
Elevated ALT 1.00 1.00-1.00 0.0001
Alcohol ≥50 g/day 1.00 1.00-1.01 0.0004
HBV DNA >4 log 1.81 1.07-3.03 0.03
Conclusions:— In chronic HBsAg carriers, liver-related morbidity and
mortality are associated with elevated HBV DNA and ALT, older age, male gender, and alcohol consumption
— Reduction of alcohol consumption along with HBV treatment may reduce liver-related morbidity and mortality in HBsAg carriers
Ngo Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 1944.
Therapeutic Strategies for HBV Treatment
26
Tenofovir Versus Adefovir inAsian Patients
TDF has shown superior efficacy to ADV in treatment-naïve CHB patients in 2 pivotal studies
Efficacy and safety of TDF among Asian CHB patients participating in TDF studies GS-174-0102 (HBeAg-) and GS-174-0103 (HBeAg+) were reported
Week 2405-Year
Liver Biopsy
Week 48Liver Biopsy
Paired Biopsies in 391 TDF (92%) and
192 ADV (89%)
Pretreatment Liver Biopsy
RA
ND
OM
IZA
TIO
N 2
:1
TDF 300 mg (n=426*)
ADV 10 mg (n=215*)
Open Label8 Years
Double Blind
TDF 300 mg
≥ Week 72 Option forFTC+TDF if Viremic
Lee S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 980.
27
Tenofovir Versus Adefovir in Asian Patients: Results
189 Asian pts were enrolled across the 2 studies
Asians comprised ~30% of all patients
— 127/426 (30%) on TDF— 62/215 (29%) on ADV
TDF demonstrated superior HBV DNA suppression relative to ADV in Asian patients following 48 weeks of randomized treatment
Efficacy, safety, and resistance analyses were consistent with the results of the overall studies
TDFTDF ADVADV
0
10
20
30
40
50
60
70
80
90
100
HBV DNA <400c/ml(69 IU/ml)
Normal ALT Histologic response
Pe
P<0.001
Missing=FailureMissing=Failure
Per
cen
tag
e (%
)P
erce
nta
ge
(%)
85%
42%
72%65%
77%71%
Lee S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 980.
28
Study 102: 2-Year TDF Treatment and ADV Switch Data in HBeAg- With CHB
Week 48 phase 3 data showed TDF superior to ADV:—HBV DNA <400 copies/mL: 93% TDF vs 63% ADV (P<0.001)
96-week data presented
Randomized, double-blind comparison of TDF vs ADV for HBeAg- chronic hepatitis B HBV DNA >105 c/mL and ALT >ULN and <10x ULN Knodell necroinflammatory score ≥3 LAM experienced or naïve
Marcellin P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 146.
Week 240Liver Biopsy
Week 48Liver Biopsy
Pretreatment Liver Biopsy
RA
ND
OM
IZA
TIO
N 2
:1
Tenofovir 300 mg (n=250)
Adefovir 10 mg (n=125)
Open Label8 Years
Double Blind
TDF 300 mg
Week 96 End of Study
5 Years2 Years
Week 72 HBV DNA ≥400 copies/mL Option to Add Emtricitabine (FTC) to TDF in a Fixed-Dose Tablet
1 Year
TDF 300 mg
29
Study 102: HBV DNA <400 copies/mL
TDF demonstrated durable, potent antiviral activity through Week 96:— 99% of patients on therapy had HBV DNA <400 copies/mL
No resistance to TDF detected after 2 years on TDF monotherapy
ITT Analysis
Randomized Double Blind
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
Open Label
P=0.67291%
89%
250
125
234
122
245
125
243
124
248
120
247
123
242
123
243
122
TDF-TDF n=
ADV-TDF n=
On-Treatment Analysis
Randomized Double Blind
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
Open Label
P=0.16699%100%
250
125
214
109
242
123
239
121
242
117
241
117
226
110
224
109
TDF-TDF n=
ADV-TDF n=
LAM Exp.
97%
100%
LAM Exp.
93%
96%
Marcellin P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 146.
30
Study 103: 2-Year TDF Treatment and ADV Switch Data in HBeAg+ With CHB
Week 48 phase 3 data showed TDF superior to ADV:—HBV DNA <400 copies/mL: 76% TDF vs 13% ADV (P<0.001)
96-week data presented
Randomized, double-blind comparison of TDF vs. ADV for HBeAg+ chronic hepatitis B HBV DNA >106 c/mL and ALT ≥2x and <10x ULN Knodell necroinflammatory score ≥3 Nucleos(t)ide naïve
Heathcote E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 158.
Week 240Liver Biopsy
Week 48Liver Biopsy
Pretreatment Liver Biopsy
RA
ND
OM
IZA
TIO
N 2
:1
Tenofovir 300 mg (n=250)
Adefovir 10 mg (n=125)
Open Label8 Years
Double Blind
TDF 300 mg
Week 96 End of Study
5 Years2 Years
Week 72 HBV DNA ≥400 copies/mL Option to Add Emtricitabine (FTC) to TDF in a Fixed-Dose Tablet
1 Year
TDF 300 mg
31
Study 103: HBV DNA <400 copies/mL
TDF demonstrated durable, potent antiviral activity through Week 96:—82% of pts viremic on ADV at Week 48 were <400 c/mL on TDF at Week 96
No resistance to TDF detected after 2 years on TDF monotherapy
Heathcote E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 158.
