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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
Immunotolerantphase
Immuno-activephase
Inactive phaseLow replication Reactivation phase
Cirrhosis
109-1012 IU/mL >2000-<109 IU/mL <2000 IU/mL >2000 IU/mL
Inactive cirrhosis
Treatment indicated Treatment indicated
HBsAgOccult infection
EASL Clinical Practice Guidelines, J Hepatol 2012
Indications de traitement• Patients en phase immunoactive
– AgHBe+, CV > 2000 UI/mL, ALT augmentées– AgHBe-, CV > 2000 UI/mL, ALT fluctuantes
• Porteurs inactifs– AgHBe-, CV < 2000 UI/mL, ALT normales– Si traitement immunosuppresseur /prévention de la réactivation virale
• Patients immunotolérants– AgHBe+, CV > 6log UI/mL, ALT normales– Si ATCD familiaux de cirrhose ou de CHC
• Femme enceinte– Si CV > 6 log UI/mL– Dernier III de grossesse pour prévention de la transmission verticale– Avec HBIG et vaccin chez le bébé
Objectifs du traitement
• VirosuppressionCharge virale sérique indétectable en PCR
• Normalisation des transaminases, amélioration de l’histologie hépatique, prévention de la progression de la maladie hépatique et du CHC
• Séroconversion HBeDisparition de l’AgHBe, apparition d’Ac anti-HBe
• Séroconversion HBsDisparition de l’AgHBs, apparition d’Ac anti-HBs
Antivirals approved for the treament of chronic hepatitis B
Drug Type Approved
Nucleoside analogs • Lamivudine• Entecavir • Telbivudine
Nucleotide analogs • Adefovir dipivoxil• Tenofovir disoproxil fumarate
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
The main differences between HIV, HBV and HCV
H
HBV1,2
Host cell
cccDNA
Host DNA
Integrated DNA
Nucleus
H
HIV1
Host cell
Host DNA
Proviral DNA
Nucleus
H
HCV1,3
Host cell
Host DNA
Nucleus
HCV RNA
Life-long suppression of viral replication
Definitive viral clearance and SVR
Long-term suppression of viral replication
Adapted from 1. Sorriano V, et al. J Antimicrob Chemother 2008;62:1-4. 2. Locarnini S and Zoulim F. Antiviral Therapy 2010;15 (suppl 3):3-14. 3. Sarrazin C and Zeuzem S. Gastroenterology 2010;138:447-462.
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
Prop
ortio
n w
ith u
ndet
ecta
ble
HB
V D
NA
(%)
0
20
40
60
80
100LVD 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
LVD7.2
-8
-6
-4
-2
0
Mea
n H
BV
DN
A re
duct
ion
(log 1
0 cop
ies/
mL)
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
ResponseHBeAg- Patients
(Study 102)HBeAg+ Patients
(Study 103)
Year 5 Year 6 Year 5 Year 6
HBV DNA < 400 copies/mLIntent-to-treat*, % (n/N)
83(291/350)
81(281/345)
65(160/248)
63(157/251)
HBV DNA < 400 copies/mLOn 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. #374.10
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
Baseline 6 12 24 36 48 600
20
40
60
80
100
0
67
8595 96 98 100
Viro
logi
c re
spon
se*,
pati
ents
(%)
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 at week 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.
Combinaisons thérapeutiques
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
RAN
DOM
IZAT
ION
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:
HBV
DNA
<50
IU/m
L(%
pati
ents
)
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 HBsAg through Week 96: overall
0 12 24 36 48 60 72 84 96
0
0.2
0.4
0.6
0.8
1
1.2
ETV
ETV+TDF
Mean decline in HBsAg level from baseline to Wk 96 = 0.67 (±0.1) log10 IU/mLin both groups
Mea
n HB
sAg
decl
ine
from
bas
elin
e, 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 12 24 36 48 60 72 84 96
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
ETV HBeAg(-)ETV+TDF HBeAg(-)ETV HBeAg(+)ETV+TDF HBeAg(+)
0 12 24 36 48 60 72 84 96
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
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)
Mea
n HB
sAg
decl
ine
from
ba
selin
e, lo
g 10 IU
/mL (
SE)
Mea
n HB
sAg
decl
ine
from
