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Traitement antiviral des hépatites B et bénéfices à long terme
Fabien ZoulimService d’hépatologie, Hospices Civils de Lyon
INSERM Unité 1052Université de Lyon
HBeAg(+) HBeAg(-) / anti-HBe(+)
ALT
HBV DNA
Minimal CH Moderate to severe CH Moderate to severe CHRemission
Cirrhosis
Immunotolerant
phase
Immuno-active
phase
Inactive phase
Low replication Reactivation phase
Cirrhosis
109-1012 IU/mL >2000-<109 IU/mL <2000 IU/mL >2000 IU/mL
Inactive cirrhosis
Treatment indicated Treatment indicated
HBsAg
Occult infection
EASL Clinical Practice Guidelines, J Hepatol 2012
Antivirals approved for the treament of
chronic hepatitis B
Drug Type Approved
Nucleoside analogs • Lamivudine
• Entecavir
• Telbivudine
Nucleotide analogs • Adefovir dipivoxil
• Tenofovir disoproxilfumarate
Cytokines • Interferon alfa
• Pegylated Interferon alfa-2a
Zoulim & Locarnini, Gastroenterology 2009; Zoulim Antiviral Research 2012; Mico et al J Hepatol 2013; Lucifora et al Science 2014
NK cells
Innate responses
CD8+ cells
B cells
CD4+ cells
Adaptive immune
responses
Nucleos(t)ide analogues
Interferon
alphaNTCP
Efficacité virologique
6.9Mean baseline
HBV DNA 9.7 9.6 9.59.5 8.68.99.9 10.1 7.6 7.6 7.77.4 7.07.1
93
TDF
Pro
po
rtio
n w
ith
un
dete
cta
ble
HB
V D
NA
(%
)
0
20
40
60
80
100
LVD vs.
LdT18†
LVD vs.
ETV16†
ADV vs.
TDF14*
PEG vs.
LVD19*
36
LVD
67
ETV
60
LdT
40
LVD
76
TDF
13
ADV
25
PEG
40
LVD
72
LVD
90
ETV
88
LdT
71
LVD
63
ADV
63
PEG
73
LVD
7.2
-8
-6
-4
-2
0
Me
an
HB
V D
NA
re
du
cti
on
(lo
g10
co
pie
s/m
L)
LVD vs.
LdT18†
LVD vs.
ETV17†
ADV vs.
TDF14*
PEG vs.
LVD20*
HBeAg-positive HBeAg-negative
-4.6
-5.4
-6.9-6.5
-5.5
-6.2
-3.9-4.5
-5.8
-4.5-5.0 -5.2
-4.4-4.1-4.1
-5.0
Gish, Jia, Locarnini & Zoulim, Lancet Infect Dis 2012
Response
HBeAg- Patients
(Study 102)
HBeAg+ Patients
(Study 103)
Year 5 Year 6 Year 5 Year 6
HBV DNA < 400 copies/mL
Intent-to-treat*, % (n/N)
83
(291/350)
81
(281/345)
65
(160/248)
63
(157/251)
HBV DNA < 400 copies/mL
On treatment†, % (n/N)
99
(292/295)
99.6
(283/284)
97
(170/175)
99
(167/169)
* LTE-TDF (missing = failure/addition of FTC = failure)† Observed (missing = excluded/addition of FTC = included)
♦ 80% of 585 patients entering the open-label phase remained on study at Year 6; 73% of
enrolled patients remained on study
♦ HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years
♦ 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion)
♦ No resistance to TDF was detected through 6 years
TDF administration: Virologic Suppression at Year 6
Marcellin P, et al. AASLD 2012; Boston. #374.7
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Italian ETV cohort: 100% of naive patients achieved HBV-DNA undetectability at 60 months
*Undetectable HBV-DNA† A 78-year-old woman with AH and a 48-year-old renal-transplanted woman with compensated cirrhosis
Adapted from Lampertico P, et al. AASLD 2012, poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013].
Safety
• Favourable safety profile after 53 months of treatment
• Renal safety profile: two patients reduced ETV dose due to eGFR decline†
Resistance
• One patient (0.2%) developed resistance
0
67
85
95 96 98 100
0
20
40
60
80
100
Baseline 6 12 24 36 48 60
Vir
olo
gic
resp
on
se*,
pat
ien
ts (
%)
405418 391Patients
on follow-up 344 307 259 97
Management of partial response – The case of Entecavir
Zoutendijk et al, HepatologyVolume 54, Issue 2, pages 443-451, 25 JUL 2011
Kaplan-Meier curve for the probability of achieving virological response for 243 NA-naïve patients according to HBeAg status at baseline. P value was determined using log-rank testing.
Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naïve patients with a partial virological response
Zoutendijk et al Hepatology Volume 54, Issue 2, pages 443-451, 25 JUL 2011
.Kaplan-Meier curve for the probability of achieving a VR for NA-naïve patients with a PVR according to HBV DNA atweek 48. Three patients were switched to TDF plus emtricitabine, and one patient received TDF add-on therapy. P value was determined using log-rank testing.