On-Treatment AnalysisRandomized Double Blind
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
Open Label
P=0.37489%85%
176
90
142
79
173
88
165
85
166
84
160
85
148
83
144
81
TDF-TDF n=
ADV-TDF n=
Pe
rce
nta
ge
(%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
P=0.80178%
78%
176
90
165
86
174
89
170
88
172
88
171
90
168
89
164
87
TDF-TDF n=
ADV-TDF n=
ITT AnalysisRandomized Double Blind Open Label
32
Long-Term Use of Tenofovir Reduces Liver Fibrosis in HIV/HBV Co-Infection
Study assessed the effect of TDF on liver fibrosis 130 co-infected patients treated with TDF and
followed for a median of 29.5 months— At baseline, 45 patients presented with Fibrometer®
stage F0-F1, 29 patients with stage F2, and 56 patients with stage F3-F4
Assessments included:— Fibrometer® (platelets, prothrombin time, AST,
α2-macroglobulin, hyaluronic acid, urea, age)— Paired liver biopsies
Lacombe K, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 914.
33
Reduction in Fibrosis Scores by Fibrometer® and Paired Liver Biopsies
Conclusion: In a population with HIV/HBV co-infection, TDF induced a significant decrease in fibrosis and histologic activity level after mean treatment duration of 29.6 months
Fibrometer ® Paired Liver Biopsies
Lacombe K, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 914.
F0-F1(remained,
n=8)
F2(remained,
n=6)
F3-F4(remained,
n=11)
n=1n=1
n=1n=1n=4n=4
n=7n=7n=0n=0
0Time after treatment initiation (months)
12 24 36
0.20
0.40
0.60
0.80
1.00
F3-F4
F2
F0-F1
DA
VG
Fib
rom
eter
® S
core
34
HBV Genotype Is the Strongest Predictor of Response to Interferon-Alfa Treatment
Pooled analysis evaluating effect of HBV genotype on treatment outcome following IFN-α for 6-12 mos for CHB (N=1,229)
— Standard interferon-α (n=298), pegylated interferon-α (n=491), pegylated interferon-α with lamivudine (n=440)
— HBeAg status: positive (n=703), negative (n=526)— HBV genotypes: A (n=174), B (n=245), C (n=464), D (n=346)
HBV genotype determined by direct sequencing of X or S gene
Sustained virologic response determined 6 mos after Tx and defined as:
— Normalization of ALT— HBV DNA <20,000 c/mL— In HBeAg+, HBeAg seroconversion
Erhardt A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 883.
35
HBV Genotypes as Predictors of Response to Interferon-Alfa: Multivariate Analysis
Conclusion: Multivariate analysis adjusted for treatment identified genotype D, HBeAg-negative status, and elevated ALT level as independent predictors for failing to achieve SVR
Erhardt A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 883.
% S
VR
0
20
40
60
Genotype A
10
30
50
Genotype B
Genotype C
Overall SVR
HBeAg Pos SVR
HBeAg Neg SVR
Genotype D
OR(95% CI) P value
HBV genotype
A vs D 3.620(2.316-5.657) 0.0001
B vs D 2.621(1.618-4.245) 0.0001
C vs D 3.184(2.054-4.936) 0.0001
ALT >5 vs ≤5x ULN
1.432(1.056-1.940) 0.02
HBeAg neg vs pos 2.124(1.527-2.966) 0.0001
Independent Predictors for SVRSVR by Genotype and HBeAg Status
36
ETV-060: Histologic Assessment of Long-Term ETV Treatment in CHB
Open-label, rollover study assessed histologic improvement in patients who had evaluable liver biopsies after receiving at least 3 years of ETV therapy
— Subset of studies that enrolled nucleoside-naïve (n=66) or LAM-refractory (n=84) pts
Histologic improvement defined as
— ≥2-point decrease in Knodell necroinflammatory [NI] score
— ≥1-point decrease in Knodell fibrosis score
Thirty-seven naïve patients and 27 LAM-refractory patients had biopsies from 3 required time points (baseline, Week 48, and Week 148)
Katano Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 889.
37
Results of Histologic Assessment ofLong-Term ETV in CHB
Liver histology improved significantly after 3 years of continuous ETV Tx
Treatment beyond 48 weeks resulted in continued improvement in fibrosis scores in both naïve and LAM-refractory patients
≥1-Point Decrease Knodell Fibrosis Score
Pa
tie
nts
%
≥2-Point Decrease Knodell NI Score*
*P<0.0001; †P=0.0002; ‡P=0.043 (all compared with baseline)
†
‡
*
Katano Y, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 889.
17
47
12
32
0
20
40
60
80
100
Week 48 Week 148
Nucleoside Naïve LAM Refractory 84
100
58
89
0
20
40
60
80
100
Week 48 Week 148
38
Studies ETV-022/-901: Entecavir Therapy in HBeAg+ CHB
Han S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 893.
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-responders(At Week 48 or who became non-responders during Year 2)
151 Virologic Responders(At Week 96)
11 Responders(At Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up)
Week 144
ETV-022 ETV-901
Week 96 5 Years
NR=8
VR=198
R=37
243
Study DesignStudy Design
39
Studies ETV-022/-901: Baseline Characteristics
Han S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 893.