ba
selin
e, lo
g 10 IU
/mL (
SE)
Duration of treatment (weeks)
HBsAg decline through Week 96 by baseline HBV Genotype
0 12 24 36 48 60 72 84 96
0
0.4
0.8
1.2
1.6
20 12 24 36 48 60 72 84 96
0
0.4
0.8
1.2
1.6
2
ETV ETV + TDF
Duration of treatment (weeks) Duration of treatment (weeks)
Mea
n HB
sAg
decl
ine
from
ba
selin
e, lo
g 10 IU
/mL (
SE)
Mea
n HB
sAg
decl
ine
from
ba
selin
e, lo
g 10 IU
/mL (
SE)
A A
BBC
CD D
O
Genotype
O = Other
GenotypeO
Start TDF during follow-upif prespecified safety criteria met
Study GS-US-174-0149 Design
• Randomized, controlled, open-label study (N=740)– Stratified by screening HBeAg status and HBV genotype
• Inclusion criteria – HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL– ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)– No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography
20
0 48 12072
TDF + PEG
TDF+PEG → TDF
24
n=186
n=184
n=185
n=185 PEG
16
TDF
Week
Primary endpoint: HBsAg loss
Results: HBsAg Loss Over Time (Week 72)
• 7 patients had HBsAg seroreversion on or after Week 48 (n=4 treated with TDF + PEG 48 wk; n=3 with TDF + PEG 16 wk →TDF 32 wk)
21
Patie
nts W
ith H
BsAg
Loss
, Ka
plan
-Mei
er E
stim
ate
(%)
0.100.090.080.070.060.050.040.030.020.010.00
48 weeks
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Week
0.150.140.130.120.11
72 weeks
TDF + PEG 16 wk →TDF 32 wk
TDF + PEG 48 wk 9.1%
0%
2.8%
2.8%
p=0.003
p<0.001
p=NS
p=NS PEG 48 wk
TDF 120 wk
Marcellin P, et al. Gastroenterology. 2015
Résistances aux antiviraux
Terminal protein Spacer POL/RT RNaseH
1 183 349 (rt) 692 (rt 344) 845 a.a.
I(G) II(F) A B C D E
F_V_LLAQ_YMDD
*rtA181T/V and/or rtN236T cause reduced sensitivity*rtA194T association with rtL180M+rtM204V (to be confirmed)
LMV resistance/ rtL80IrtL180M
rtM204V/ILdT resistance
rtA181T/VADV resistance rtA181T/V rtN236TTDF resistance* ?ETV resistance rtL180M rtM204I/V
rtT184*** rtS202**** rtM250I/Vrtl169T
***S/A/I/L/G/C/M****C/G/I
Zoulim F & Locarnini Gastroenterology 2009;137:1593-1608.
rtV173L
* Role of complex mutants: rtA181T+rtN236T ?
Lamivudine Resistance Accelerates Progression of Liver Disease
YMDDm
WT
Placebo
5%
13%
21%
Liaw YF et al. N Engl J Med. 2004;351:1521-1531
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
Zoulim & Locarnini, Gastroenterology, 2009
Kinetics of HBV drug resistance emergence
Si Ahmed et al. Hepatology. 2000; Yuen et al Hepatology 2001; Locarnini et al Antiviral Therapy 2004; Villet et al Gastroenterology 2006 J Hepatol 2007 & 2008; Pallier et al J Virol 2007; Yim et al Hepatology 2006.
Treatment begins
Drug-resistant variant
Drug-susceptible virus
Naturally—occurring viral variants
Time
HB
V re
plic
atio
n
Primary resistance mutations
Secondary resistance mutations/ compensatory resistance mutations
?
Multiple drug resistant mutants with complex pattern of mutations+ one mutation + one mutation
Drug A Drug B
Risk of selection of MDR mutants by sequential therapy- drugs sharing cross-resistance characteristics- incomplete viral suppression- liver transplantation
The problem of sequential therapy with nucleoside analogues
Zoulim F, et al. J Hepatol. 2008;48:S2-19. Yim et al, Hepatology 2006; Villet et al Gastroenterology 2006 & 2009
103
104
105
106
107
108
109
0 20 40 60 80 100 120
Treatment (months)
HB
V D
NA
(cop
ies/
ml)
entecavirIFNadefovir
lamivudineGenotype H
lamivudine
Drugs sharing cross-resistance characteristics:Switching strategy emergence of MDR mutant
L180M+S202G+M204V
L180M+M204V
Villet et al, J Hepatol 2007
ADV rtN236T +/or rtA181V
Wild-type virus
ADV-resistant virus LAM-resistant virusLAM rtM204V/I ± rtL180M
ETV-resistant virus
rtT184 or rtS202 or rtM250ETVrtM204V/I rtL180M+/-
TDF
TDF: what can we expect?
rtM204V/I +/- rtL180MLAMthen ETV
rtT184 or rtS202 or rtM250
LAM + TDF – what do we see?