6
3
LVD ADV LdT ETV TDF
0
10
20
30
40
50
60
70
80
23
Pro
port
ion o
f patients
(%
)
46
55
71
80
0
11
18
29
5
25
0.2 0.51.2
0
1 2 3 4 5 1 2 3 4 5 1 2 1 2 3 4 5 1 2 3
0 0
Option to add
emtricitabine
at week 72*
*Patients confirmed to be viraemic at Week 72 or beyond could add emtricitabine to TDF at the discretion of the
investigator. Clinical data on the safety and efficacy of emtricitabine and TDF in CHB are pending
Rates of resistance with lamivudine (LVD), adefovir (ADV), telbivudine
(LdT), entecavir (ETV) and tenofovir (TDF) among NA-naïve patients
4
0
High barrier to resistance
Gish, Jia, Locarnini & Zoulim, Lancet ID 2012
5
0
6
3
LVD ADV LdT ETV TDF
0
10
20
30
40
50
60
70
80
23
Pro
port
ion o
f patients
(%
)
46
55
71
80
0
11
18
29
5
25
0.2 0.51.2
0
1 2 3 4 5 1 2 3 4 5 1 2 1 2 3 4 5 1 2 3
0 0
Option to add
emtricitabine
at week 72*
*Patients confirmed to be viraemic at Week 72 or beyond could add emtricitabine to TDF at the discretion of the
investigator. Clinical data on the safety and efficacy of emtricitabine and TDF in CHB are pending
Rates of resistance with lamivudine (LVD), adefovir (ADV), telbivudine
(LdT), entecavir (ETV) and tenofovir (TDF) among NA-naïve patients
4
0
High barrier to resistance
Gish, Jia, Locarnini & Zoulim, Lancet ID 2012
5
0
57% in lamivudineresistant patients
Drug and patient population
Resistance at year of therapy expressed as
percentage of patients
1 2 3 4 5 6
Lamivudine 23 46 55 71 80 -
Telbivudine HBeAg-Pos 4.4 21 - - - -
Telbivudine HBeAg-Neg 2.7 8.6 - - - -
Adefovir HBeAg-Neg 0 3 6 18 29 -
Adefovir (LAM-resistant) Up to 20% - - - - -
Tenofovir 0 0 0 0 0 0
Entecavir (naïve) 0.2 0.5 1.2 1.2 1.2 1.2
Entecavir (LAM resistant) 6 15 36 46 51 57
Incidence of drug resistance over time
CL Lai Clin Infect Dis 2003; CL Lai NEJM 2007; Hadzyiannis Gastroenterology 2006;Marcellin NEJM 2008; CL Lai & Chang NEJM 2006; Zoulim & Locarnini Gastroenterology 2009
Cross-resistance data for the main mutants and the commercially available drugs
Zoulim & Locarnini Gastroenterology 2009; J Hepatol 2012
Pathway Amino Acid
Substitutions in
the rt Domain
LMV LdT ETV ADV TFV
Wild-type S S S S S
L-Nucleoside
(LMV/LdT)
M204I/V R R I S S
Acyclic
phosphonate
(ADV)
N236T S S S R I
Shared (LMV, LdT,
ADV)
A181T/V R R S R I
Double (ADV, TFV) A181T/V + N236T R R S R R
D-Cyclopentane
(ETV)
L180M+M204V/I
± I169 ± T184
± S202 ± M250
R R R S S
Multi-Drug
Resistance
A181T+N236T+
M250V
R R R R R
Tenofovir rescue of Adefovir failure
• 105 Patients with chronic hepatitis B refractory to ADVrandomized in a controlled trial of TDF versus TDF + FTC.
• 63 Patients had been exposed to lamivudine before the trial.
RA
ND
OM
IZA
TIO
N 1
:1
Tenofovir DF 300 mg
FTC 200mg/Tenofovir DF 300 mg
Total Study Duration = 168 Weeks (Blinded or Open Label)
Week 24Roll over to open label FTC/TDF or discontinue if confirmed
(within 4 weeks) plasma HBV DNA 400 copies/mL
Double Blind
Blinded Study Medicationor
Open Label FTC/TDF
Week 48Primary Analysis
Week 168
Berg et al, Gastroenterology 2010
Manns M, et al., EASL 2008; Oral # 1587.