Age, mean (years) 35 36
Male (%) 77 80Race:
Asian (%)
Non-Asian (%)
58
42
6436
HBV DNA by PCR, mean (log10 copies/mL)
9.62 9.91
ALT, mean (U/L) 140 122
HBV genotype (%) A B C D Other
27
1931
1013 26
2730
4 13
ETV-022(N=354)
ETV-901
(N=146)
40
Studies ETV-022/-901: Proportion With HBV DNA <300 c/mL Through 5 Years
Han S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 893.
Pro
po
rtio
n o
f P
atie
nts
(%
)H
BV
DN
A <
300
cop
ies/
mL
55%
Year 1
83%
Year 2
89%
Year 3
67%
n= 236/354
Year 4
91%
80/146
116/140 116/131 98/108
Year 5
88/94
94%Year 1
ETV-022 HBeAg(+) ETV Long-Term Cohort (ETV-022→ETV-901)
20
40
60
80
100
0
41
Studies ETV-022/-901:Long-Term HBV DNA Suppression
Conclusion: Long-term treatment with ETV results in durable suppression of HBV DNA replication, with 1 person developing ETV resistance over 5 years of surveillance
Han S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 893.
0
2
4
6
8
10
12
0 Year 1 Year 2 Year 3 Year 4 Year 5
Mea
n H
BV
DN
A
(lo
g10
co
pie
s/m
L)
300 copies/mL
n= 146 146 140 131 108 94
HBeAg+ ETV Long-Term Cohort (ETV-022 → ETV-901)
42
Studies ETV-022, -027, and -901: Long-Term ETV Reverses Fibrosis/Cirrhosis in CHB
Long-term histologic results for a subset of patients (n=57) treated with ETV for a median of 280 weeks
— Nucleoside-naïve HBeAg+ and HBeAg- patients treated with ETV in studies ETV-022 or ETV-027 who:
• Had a liver biopsy in study ETV-901 and
• Received a minimum of 3 years cumulative ETV therapy
Co-primary end points— Histologic improvement (≥2-point decrease in Knodell
necroinflammatory score and no worsening of Knodell fibrosis score) compared with baseline
— Improvement in Ishak fibrosis score (≥1-point decrease) compared with baseline
Liaw Y-F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 894.
43
Ishak Fibrosis Score
1
2
3
4
5
6
Missing
0
Pat
ien
ts (
n)
Distribution of Ishak Fibrosis Scores at Baseline, Year 1, and Years 3-7
96% of patients in the long-term histology cohort who received continuous treatment with ETV achieved histologic improvement
All patients with advanced fibrosis/cirrhosis at baseline (Ishak fibrosis score ≥4) demonstrated an improvement in fibrosis
Liaw Y-F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 894.
0
10
20
30
40
50
60
Baseline Week 48 Long-Term
44
Continued LdT Results in High Rates of Maintained Response in HBeAg-Positive Patients
Maintained Treatment Response (HBeAg seroconversion and HBV DNA <300 copies/mL) 66/86 (76.7%)
Maintained PCR negativity (HBV DNA <300 copies/mL) 73/88 (83.0%)
ALT normalization 77/85 (90.6%)
Maintained HBeAg loss 88/88 (100.0%)
Maintained HBeAg seroconversion 80/86 (93.0%)
HBsAg loss 3/88 (3.4%)
HBsAg seroconversion 1/88 (1.1%)
Maintained HBeAg loss and HBV DNA <5 log10 copies/mL 88/88 (100.0%)
Maintained HBeAg seroconversion and HBV DNA <3 log10 copies/mL
71/86 (82.6%)
Virologic failure (HBV DNA ≥1000 copies/mL) 8/88 (9.1%)
Continued telbivudine treatment in patients results in high rates of maintained treatment responses and control of CHB at 3 years
Long-term telbivudine treatment can lead to HBeAg clearance/seroconversion
Study evaluating maintained treatment response to LdT at week 156 HBeAg-positive CHB patients on LdT who achieved HBeAg seroconversion and
undetectable HBV DNA by week 104 and followed to week 156
Gane E, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 942.
45
Cost-Effectiveness Simulation Analysis of TDF, LAM, ADV, and ETV in HBeAg-Negative CHB Patients
Study evaluating the impact of initiating treatment with TDF, LAM, ADV, and ETV on cost and quality of life in HBeAg- patients in the United States
Simulation analysis using a Markov model developed to predict incidence and cost of CHB-related complications
— Patients assumed to be treatment naïve at initiation of Tx
— Assigned levels of viral suppression and risk of developing viral resistance specific to their treatment
— Patients who became resistant could switch or add on another treatment
— Patients who developed resistance to initial and subsequent treatments were assumed to discontinue treatment, and incidence of complications was modeled assuming no further viral suppression
Deniz H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 976.
46
Results of Cost-Effectiveness Simulation Analysis
TDF LAM ADV ETV
Total pharmacy and medical cost per patient (US$)
117,794 152,336 138,950 141,409
Cost of initial and subsequent HBV treatments (US$)
94,781 101,990 105,449 117,648
Quality-adjusted life years 10.28 8.93 9.72 10.28
Conclusion: Although the long-term medical costs associated with care and treatment of HBeAg-negative patients are not completely known, this study suggests that TDF will be a more cost-effective treatment than LAM, ADV, and ETV
Deniz H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 976.