Maximising the barrier to resistance
6
3
LVD ADV LdT ETV TDF0
10
20
30
40
50
60
70
80
23
Pro
porti
on o
f pat
ient
s (%
)
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 30 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
40
High barrier to resistance
Gish, Jia, Locarnini & Zoulim, Lancet ID 2012
50
6
3
LVD ADV LdT ETV TDF0
10
20
30
40
50
60
70
80
23
Pro
porti
on o
f pat
ient
s (%
)
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 30 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
40
High barrier to resistance
Gish, Jia, Locarnini & Zoulim, Lancet ID 2012
50
57% in lamivudine resistant patients
Multiple factors are associated with the barrier of resistance & drug efficacy
•Adherence• Immune status•Prior antiviral exposure•Metabolism•Body mass
Patient
Antiviral Drug
•Antiviral potency•Number of mutations needed to overcome drug suppression
•Level of exposure to drug•Chemical structure Virus
Locarnini S, et al. Antivir Ther. 2004;9:679–93. Locarnini S, et al. Antivir Ther. 2007;12:H15-H23. 3. Ghany M & Liang TJ. Gastroenterology 2007;132:1574-85. Zoulim F, et al. Antiviral Res. 2004;64:1-15. Locarnini S, et al. J Hepatol. 2003;39:S124-S132.; Zoulim & Locarnini Gastroenterology 2009
•Replication fitness and space
•Persistence of archived mutations as cccDNA
•Pre-existing mutations
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 SL-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 RD-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
Manns M, et al., EASL 2008; Oral # 1587.
Tenofovir efficacy in LAM Experienced vs. Naïve
Study 103:
N=176Study 102:
N=250 TotalLAM-Naïve, nLAM-Experienced, n
1688
20941
37749
• 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
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
umul
ated
resp
onse
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
umul
ated
resp
onse
P = NS
Tenofovir rescue of Adefovir failure
•105 Patients with chronic hepatitis B refractory to ADV randomized in a controlled trial of TDF versus TDF + FTC.
•63 Patients had been exposed to lamivudine before the trial.
RAN
DOM
IZAT
ION
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
P
e
r
c
en
t
age
(
%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
TreatmentTDFFTC/TDF
P
e
r
c
en
t
age
(
%
)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study0 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 Study0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
TreatmentTDFF
TreatmentTDFFTC/TDF
Virologic Response to TDF vs TDF + FTC in patients with
previous failure to ADV (study # 106)
82% FTC/TDF82% 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
enta
ge (%
)
*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 2614 14 14 14 14 14 14 1411 11 11 11 10 10 10 1017 16 16 16 16 16 16 1612 12 12 12 12 11 10 10
n =n =n =n =n =n =
Response by Baseline Resistance at Week 168TDF vs. FTC/TDF for Treatment-Experienced Patients:
Weeks on Study
Berg et al, Gastroenterology 2010; J Heaptol 2014
Rescue therapy with ETV + TDF in CHB patients with advanced liver disease and complex viral resistance patterns or showing partial antiviral responses to preceeding therapies (Virgil network)
ETV + TDF combination in patients with treatment failure
Petersen J, et al. J Hepatol 2012.
HBV DNA Viremia
1002100310041005100610071008100910101011
Baseline 3 6 9 12 15 18 21 24
10 6
Δ 3 log10 c/mL reductionP=0.0001
LLoD
HBV
DNA
[IU/m
l]
Months
Suggested treatment adpatation in patients with treatment failure
Type of failure Treatment adaptationLamivudine 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 FTC4) If rtA181V/T substitution, alone or in combination with rtN236T, switch to TFV plus ETV
Telbivudine resistance 1) switch to TFV 2) add TFV3) a switch to ADV is not recommended
Entecavir resistance 1) add TFV
Tenofovir resistance 1) not been confirmed so far 2) genotyping and phenotyping required3) may add ETV
EASL CPG, J Hepatol 2009 & 2012; Zoulim & Locarnini Liver Int 2013
Management algorithmAntiviral 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.
Num
ber o
f pat
ient
s
Baseline Week 48 Long-term0
10
20
30
40
50
60
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
Pat
ien t
s ( %
)
Baseline Year 1 Year 50
20
40
60
80
100
6543210
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)
Prob
abili
ty o
f eve
nt*
%
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 6 12 18 24 30 36 42 48 54 600
20
40
60
80
100
Months
Decompensation rate/year: 0% HCC rate/year: 2.8%
86%
100%HCC
Decompensation
Patients at risk 155 153 149 145 135 125 115 105 92 58 20
Co m
p lic
atio
n-fre
e s u
rviv
l al*
(%)
*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 6 12 18 24 30 36 42 48 54 600
20
40
60
80
100
Months
Sur
viv l
al (%
)
Patientsat risk 155 154 151 147 142 133
91%Overall survival*
124 111 98 61 21
Liver–related survival*95%
Death for HCC: 2 patientsOLT 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]
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 102/103Long 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
Age Every 5 y>30 0‒6
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 #43Yang 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 protocolKim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral#43
Studies 102/103HCC Incidence Based on Cirrhosis Status at Baseline
HC
C d
iagn
osis
(%)
No. at risk
Non-cirrhotic 482 453 425 396 377 360 343 324*
Cirrhotic 152 146 137 132 126 120 115 109*
00.5
11.5
22.5
33.5
44.5
5
0 48 96 144 192 240 288 336Week
Cirrhotic
Non-cirrhotic
n=64.5%
n=81.5%
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 102/103Observed 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.