Tenofovir efficacy in LAM Experienced vs. Naïve
Study 103:N=176
Study 102: N=250 Total
LAM-Naïve, n
LAM-Experienced, n168
8
209
41
377
49
• Study 102 actively
enrolled both
LAM experienced and
LAM-naïve patients
• Study 103 enrolled
eight LAM experienced
patients despite
LAM-naïve inclusion
criteria
P=0.718
88%
86%P=0.718
Naive (N=377)
Lam Exp (N=49)P
erc
enta
ge (
%)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 16 20 24 28 32 36 40 44 48
88%
86%P=0.718
Naive (N=377)
Lam Exp (N=49)P
erc
enta
ge (
%)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 16 20 24 28 32 36 40 44 48
ITT Missing=Failure
Combined data includes both HBeAg +/- patients
Reijnders, JGP et al. J Hepatol 2010
Virologic response to Entecavir according to Lamivudine exposure
% C
um
ula
ted
re
spo
nse
2 80 10 124 60
20
60
80
40
100LVD-naïve (N=118)
LVD-experienced without development of LVD-resistance (N=20)
LVD-experienced with a prior history of LVD-resistance (N=14)
LVD-experienced with LVD-resistant mutations at baseline (N=9)
P = 0.007
2 80 10 124 60
100
20
60
80
40
Reijnders, JGP et al.. J Hepatol. 2010
Virologic response to Entecavir
according to Adefovir exposure
ADV-naïve (N=119)
ADV-experienced without development of ADV-resistance (N=30)
ADV-experienced with ADV-resistant mutations at baseline (N=12)
% C
um
ula
ted
re
spo
nse
P = NS
P
e
r
c
en
t
age
(
%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Treatment
TDFFTC/TDF
P
e
r
c
en
t
age
(
%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
P
e
r
c
en
t
age
(
%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Treatment
TDFF
Treatment
TDFFTC/TDF
Virologic Response to TDF vs TDF + FTC in patients with
previous failure to ADV (study # 106)
82% FTC/TDF
82% TDF
ITT: NC=F*
Two patients on study at Week 168 had HBV DNA ≥400 copies/mL
Berg T, et al., AASLD 2010; Oral# 136.
Perc
en
tag
e (
%)
*NC=F, Non-completer counted as failure in this ITT analysis, including patients who switched to open-label FTC/TDF fixed-dose combination
% of Patients with HBV DNA < 400 copies/mL (69 IU/mL)
29 29 29 29 27 26 24 24
33 33 33 31 30 29 27 26
14 14 14 14 14 14 14 14
11 11 11 11 10 10 10 10
17 16 16 16 16 16 16 16
12 12 12 12 12 11 10 10
n =n =n =n =n =n =
Response by Baseline Resistance at Week 168
TDF vs. FTC/TDF for Treatment-Experienced Patients:
Weeks on Study
Berg et al, Gastroenterology 2010; J Heaptol 2014
Suggested treatment adpatation in patients with treatment failure
Type of failure Treatment adaptation
Lamivudine resistance 1) switch to TFV
2) add TFV in difficult cases (add ADV if TFV not available)
Adefovir resistance 1) switch to TFV (if available)
2) if no history of LMV, switching to ETV is also effective.
3) If rtN236T substitution, consider adding ETV to the TFV or switch
to TFV plus FTC
4) If rtA181V/T substitution, alone or in combination with rtN236T,
switch to TFV plus ETV
Telbivudine resistance 1) switch to TFV
2) add TFV
3) a switch to ADV is not recommended
Entecavir resistance 1) add TFV
Tenofovir resistance 1) not been confirmed so far
2) genotyping and phenotyping required
3) may add ETV
EASL CPG, J Hepatol 2009 & 2012; Zoulim & Locarnini Liver Int 2013
Management algorithm
Antiviral treatment
Treatment failure
Viral load asssessment
Second line therapybased on cross-resistance data(switch or add-on)
Check compliance Primary non response
Switch to more potent drug
Viral genome sequence analysis
Wild type virus HBV drug resistant mutant
Check compliance
Zoulim and Perrillo, J Hepatol, 2008; EASL CPG J Hepatol 2012
Management algorithm
Antiviral treatment
Treatment response
Viral load asssessment
Zoulim and Perrillo, J Hepatol, 2008; EASL CPG J Hepatol 2009
Check for HBe/HBs seroconversion on a regular basis (6 monthly)
Bénéfice histologique et clinique
Histology: long-term ETV therapy and regression of fibrosis and cirrhosis
88% of patients had regression of fibrosis†, including 10/57 patients with advanced fibrosis or cirrhosis (Ishak score ≥ 4) at phase 3 study baseline
• 57 NUC-naive HBeAg(+) and HBeAg(-) CHB patients from phase 3 studies who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes
• Liver biopsy after median 6 years of ETV (range 3–7 years)
Adapted from Chang TT, et al. Hepatology 2010;52:886–93.
† ≥1-point decrease in Ishak fibrosis score.
0
10
20
30
40
50
60
Baseline Week 48 Long-term
Missing
6
5
4
3
2
1
0
Ishak Fibrosis Score
51% of patients had regression of fibrosis†, including 71/96 patients with cirrhosis (Ishak score ≥ 5) at phase 3 study baseline
• 348 HBeAg(+) and HBeAg(-) CHB patients from phase 3 studies who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes
• Liver biopsy after 5 years of TDF
Histology: long-term TDF therapy and regression of fibrosis and cirrhosis
Adapted from Marcellin P, et al. Lancet 2013;381:468–75.