New Therapies and Strategies for HBV Treatment
48
Clevudine (L-FMAU)
CLV is a pyrimidine nucleoside analog— No mitochondrial toxicity — Inhibition of synthesis of dsDNA from ssRNA
Randomized, placebo-controlled trial – 30 mg/day— HBV DNA reduction of 5.10 log10 c/mL at week 24— Prolonged suppression 24 weeks after dosing (-2.02 log)
Resistance profile similar to other L-nucleosides— M204I; L180M; 204I/V; A181T
Phase 3 clinical trials for US registration; approved in Korea (Bukwang Pharmaceuticals)
Byung CY, et al. Hepatology. 2007;45:1172 - 1178.
49
CLV Versus LAM Comparison in HBeAg-Positive CHB Patients
Randomized, blinded trial (N=55)— CLV 30 mg/d vs
LAM 100 mg/d— Entry: treatment naïve, HBV DNA
>3 million c/mL; ALT >1x ULN At 48 weeks, all analyses
favored CLV:— More pts with HBV DNA
<300 c/mL— Greater HBV DNA decrease
• CLV: 4.7 log (3.3-6.2)• LAM: 3.2 log (0.2-5.7)
— More HBe seroconversion(17% vs 8%)
— Less resistance (0 vs. 9 patients)
Conclusion: CLV more effective than LAM in HBeAg-positive CHB pts
Pat
ien
ts (
%)
Lau G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 911.
HBV DNA <300 c/mLat Week 48
59
72
32
46
0
20
40
60
80
100
Week 32 Week 48
CLV LAM
50
Clevudine: Efficacy and Resistance 34 treatment-naïve pts with CHB (24 HBeAg+) treated with CLV (30
mg/d) for median 52 weeks— Mean HBV DNA 7.3±1.1 log10 c/mL— Mean ALT 263±234 U/L— Cirrhosis – 10 patients
Results— HBeAg negative: 10/10 HBV DNA undetectable at week 24— HBeAg positive:
• 58.3% and 75% undetectable at weeks 24 and 48
• 2 pts with viral breakthrough at weeks 48 and 56 – mutation rtM204I detected in both
Conclusions: — CLV effective in CHB— rtM204I a common mutation in CLV failure
Kwon SY, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 943.
51
CLV Versus ETV in Treatment-Naïve CHB
Non-randomized, cohort study of treatment-naïve CHB pts (N=148)
— CLV 30 mg/day (n=39) vs ETV 0.5 mg/day (n=109)
— Longer treatment with ETV (16.6±2.8 mos) compared with CLV (9.9±3.3 mos) (P<0.001)
Similar HBV DNA suppression observed
Conclusions:— CLV and ETV appear similarly
potent at 48 weeks
— Longer F/U needed to assess long-term HBV DNA suppression and resistance profiles
Pat
ien
ts (
%)
Sul H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 912.
HBV DNA <140 c/mL
44.4
55.9
13.5
30.8
55.3
12.7
0
20
40
60
80
100
12 wks 24 wks 48 wks
ETV CLV
52
In Vitro Simvastatin Is Active Against Drug-Resistant and Wild-Type HBV Strains
In vitro, simvastatin inhibits HBV extracellular virion production and intracellular DNA intermediate forms
Study in which cultured HBV-producing HepG2.2.15 cells treated with 9 consecutive daily doses of SIM, LAM, or ADV
Comparable efficacy of SIM, LAM, and ADV against clinically relevant resistant viruses found
Clinical studies are needed to test in vivo significance and utility of SIM in treatment of CHB
Bader T, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 877.
SIM EC50 (uM) LAM EC50 (uM) ADV EC50 (uM)
WT 8.2 0.2 1.5
M204V 9 >100 1.8
N236T 9.3 0.6 8.1
53
In Vitro Interferon Gamma: Anti-HBV Activity With and Without LAM or ADV
IFN γ-1b is a type 2 IFN that binds to a unique cell surface receptor In vitro model, HepG2.2.15 cells transfected with wild-type HBV
— Treated with IFN γ-1b or peginterferon α-2a 2 days after plating or LAM or ADV 3 days after plating
— IFN γ-1b also combined with peginterferon α-2a, LAM, or ADV All showed potent antiviral activity
— LAM and ADV activity increased in presence of IFN γ-1b Models support in vivo testing of IFN γ-1b alone or in combination
with nucleos(t)ide analogs in CHB
Blatt L, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 898.
*Increased potency
IFN gamma IFN alfa-2a LAM ADV
EC50 20 pg/mL 90 pg/mL 540 nM 620 nM
+IFN γ-1b _ _ ↑ 6-fold * ↑ 15-fold*
54
Combination Therapy: EASL Clinical Practice Guidelines—Management of CHB
As of yet, no data to support de novo combination therapy in Tx-naïve patients receiving first-line nucleos(t)ide analogs (ETV or TDF)
Some experts recommend de novo combination therapy to prevent resistance in high-risk patients (eg, high HBV DNA level) or persons in whom resistance is life threatening (eg, cirrhosis, transplant)
— TDF plus either LAM or FTC may be considered in such patients
Combination (“add-on”) therapy is recommended for patients with treatment failure
— Agents that do not share cross-resistance
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B. J Hepatol. 2008 [Epub ahead of print].
55
4-Year Follow-Up of “Add-On” ADV in LAM-Resistant Patients
LAM-resistant pts treated with add-on ADV (10 mg/d) plus LAM (100 mg/d) for mean of 55 mos (N=145)
— 73% cirrhotic; 92% HBeAg negative
Results:— Overall, 81% HBV DNA undetectable, with continued improvement through 5 years
of Tx
— 84% ALT normalization— 3 developed new rtA181T (2 became undetectable); no rtN236T observed— 23 pts with increase serum Cr >0.5 mg managed with ADV dose adjustment (10 mg
QOD) with stabilization or improvement
Conclusion:In patients with LAM-resistant HBV, ADV add on to LAM is an effective and safe Tx strategy
Lmpertico P, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 906.
58 68 78 88 86
0
50
100
1 2 3 4 5
Year
% H
BV
DN
A
Un
det
ecta
ble
by
Yea
r o
f T
x
56
5-Year “Add-On” ADV in LAM-Resistant Patients
Prospective, single-center cohort (N=41) — HBeAg-negative CHB with LAM resistance— Median HBV DNA 6 million c/mL
ADV (10 mg/d) plus LAM (100 mg/d) Results:
— Significant HBV decline through 5 years of Tx— ALT normalization in 93% at 5 years of Tx— No ADV resistance observed
Conclusion: ADV+LAM is effective in HBeAg-negative CHB with LAM resistance
Pat
ien
ts (
%)
Hadziyannis S, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 924.
6881 86 86 9588 85
93 92 93
020406080
100
Year 1 Year 2 Year 3 Year 4 Year 5
HBV DNA ≤250 c/mL
ALT Normalization
57
De Novo ADV+LAM Compared With “Add-On” ADV to LAM
Retrospective, single-center, cohort study (N=201)
Pts receiving ADV+LAM for median 17 months (range 3-48)
— De novo (n=151)• HBeAg+ 38%; cirrhosis 38%; mean
HBV DNA 4.9 log
— “Add-on” (n=50)• HBeAg+ 68%; cirrhosis 80%; mean
HBV DNA 4.0 log
De novo strategy more effective — Greater virologic suppression
— 3 “add-on” pts acquired ADV-R in setting of prior LAM-R
Carey I, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA.Abst 930.
HBV DNA Suppression
-5
-4
-3
-2
-1
03 6 12 18
MonthsL
og 1
0 H
BV
DN
A c
/mL
De Novo Add On
58
CLV Compared With LAM as “Add-On” in Patients With ADV Failure
Open-label, non-randomized cohort followed for ~12 months; evaluated adding CLV (30 mg/d) or LAM (100 mg/d) to ADV after viral failure
450 LAM-resistant CHB pts treated with ADV — 29 with viral breakthrough on ADV after median 60 months— 6 with ADV-resistant variants: rtA181VT or rtN236T— CLV added (n=12); LAM added (n=17)
Similar outcomes regarding effectiveness, safety, and tolerability No additional resistance mutations observed
CLV+ADV (n=12)
LAM+ADV(n=17) P value
Baseline HBV DNA (median log10 c/mL) 6.43 6.13 NR
HBV DNA ↓ at wk 24 (median log10 c/mL) - 2.97 - 2.27 0.28
% HBV DNA undetectable at wk 24 50% 29% 0.22
Park NH, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 961.
59
Switch to ADV+ETV in Patients Failing ADV+LAM
Observational, open-label, cohort study of switching ETV (1 mg/d) for LAM in pts failing ADV+LAM (N=13)
— Failure after ADV+LAM combination (n=9) or sequential (n=4)— Baseline HBV DNA 2x105 c/mL (range 9x103-4x107)
Results (median of 10 mos)— Median ↓ 3 log10 c/mL (range 1.6-4.3)
• 10/13 with HBV DNA <400 c/mL
• 2/3 without full suppression had rtA181T variant
— Significant reduction in ALT (median 0.72 ULN, P=0.034)— No significant adverse events
Further research on nucleotide analog (ADV or TDF) plus ETV is warranted
Schollmeyer J, et al. October 31-November 4, 2008; San Francisco, CA. Abst 925.
60
ETV+TDF in Patients With Multi-Drug-Resistant CHB
Open-label, single-center, cohort study 12 treatment-experienced patients with CHB-related cirrhosis
— 11/12 with genotypic resistance to LAM±ADV— 7/12 received LAM+ADV at time of switch— HBV DNA level 5x106 c/mL (7x104-7x109)
TDF (245 mg/d) plus ETV (1 mg/d) for median 6 months — No AEs or decompensation observed— Median ↓ HBV DNA 4.6 log10 c/mL (1.7-7.8) — 9/12 with HBV DNA <400 c/mL
Further research is needed to test TDF+ETV combination
Schollmeyer J, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 985.
61
De Novo TDF+LAM or FTC Is Associated With Early Virologic Response in HIV/HBV Co-Infected Patients
Retrospective study comparing de novo vs add-on therapy for HBV in HIV/HBV co-infected patients
— Group 1: TDF plus either LAM or FTC (n=15)
• Never received or no LAM in 4 years
— Group 2: LAM initially with add-on TDF (n=46)
Results— More Group 1 achieved HBV DNA
<3 log at 6 mos— 14 pts in Group 2 had HBV DNA decrease
<1 log at 6 mos• 7 considered noncompliant
• 7 had HBV clearance at median of 20 mos.
— LAM baseline resistance higher in Group 2 (46% vs 11%, P=0.026)
Conclusion: de novo therapy leads to an earlier virologic response than add-on therapy
Pat
ien
ts (
%)
100%
77%
Percent <3 log10 IU/mL at 6 Mos
Lada O, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 922.