† ≥1-point decrease in Ishak fibrosis score.
Ishak Score
0
20
40
60
80
100
Baseline Year 1 Year 5
6
5
4
3
2
1
0
VIRGIL European cohort: compared with no response, avirological response to ETV is significantly associated with
lower probability of disease progression in cirrhotics
Patients with compensated cirrhosis (n = 89) and decompensated cirrhosis (n = 9)
0 48 96 1440
20
40
60
80
100
p = 0.04
Time (weeks)
Pro
bab
ility
of
even
t* %
HR: 0.22, 95% CI 0.05–0.99
**VR defined as HBV-DNA <80 IU/mL.
No virological response
Virological response**
Cirrhotic patients had previously received:
• ADV: 31%• LAM: 34%
*Primary outcome was occurrence of a
clinical event defined as a composite
endpoint of development of
hepatic decompensation, HCC
or death
Adapted from Zoutendijk R, et al. Gut 2013;62:760–5.
Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013]
Prospective real-world study, assessing 5-year efficacy and safety of ETV in NUC-naive CHB
Italian ETV cohort: complication-free survival in patients with compensated cirrhosis
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 Months
Decompensation rate/year: 0%
HCC rate/year: 2.8%
86%
100%
HCC
Decompensation
Patients
at risk155 153 149 145 135 125 115 105 92 58 20
*Kaplan–Meier estimates.
Baseline characteristics (418 NUC-naive patients): • Median (range)
age: 58 (18–82) • Cirrhosis: 49%• Concomitant
diseases: 56%• HBeAg(-)ve: 83%
Italian ETV cohort: overall and liver-related survival in patients with compensated cirrhosis
*Kaplan–Meier estimates.OLT = death.
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 Months
Patients
at risk155 154 151 147 142 133
91%Overall survival*
124 111 98 61 21
Liver–related survival*95%
Death for HCC: 2 patients
OLT for HCC: 4 patients
Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013]
BE-LOW (ETV-110): study design
• Randomized, open-label, Phase IIIb trial
• NA-naïve CHB, HBeAg(+) or HBeAg(–)
• HBsAg levels were quantified (Abbott Architect assay at a central laboratory) at baseline and Weeks 12, 48 and 96
RA
ND
OM
IZA
TIO
N 1
:1
ETV 0.5 mg + TDF 300 mg, once daily (N=197)*
Week 96Baseline
ETV 0.5 mg, once daily(N=182)*
Primary endpointHBV DNA <50 copies/mL#
Further anti-HBV therapy at discretion
of investigator –up to 24 weeks
follow-up
Dosing x 100 weeks
*Modified intent-to-treat population: received at least one dose of study medication#HBV DNA assayed by Roche COBAS™ TaqMan-HPS assay
. Lok A, et al. Gastroenterology 2012
HBV DNA <50 IU/mLat Weeks 48 and 96: overall
*Primary endpoint
Difference 6.9% (95% CI –1.0, 14.9)
P=NS
Number of patients:
HB
V D
NA
<5
0 I
U/m
L(%
pat
ien
ts)
0
20
40
60
80
100
158197
80.2
128182
70.3
Week 48164197
83.2
139182
76.4
Week 96*
ETV
ETV+TDF
Difference 9.9%
(95% CI 1.5, 18.4)
Non-completer = failure
Change in quantitative HBsAgthrough Week 96: overall
0
0.2
0.4
0.6
0.8
1
1.2
0 12 24 36 48 60 72 84 96
ETV
ETV+TDF
Mean decline in HBsAg level from baseline to Wk 96 = 0.67 (±0.1) log10 IU/mLin both groups
Me
an H
BsA
gd
ecl
ine
fro
m b
ase
line
, lo
g 10
IU/m
L (S
E)
Duration of treatment (weeks)
Zoulim et al, J Hepatol 2015
HBsAg decline through Week 96 by baseline HBeAg status and baseline ALT
0
0.2
0.4
0.6
0.8
1
1.2
0 12 24 36 48 60 72 84 96
ETV HBeAg(-)
ETV+TDF HBeAg(-)
ETV HBeAg(+)
ETV+TDF HBeAg(+)
0
0.2
0.4
0.6
0.8
1
1.2
0 12 24 36 48 60 72 84 96
ETV ALT<2*ULNETV+TDF ALT<2*ULNETV 2*ULN<=ALT<5*ULNETV+TDF 2*ULN<=ALT<5*ULNETV ALT=>5.0*ULNETV+TDF ALT=>5.0*ULN
By HBeAg status By baseline ALT
Duration of treatment (weeks)
Me
an H
BsA
gd
ecl
ine
fro
m
bas
elin
e, l
og 1
0IU
/mL
(SE)
Me
an H
BsA
gd
ecl
ine
fro
m
bas
elin
e, l
og 1
0IU
/mL
(SE)
Duration of treatment (weeks)
HBsAg decline through Week 96 by baseline HBV Genotype
0
0.4
0.8
1.2
1.6
2
0 12 24 36 48 60 72 84 96
0
0.4
0.8
1.2
1.6
2
0 12 24 36 48 60 72 84 96
ETV ETV + TDF
Duration of treatment (weeks) Duration of treatment (weeks)
Me
an H
BsA
gd
ecl
ine
fro
m
bas
elin
e, l
og 1
0IU
/mL
(SE)
Me
an H
BsA
gd
ecl
ine
fro
m
bas
elin
e, l
og 1
0IU
/mL
(SE)
A A
BB
C
C
D D
O
Genotype
O = Other
Genotype
O
Prévention du CHC par le traitement antiviral
*Marcellin P, et al. Lancet. 2013 Feb 9;381(9865):468-75.
Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral #43
Studies 102/103
Long Term TDF Therapy and Risk of HCC
Phase 3, randomized, double-blind, placebo-controlled
All patients received open-label TDF after Year 1 for total study duration of 8 years
Previously reported 5-year data showed no resistance and reversal of fibrosis*
Study Aim: To compare the observed incidence of HCC in patients treated with TDF in
Studies 102/103 with the predicted HCC incidence based on the REACH-B risk calculator
TDF 300 mg
(n=426)
ADV 10 mg
(n=215)
Open-label TDF 300 mg QD
85430 1 2Year
Chronic HBV: (HBeAg– and +)
7
HCC data analysis
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed
for use to treat CHB
Emtricitabine (FTC) could be added at/after week 72
REACH-B Model
Hypothetical Patient:
• 60-year-old HBeAg+ male, ALT 60, HBV DNA 100,000 copies/mL
• REACH-B score: 17
Year
HC
C R
isk (
%)
Variable Data Score
Sex Male/female 0‒2
AgeEvery 5 y
>300‒6
ALT, U/L
<15
15‒44
>45
0‒2
HBeAg +/– 0‒2
HBV DNA,
copies/mL
Und.
~104
~105
~106
>106
0‒5
Prediction model to estimate HCC risk in non-cirrhotic patients up to 10 years
Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral #43
Yang et al, Lancet Oncology. 2011;12(6):568-74
REACH-B is a risk calculator developed in non-cirrhotic pts
so It may underestimate the risk
*Patients completing 336 weeks in study as defined by protocol
Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral#43
Studies 102/103
HCC Incidence Based on Cirrhosis Status at BaselineH
CC
dia
gn
os
is (
%)
No. at risk
Non-cirrhotic 482 453 425 396 377 360 343 324*
Cirrhotic 152 146 137 132 126 120 115 109*
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 48 96 144 192 240 288 336
Week
Cirrhotic
Non-cirrhotic
n=6
4.5%
n=8
1.5%
REACH-B is a risk calculator developed in non-cirrhotic pts so
It may underestimate the risk
SIR = 0.50* 95% CI (0.294, 0.837)
1st significant difference
All Patientsn=634
*Statistically significant at nominal -level of 0.05.
Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral#43
Studies 102/103
Observed vs. Predicted HCC Cases
Incidence of HCC in patients on TDF in Studies 102/103 was lower than predicted by the
REACH-B model
In non-cirrhotic patients, the effect of TDF becomes noticeable between 2–3 years of therapy
and became statistically significant (55% reduction) at 6 years of therapy
SIR = 0.45*
95% CI (0.227, 0.909)
1st significant difference
Non-cirrhoticsn=482
REACH-B is a risk calculator developed in non-cirrhotic pts so
It may underestimate the risk
Propensity score (PS) matching for age, sex, pre-existing cirrhosis, HBeAg,
HBV-DNA, AST, ALT, GGTP, bilirubin, albumin, platelet counts
ETV groupNUC-naive CHB patients
Treated with ETV 0.5 mg, 2004–2010 n = 472
316 matched patients
Historical control groupUntreated CHB patients*Followed up, 1973–1999
n = 1143
316 matched patients analysed
• Retrospective cohort study from Toranomon Hospital, Tokyo, Japan
• Aim: to compare HCC incidence with ETV† vs no NUC therapy
Japanese cohorts: study design
Created from Hosaka T, et al. Hepatology 2013; [Epub ahead of print].
doi: 10.1002/hep.26180.
Median follow-up: 3.3 years
HCC cases: 6(5.63 cases/1000 patient-years)
Median follow-up: 7.6 years
HCC cases: 72(24.1 cases/1000 patient-years)
Cirrhosis was determined by laparoscopy, liver biopsy, imaging modalities or portal hypertension
*NUCs not available at this time in Japan.†ETV is not indicated for the prevention of HCC in CHB patients
Japanese cohorts: ETV reduced HCC incidence, compared with controls
PS-matched cohort multivariate cox regression analysis:*
HR 0.37 (95% CI 0.15–0.91) p = 0.030
*Adjusted for age, sex, alcohol, smoking, cirrhosis, HBV genotype, HBeAg status, HBV-DNA, ALT, albumin, γGTP, total bilirubin and platelet count.