0
20
40
60
80
100
Group 1 Group 2
62
Treatment of CHB in HIV/HBV Co-Infected Patients With TDF Containing HAART
HIV/HBV co-infected patients naïve to antiretroviral therapy (N=47)
— Median CD4 count 42 cells/mm3
— Median HBV DNA 8 log10 IU/mL— 34/47 (64%) HBeAg positive
Treated with combination HAART containing TDF alone (n=11) or TDF+FTC or LAM (n=36)
— Median follow-up 27 months— Median TDF exposure 25 months
Matthews G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 907.
63
High Rate of HIV and HBV Suppression With TDF-Containing HAART
HIV responses— All HIV RNA <50 c/mL— Median CD4 count 342 cells/mm3 after Tx
HBV responses— HBV DNA
• 72% <20 IU/mL
• 94% <400 IU/mL
• No patient >1000 IU/mL
— HBeAg loss 36%— HBeAb seroconversion 33%— HBsAg loss 6%
Conclusion: TDF-containing ART with and without FTC or LAM was very effective in controlling HIV and HBV in HIV/HBV co-infected patients with advanced HIV disease
Matthews G, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 907.
64
PegIFN alfa-2a With or Without Ribavirin for CHB
RBV inhibits viral replication and modulates immune response
— Role in CHB unknown
Multicenter, randomized, clinical trial in HBeAg-negative CHB patients (N=133)
— Male, 74%; mean age, 42.2 yrs; HBV genotype D, 80%— PegIFN alfa-2a 180 mcg weekly plus either placebo or
RBV 1000-1200 mg/d for 48 weeks
Janssen H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 991.
65
RBV Does Not Improve Response Compared With PegIFN Alone for HBeAg-Negative CHB
Week 48 End of Treatment
Week 72 End of Follow-Up
PegIFN+Placebo
(n=69)
PegIFN+RBV
(n=64)
PegIFN+Placebo
(n=69)
PegIFN+RBV
(n=64)
HBV DNA <10,000 c/mL 67% 55% 20% 19%
HBV DNA <400 c/mL 52% 28% 9% 6%
ALT normal 41% 53% 41% 52%
Conclusion: No benefit to adding RBV to PegIFN Tx in HBeAg-negative CHB
Janssen H, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 991.
Resistance IssuesWith HBV Treatment
67
HBV Resistance to Nucleos(t)ide Analogues
As anti-HBV therapy may be indefinite for the large majority of patients, treatment and prevention of long-term resistance is a major issue
Pre-existing resistance may be important to recognize in order to tailor first-line anti-HBV therapy
The resistance profile of TDF, the latest approved drug for treatment of CHB, was studied and discussed in particular at this meeting
68
Most Common HBV Cross-Resistance Mutations
Durantel, et al. Hepatology. (2004); Brunelle, et al. Hepatology. (2005); Yang, et al. Antivir Ther. (2005); Villet, et al. Gastroenterology. (2006); Delaney, et al. Antimicrob Agents Chemother. (2006); Villet, et al. J Hepatol. (2007); Brunelle, et al. Antimicrob Agents Chemother. (2007); Qi, et al. Antivir Ther. (2007);Tenney, et al. Antimicrob Agents Chemother. (2004 & 2007) ; Villet, et al. J Hepatol. (2008).
*(+L180M+ M204I/V)
Lamivudine Telbivudine Entecavir Adefovir Tenofovir
Wild-type S S S S S
M204l R R I/R S S
L180M+M204V R R I S S
A181 T/V I S S R S
N236T S S S R I
I169T+V173L+M250V* R R R S S
T184G+S202lI/G* R R R S S
69
Rates of HBV Resistance Over Time in HBeAg-Positive, Treatment-Naïve Patients
Marcellin P, et al. J Hepatol. 2005;42(suppl2):31-32; Lai CL, et al. Hepatology. 2006;44(suppl):222A;Colonno R, et al. Hepatology. 2006;44(suppl):229A; Shiffman ML, et al. Hepatology. 2004;40(suppl):172A; Chung YH, et al. Hepatology. 2006;44(suppl):698A; Heathcote J, et al.Hepatology. 2007;46 (suppl 1):861.
0
10
20
30
40
50
60
70
Lamivudine Adefovir Entecavir Telbivudine Tenofovir
Year 1
Year 2
Year 3
Year 4
Year 5
Pat
ien
ts W
ith
Res
ista
nce
(%
)
70
Rates of HBV Resistance Over Time in HBeAg-Negative, Treatment-Naïve Patients
ETVLAM ADV LdT CLVFTC TDF
Pat
ien
ts W
ith
Res
ista
nce
(%
)
0%
20%
40%
60%
80%
1
3
5
Years2
4
Marcellin P, et al. J Hepatol. 2005;42(suppl2):31-32; Lai CL, et al. Hepatology. 2006;44(suppl):222A;Colonno R, et al. Hepatology. 2006;44(suppl):229A; Shiffman ML, et al. Hepatology. 2004;40(suppl):172A; Chung YH, et al. Hepatology. 2006;44(suppl):698A; Heathcote J, et al. Hepatology. 2007;46 (suppl 1):861.
71
Pre-Existing Antiviral Resistance Mutations
Pre-existing HBV antiviral resistance (AVR) mutations in treatment-naïve CHB patients is believed to occur at a low frequency
— Lamivudine ~10%— Entecavir ~1%-2%
Pre-existing AVR may significantly compromise antiviral efficacy in the treatment of CHB
However, clinical significance of pre-existing AVR mutations is unknown
Ludwig AD, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 884.
72
Prevalence and Effect of Pre-Existing Antiviral Resistance Mutations
Prevalence of AVR mutations was determined using INNO-LiPA HBV DRv2 and DRv3 line probe assay and confirmed by direct sequencing in treatment-naïve CHB patients (N=313)
Patient Characteristics (N=313)Patient Characteristics (N=313)
Mean age (years) 48±13
%Male:% female 61:39
% HBeAG-positive 41
Mean ALT (U/L 84±171
Mean HBV DNA (IU/mL) 7.0±2.4
Mean platelets (Bil/L 228±67
% Cirrhosis (on ultrasound or liver biopsy) 12
HBV genotype (A/B/C/D) 6/35/55/3
Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 888.
Resistance DetectedResistance Detected
RT Substitution Frequency (%)
L80V/I 4V173L 0L180M 3
M204V/I 12A191V/T 1
I233V 1N236T 0A194T 0.7
T184G/L 1S202C/I 2M250V 2
73
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8 9 10 11 12
Effect of Pre-Existing Antiviral Resistance Mutations
Mutation associated with 180/204 resistance pathway: 12%
Mutant virus was always detected as a mixed species
— rt180+rtM204 represents >90%
— rt180 or rt204 in isolated cases
ETV-resistance mutations: 5% Mutations assoc. with rt181/236
resistance pathway: 0%-1% Effect of pre-existing AVR
on anti-HBV therapy was analyzed
— LAM resistance affects LAM but not TDF efficacy
Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 888.
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8 9 10 11 12
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
LAM 100 mg dailyLAM 100 mg dailyEffect of LAM in a Patient With Pre-existing LAM-Resistant MutationEffect of LAM in a Patient With Pre-existing LAM-Resistant Mutation
Time on LAM (mos)Time on LAM (mos)
HB
V D
NA
(lo
g10
IU
/mL
)H
BV
DN
A (
log
10 I
U/m
L)
AL
T (
IU/m
L)
AL
T (
IU/m
L)rtL180M+
rtM204I
HBe Ag+,Anti-HBe- HBe Ag+,
Anti-HBe-
HBe Ag+,Anti-HBe-
HBe Ag+,Anti-HBe-
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
TDF 300 mg dailyTDF 300 mg daily
Effect of TDF in a Patient With Pre-existing LAM-Resistant MutationEffect of TDF in a Patient With Pre-existing LAM-Resistant Mutation
Time on TDF (mos)Time on TDF (mos)
HB
V D
NA
(lo
g10
IU
/mL
)H
BV
DN
A (
log
10 I
U/m
L)
AL
T (
IU/m
L)
AL
T (
IU/m
L)
rtL180M+rtM204I
HBe Ag+,Anti-HBe-
HBe Ag+,Anti-HBe-
HBe Ag+,Anti-HBe-
HBe Ag+,Anti-HBe-
PCRnegative PCR
negative
HBV DNA ALT
HBV DNA ALT
74
Conclusion: Pre-Existing AVR in Treatment-Naïve, CHB Patients
Pre-existing ARV resistance can be found in treatment-naïve CHB patients
— rt180/204 mutation is relatively common— rt184/202/250 mutations also are detectable— rt181/236 mutation is much less common
Prevalence of LAM-related resistance in naïve pts compromises utility of LAM, but not TDF, monotherapy as first line
AVR testing among treatment-naïve patients is important in order to tailor and optimize anti-HBV therapy
Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 884.
75
rtA194T Does Not Reduce TDF Efficacy in Patients With LAM-Resistant CHB
Study to determine effect of rtA194T on Tx response to TDF in patients with LAM-resistant HBV
Consecutive, Tx-experienced adults with CHB enrolled and tested for antiviral resistance (N=283)
— Resistance testing if virologic breakthrough (HBV DNA increase > 1 log IU/ml compared with nadir) and failure to achieve undetectable HBV DNA in 6 months of therapy
10 patients found to harbor rtA194T (all in association with rtL180M and rtM204V/I)
— All had been treated with LAM for mean duration of 42 months
Mean age (years) 48
Males (N) 7
HBeAg+ (N) 4
Cirrhosis (N) 7
HBV DNA (log IU/mL) 5.52.5
Breakthrough on LAM (N) 6
Suboptimal response on LAM (N) 4
Baseline Characteristics of 10 Pts With rtA194T
Baseline Characteristics of 10 Pts With rtA194T
Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 880.
76
Effect of rtA194T on TDF Salvage Therapy
Results— 5 patients received salvage TDF
• 4 with TDF (300 mg/d) and 1 with TDF+FTC (200 mg/d)
— All had >3 log IU/mL reduction in HBV DNA at 3 months of Tx
— 4 undetectable HBV DNA with normal ALT (mean F/U 5.8 mos)
Conclusions— rtA194T does not reduced TDF efficacy— rtA194T may represent a viral polymorphism or
compensatory mutation rather than a signature mutation leading to nucleotide resistance
Fung SK, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 880.