Cu
mu
lati
ve H
CC
rat
es (
%)
Log-rank test: p<0.001
Treatment duration (years)
0
10
20
30
7.2%
13.7%
3.7%
1.2%
0 1 3 5 72 4 6
No. at riskETVControl
316316
316316
264277
185246
101223
44200
2187
2170
Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180. HR, hazard ratio; PS, propensity score
Control
ETV
Japanese cohorts: significantly reduced HCC incidence with ETV compared to controls in cirrhotic patients
50
40
30
20
10
0
Log-rank test: p = 0.440
No cirrhosis
1.6%3.6%
2.5%0%
237231 231
237 192201 181
132 66169 143
27ETVControl
No at risk
Treatment duration (years )
Cu
mu
lati
ve H
CC
rat
e (%
)
Treatment duration (years)
50
40
30
20
10
0
Cu
mu
lati
ve H
CC
rat
e (%
)
Cirrhosis
7985 85
79 7276 65
53 3554 47
17ETVControl
No at risk
0 1 3 52 4
Log-rank test: p < 0.001
20.9%
4.3%
38.9%
7.0%
0 1 3 52 4
Control
ETV
Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180.
Japanese cohorts: HCC incidence lower with ETV than with LAM in cirrhotic patients
LAM
No at risk
Cirrhosis
0 1 3 52 4Treatment duration (years)
20.9%
38.9%
4.3%7.0%
22.2%
12.2%
50
40
30
20
10
0
Cu
mu
lati
ve H
CC
rat
e (%
)
Log-rank test:
ETV vs LAM: p = 0.043ETV vs control: p < 0.001LAM vs control: p = 0.019
497985
49
8579
417276
35
6553
323554
29
4717ETV
Control
ETV
Control
LAM
Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180.
ETV vs LAM sub analysis:
• Additional cohort of 949 LAM-
treated patients were recruited
(1995–2007)
• Of 492 LAM-treated patients who
met the same inclusion criteria as
the ETV group (no rescue therapy),
PS-matching resulted in a cohort of
182 patients (49 had cirrhosis)
Vers un traitement plus précoce de l’hépatite B: le cas du patient
immunotolérant
Mason, W. S. et al. 2009 / 2010. J. Virol
Devons nous redéfinir la tolérance immunitaire et
repenser les indications thérapeutiques ?
Observation d’une expansion clonale des hépatocytes
- Cellules qui n’expriment pas les antigènes viraux
- Diminution de la charge virale malgré l’absence de lésion hépatique mesurable
- L’une des premières étapes du CHC
Tolérance Immunitaire
- Presque tous les hepatocytes sont infectés- Viremies > 10E9 copies/mL- Devrions nous réaliser une biopsie lorsque
la charge virale diminue sans élévation des ALAT ? Et penser à un traitement antiviral ?
Zoulim & Mason, W. S. Gut 2012
Baseline Characteristics
CharacteristicTDF
(n=64)
FTC/TDF
(n=62)
Mean age, years (SD) 33 (9.5) 33 (11.2)
Male, n (%) 31 (48.4) 31 (50)
Race, n (%)
Asian 56 (87.5) 56 (90.3)
Caucasian 4 (6.3) 1 (1.6)
Other 4 (6.3) 5 (8.0)
Region, n (%)
Asia/Pacific 37 (57.8) 43 (69.4)
Europe 9 (14.1) 8 (12.9)
North America 18 (28.1) 11 (17.7)
Mean HBV DNA, log10 IU/mL (SD) 9.2 (0.4) 9.2 (0.4)
HBV genotype, n (%)
B 33 (51.6) 32 (51.6)
C 24 (37.5) 28 (45.2)
Other 7 (10.9) 2 (3.2)
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45-Oral #101
Nei
ther
Tru
vad
a (T
VD
= T
DF
+ FT
C)
or
emtr
icit
abin
e (F
TC)
are
licen
sed
fo
r u
se t
o t
reat
CH
B
Study Design
♦ Primary endpoint: HBV DNA < 69 IU/mL at Week 192
– Roche TaqMan® Real-Time Polymerase Chain Reaction Assay 2.0
♦ Key inclusion criteria:
– HBV DNA 1.7x107 IU/mL
– ALT ≤ upper limit of normal
♦ Key exclusion criteria:
– Decompensated liver disease
Patients with high HBV DNA and normal ALT (N=126)
TDF 300 mg/placebo
(n=64)
FTC 200 mg/TDF 300 mg
(n=62)
1:1 Randomization
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Mean Viral Decline From Baseline
Study week
TDFFTC/TDF
Ch
ange
in H
BV
DN
A (
log 1
0 IU
/mL)
0 16 32 48 64 80 96 112 128 144 160 176 192
–8
–6
–4
–2
0
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Proportion of Patients With HBV DNA < 69
IU/mL at Week 192*
FTC/TDF 76%
TDF 55%Pati
en
ts (
%)
Study week*Proportion (95% confidence interval [CI]); missing data = failure analysis.