77
Resistance Mutations to Nucleos(t)ide Analogs During TDF Therapy
Retrospective study to evaluate the development of HBV mutations during TDF treatment
48 patients with CHB treated with TDF for ≥12 mos — 43 previously treated with LAM (mean 27 mos)
— 33 previously treated with ADV (mean 13 mos)
At baseline and during TDF Tx, HBV resistance evaluated when HBV DNA detectable
— At baseline TDF Tx: • WT: 20 patients
• LAM-R: 22 patients
• ADV-R: 6 patients
Boemmel F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 913.
78
Effect of ADV-Resistance Mutations on TDF Therapy
Effectiveness of TDF therapy— Baseline ADV-R:
• ADV-related mutations remained detectable during TDF Tx
• 1/6 pt achieved HBV DNA <400 c/mL at 12 mos (P<0.0001)
— 4 pts without ADV-R at baseline developed ADV-related mutations on TDF (3 ADV and 1 LAM pre-treated)
• ADV-R variants (rtA181T, rtA181V, rtA181T+rtN236T) became detectable between mos 5 and 11 of TDF Tx
• 3/4 achieved an HBV DNA <400 c/mL by month 12 of TDF Tx
— No new mutations or HBV DNA breakthrough were observed during TDF Tx
Conclusion: HBV variants associated with ADV and LAM resistance can become transiently detectable during TDF treatment, but these mutations do not seem to affect response to TDF on short-term follow-up
Boemmel F, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst. 913.
79
Genotyping
(HBV pol / RT)
Method: 2 Years’ TDF Resistance in Patients With CHB
Patients were enrolled in 1 of 2 randomized studies of TDF (HBeAg- or HBeAg+)
Population di-deoxy sequencing
of serum HBV pol/RT— Covers AA 1-344 of pol/RT
(AA 1-266 of HBsAg)
— Able to detect AA substitutions present at ≥25% of viral quasi-species population
Phenotypic analyses conducted in HepG2 cells transiently transfected with a pool of recombinant HBV plasmid DNA derived from patient serum HBV
Virology Analysis Plan
All patients:– At baseline– Yearly if HBV DNA
≥400 c/mL (≥69 IU/mL)– At discontinuation of
TDF mono-therapy if HBV DNA ≥400 c/mL
Any patient post-baseline with:
– Conserved site changes in pol/RT
– Virologic breakthrough– Polymorphic site
changes
Phenotyping
(HBV pol / RT)
Snow-Lampart A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 977.
80
Results: 2 Years’ TDF Resistance in Patients With CHB
Snow-Lampart A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 977.
Genotypic Changes Observed at Week 96/last on TDF Among HBeAg- and HBeAg+ TDF-Treated Patients
Genotypic Changes Observed at Week 96/last on TDF Among HBeAg- and HBeAg+ TDF-Treated Patients
Patients Experiencing Virologic Breakthrough
0
10
20
30
40
50
60
70
80
90
100
No Change Polymorphic SiteChanges
Conserved SiteChanges
HBeAg- (n =4)
HBeAg+ (n=3)(3)(2)
(1)(1)
(0)(0)0
10
20
30
40
50
60
70
80
90
100
No Change PolymorphicSiteChanges
Conserved SiteChanges
HBeAg- (n=2)
HBeAg+ (n=12)
(1) (1)
(2)
(0)
(8)
(2)
Pat
ien
ts (
%)
WW
81
Results: 2 Years’ TDF Resistance in Patients With CHB
Patient pol/RTTenofovir EC50 (µM)
Fold Change
Patient TDF EC50 (µM) Fold Change
Snow-Lampart A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 977.
Phenotypic Analysis in Patients With
Conserved Site Changes in HBV pol/RT
8356–Baseline Wild-type 12.4±3.6
8356–Week 72 rtL101L/F 13.8±0.6 1.1
8356–Week 72 (clone) rtL101F 10.0±6.2 0.7
7916–Baseline Wild-type 9.9±3.4
7916–Week 72rtV173L, rtL180M, rtM204V
12.5±6.3 1.3
1674–Baseline (HBeAg-) 8.0±1.0
1674–Week 72 7.7±1.5 1.0
1669–Baseline (HBeAg-) 9.7±4.1
1669–Week 96 11.1±7.7 1.1
6852–Baseline (HBeAg-) 12.2±4.7
6852–Week 96 10.5±4.4 0.9
7957–Baseline (HBeAg-) 10.3±0.7
7957–Week 80 8.3±1.5 0.8
1553–Baseline (HBeAg+) 11.2±5.3
1553–Week 96 11.3±5.7 1.0
3958–Baseline (HBeAg+) 11.3±4.0
3958–Week 88 11.1±2.5 1.0
4957–Baseline (HBeAg+) 12.2±0.8
4957–Week 88 11.6±4.6 1.0
Phenotypic Analysis in Patients With Breakthrough on TDF (n=7)
82
Conclusion: 2 Years’ TDF Resistance in Patients With CHB
No HBV pol/RT amino acid substitutions associated with resistance to TDF were detected through 96 weeks of TDF monotherapy
— Annual resistance surveillance on-going through Year 8 (Week 384)
Virologic breakthrough was infrequent and not associated with phenotypic resistance to TDF
— The majority of patients experiencing virologic breakthrough had evidence of non-adherence
Development of conserved site changes was rare and not associated with phenotypic resistance to TDF
Snow-Lampart A, et al. 59th AASLD; October 31-November 4, 2008; San Francisco, CA. Abst 977.