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101
Nei
ther
Tru
vad
a (T
VD
= T
DF
+ FT
C)
or
emtr
icit
abin
e (F
TC)
are
licen
sed
fo
r u
se t
o t
reat
CH
B
Multivariate Analysis of Treatment Response
Odds ratio† CI
Female 6.0 1.9‒18.2
FTC/TDF treatment 3.9 1.4‒11.1
We
ek
19
2 r
es
po
ns
e r
ate
* (%
)
Male
Female
TDF FTC/TDF
*Proportion of patients with HBV DNA <69 IU/mL at Wk 192 among those with Wk 192 visit. †Multivariate logistic regression performed using forward selection model.
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101
Nei
ther
Tru
vad
a (T
VD
= T
DF
+ FT
C)
or
emtr
icit
abin
e (F
TC)
are
licen
sed
fo
r u
se t
o t
reat
CH
B
Safety Analysis: Clinical Parameters
TDF
(n=64)
FTC/TDF
(n=62)
Serious adverse event, n (%)* 6 (9.4)* 3 (4.8)†
Study drug-related adverse event
Grade 2 4 (6.3) 5 (8.1)
Grade 3 or 4 0 0
Death 0 1 (1.6)‡
*Urinary tract infection, HBV, appendicitis, gastroenteritis, creatine kinase increase, uterine leiomyoma; †Urinary tract infection, spontaneous abortion, ovarian cyst; ‡Homicide.
Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Safety Analysis: Laboratory Parameters
Parameter, n (%)
TDF
(n=64)
FTC/TDF
(n=62)
ALT flare* 1 (1.6) 0
sCr ≥0.5 mg/dL above BL 0 0
CrCl <50 mL/min 0 0
PO4 <2 mg/dL 1 (1.6) 0
*Serum ALT >2x baseline and >10x upper limit of normal.#Documented study drug noncompliance
#
CrCl, creatinine clearance; PO4, phosphate; sCr, serum creatinine.Chan HLY, et al. EASL 2013. Amsterdam, The Netherlands. Oral #101
Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB
Conclusions
• Traitements antiviraux puissants
• Barrière de résistance élevée
• Amélioration histologique et clinique
• Démonstration d’un impact sur le CHC / retard d’apparition
• Premières données cliniques chez le patient immunotolérant
• Arguments pour : – Dépistage de l’hépatite B
– Traitement antiviral de tout patient ayant une pathologie hépatique « évolutive » (cf recommandations internationales)
– Discuter un traitement antiviral plus précoce: immunotolérance, hépatite minime
Why a need for new antiviral targets for hepatitis B ?
• Current antivirals achieve viral suppression in the majority of patients (in western countries)
• Issues with antiviral drug resistance in developing countries (use of low barrier to resistance antivirals)
• The rate of cccDNA / HBsAg loss remains very low
• Life-long therapy is needed in the majority of the cases
• Treatment with finite duration if:
cccDNA control or loss
HBsAg loss
Zoulim, Antiviral Research 2012
Current treatment: sustained disease control achieved with NUCs/IFN in majority of patients
Entecavir1,2 Tenofovir3 PEG-IFN α-2a4,5
HBeAg positive n = 354 n = 176 n = 271
HBV DNA undetectable 67% 76% 25%a
HBeAg seroconversion 21% 21% 27%
ALT normalisation 68% 68% 39%
HBsAg loss 2% 3.2% 2.9%b
HBeAg negative n = 325 n = 250 n = 177
HBV DNA undetectable 90% 93% 63%a
ALT normalisation 78% 76% 38%
HBsAg loss 0.3% 0% 0.6%b
1. Chang T-T, et al. N Engl J Med 2006;354:1001–10.2. Lai C-L, et al. N Engl J Med 2006;354:1011–20.3. Marcellin P, et al. N Engl J Med 2008;359:2442–55.
4. Lau GKK, et al. N Engl J Med 2005;352:2682–95.5. Marcellin P, et al. N Engl J Med 2004;351:1206–17.
Results at 48 weeks a HBV DNA < 400 copies/mL; b At 72 weeks
Cumulative Probability of HBsAg
Loss During TDF AdministrationC
umul
ativ
e P
roba
bilit
y F
unct
ion
Est
imat
e
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.10
0.11
0.12
Weeks on Study
0 12 24 36 48 64 80 96 108 120 132 144 156 168 180 192
10.8%
8.5%
• TDF-TDF
• ADV-TDF
Switch to Open Label TDF
Cumulative probability of seroconversion to anti-HBs: 7.7% TDF-TDF
7.3% ADV-TDF*Kaplan-MeierHeathcote E-J, et al., AASLD 2010; Poster #477.
• TDF-TDF
• ADV-TDF
0 12 24 36 48 64 80 96 108 120 132 144 156 168 180 192
Weeks
Cu
mu
lati
ve
Pro
ba
bil
ity F
un
cti
on
Es
tim
ate
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0.00
Percentage of
TDF-TDF Patients with HBsAg Loss
Key CharacteristicHBsAg Clearance by Year 4
n/N (%)
Genotype A or D 14/95 (15%)
HBV DNA ≥ 9 log10 copies/mL 12/75 (16%)
HBsAg ≥ 4.5 log10 IU/mL 14/90 (16%)
Knodell Necroinflammatory Score ≥ 9 13/114 (11%)
Heathcote E-J, et al., AASLD 2010; Poster #477.
No HBsAg loss in : Asian patients
HBeAg negative patients
Genotype B or C
High rate of HBsAg clearance among sustained
responders to PEG-IFN-2a± LAM
Marcellin et al. APASL 2009* Modified ITT analysis (missing = non response);§ last observation carried forward
5 years post-treatment with PEG-IFN-2a ± LAM (N=230)
<10,000 cp/mL* <400 cp/mL* Cleared HBsAg§
Pati
en
ts (
%)
21%
17%
12%
64%
0
5
10
15
20
25
30
Slow kinetics of HBV clearance
• Rate of cccDNA decline (liver)
< 1 log10 copie/cell at year one
Estimated time for clearance (in the absence of
hepatocyte turnover) > 15 years
Werle et al, Gastroenterology 2004; Wong et
al Clin Gastroenterol and Hepatol 2013
• HBsAg decline (serum)
• Rate of decline: 0.007 ± 0.007 Log
UI/mL/month
Evolution of viral markers during NUC therapy
Wong et al, Clin Gastroenterol Hepatol 2013Werle et al, Gastroenterology 2004
0.01
0.1
1
10
100
2.00E+02
3.00E+02
4.00E+02
5.00E+02
6.00E+02
7.00E+02
8.00E+02
9.00E+02
No
v. 99
Jan
. 00
Sep
t. 0
0
Ma
r. 0
1
Ju
ly 0
2
Dec. 02
Dec. 03
Viral load
HBs Ag
Lamivudine 100 mg/day
Clinical example of HBsAg clearance
HBs AgPositivity cut off: 0.05
Viral loadDetection treshold
Viral loadLog Copies/ml
HBs Ag
IU/ml
* *
*: Anti-HBs antibody
Negativation of HBe Ag May 1987HBe Seroconversion between June 87 and November 1996?
Borgniet O et al., J Med Virol , 2009;81:1336-42.
Therapy
HB
V D
NA
ch
an
ge f
rom
baselin
e (
log
10
c/m
L)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
Short-term therapy is associated with rebound of viral replication
HBsAg
HBVDNA
cccDNA
Therapy
HB
V D
NA
ch
an
ge f
rom
baselin
e (
log
10
c/m
L)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
Long-term therapy is required to maintain viral suppression
HBsAg
HBVDNA
cccDNA
Therapy
HB
V D
NA
ch
an
ge f
rom
baselin
e (
log
10
c/m
L)
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
New treatment concepts for a functional cure of HBV infection
HBsAg
HBVDNA
cccDNA
Lucifora et al, Science 2014
Zoulim, et al,
Clinical Gastroenterology
and Hepatology 2013
Belloni et al, JCI 2012
Hepatocyte turn-over
cccDNA silencing
cccDNAdegradation
cccDNAformation
Bertoletti & Ferrari Gut 2012; Zoulim et al, Gastroenterology 2013
Concept of combination therapy for CHB
Innate
responses
Adaptive
responses
Viral
replication
Future directions: target & drug discovery to cure HBV infection
Immune modulation• Toll-like receptors
agonists, Gilead, Roche
• Anti-PD-1 mAb, BMS, Merck
• Vaccine therapyTransgene, Gilead, Roche Innovio, Medimmune, ITS
Development stage: preclinical, clinicalZoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at: http://www.hepb.org/professionals/hbf_drug_watch.htm.
HBx
Endosome
rcDNA
cccDNA
Polymerase
pgRNA
Core
Surface
proteins
Entry inhibitors• Lipopeptides, e.g.
Myrcludex-B
Targeting cccDNA
Inhibition of nucleocapsid assembly, Novira, Assemblypharm, Gilead, Janssen, Roche
Polymerase inhibitors • Nucleoside
analogues, e.g. Gilead, BMS
• Non-nucleoside, e.g. LB80380
Inhibitors of HBsAg release, Replicor
RNA interference,Arrowhead, Tekmira, Alnylam, GSK
The concept of combination therapy
Entry inhibition
cccDNA- formation- stability / destruction- epigenetic regulation
Viral core functions
Other viral targets
Stimulating innate responsesSpecific ligands
Stimulating adpative responsesCo-inhibitory signals
Co-stimulatory signals
Therapeutic vaccination
Functional cure / controlReal cure ?
Viral targets Immune modulation