Cum
ulati
ve H
CC ra
tes (
%)
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
ControlETV
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 riskTreatment duration (years )
Cum
ulati
ve H
CC ra
te (%
)
Treatment duration (years)
50
40
30
20
10
0Cu
mul
ative
HCC
rate
(%)
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
ControlETV
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
LAMNo 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
Cum
ulati
ve H
CC ra
te (%
)
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
ControlLAM
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
vada
(TVD
= T
DF +
FTC
) or e
mtr
icita
bine
(FTC
) are
lice
nsed
for u
se to
trea
t CHB
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
Chan
ge in
HBV
DN
A (lo
g 10 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%Patie
nts
(%)
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
vada
(TVD
= T
DF +
FTC
) or e
mtr
icita
bine
(FTC
) are
lice
nsed
for u
se to
trea
t CHB
Multivariate Analysis of Treatment Response
Odds ratio† CIFemale 6.0 1.9‒18.2
FTC/TDF treatment 3.9 1.4‒11.1
Wee
k 19
2 re
spon
se ra
te* (
%)
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
vada
(TVD
= T
DF +
FTC
) or e
mtr
icita
bine
(FTC
) are
lice
nsed
for u
se to
trea
t CHB
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 0PO4 <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
• HBsAg clearance is associated with a lower risk of HCC development
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 Administration
Cum
ulat
ive
Pro
babi
lity
Func
tion
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 Study0 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-Meier Heathcote 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 192Weeks
Cum
ulat
ive
Prob
abili
ty F
unct
ion
Estim
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 Characteristic HBsAg 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 patientsHBeAg negative patientsGenotype 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§
Patie
nts
(%)
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
Median time to negativation 52,2 years (IQR: 30,8-142,7)
Borgniet et al, J Med Virol 2009, Chevaliez et al J Hepatol 2013
Med
ian
(Log
10 c
opie
s/m
L Lo
g 10c
opie
s/ce
ll)
Reductions in Serum HBV DNA, Total Intrahepatic HBV DNA and cccDNA During Adefovir Therapy
48 weeks of ADV resulted in significant reductions in : serum HBV DNA > total intrahepatic HBV DNA > cccDNA
> 14 years of therapy to clear completely viral cccDNAWerle et al, Gastroenterology 2004
0.8 log10 (84%) decline in cccDNA, not paralleled by a similar decline in the number of HBcAg+ cells
Suggests cccDNA depleted primarily by non-cytopathic mechanisms or new rounds of hepatocyte infection occurred during therapy
Immunohistochemical Staining of Patient Biopsies at Baseline and After 48 Weeks ADV Therapy
Baseline Week 48
Werle et al, Gastroenterology 2004
Wong et al, Clin Gastroenterol Hepatol 2013Werle et al, Gastroenterology 2004
Slow decay of cccDNA and HBsAg
Persistence of intrahepatic viral DNA synthesis during Tenofovir therapy
(HIV-HBV cohort)
Boyd et al, in revisionNew round of infection and/or replenishment of the cccDNA pool occurdespite « viral suppression »
Maynard et al, J Hepatol 2005
Persistence of cccDNA after HBs seroconversion
Therapy
HB
V D
NA
chan
ge fr
om b
asel
ine
(log
10 c
/mL)
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
0 4 8 12 16 20 240
2
4
6
8
10
HBeAg positive (n=4)
HBV
DNA
(Log
10 IU
/mL)
HBeAg negative (n=37)
Follow-up Week
Buti et al AASLD 2015
ALT,
Mul
tiple
of U
LN
Follow-up Week 0 4 8 12 16 20 24
0
1
2
3
1020304050
Stopping TDF therapy after long-term viral suppression
High rates of viral replapse & ALT elevations3 patients with HBsAg loss out of 41
Therapy
HB
V D
NA
chan
ge fr
om b
asel
ine
(log
10 c
/mL)
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
New treatment concepts for a functional cure of HBV infection
Antivirals
Therapy0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
HBsAg
HBVDNA
cccDNA
Immune restoration
SERUM
LIVERDecay or epigenetic control
Vaccine therapy
Check-point inhibitors
TLR agonistsBlockade of immune-suppressive
cytokines
Chimeric antigen Receptors (CAR)
Antiviral cytokines
Entry inhibitors
Core modulators
Targeting cccDNA
Polymerase inhibitors
RNA interference
Egress Inhibitors
Core modulators
Targeting HBx
Testoni and Zoulim, Hepatology 2015
Lucifora et al, Science 2014Zoulim, et al, Clin Gastroenterol Hepatol 2013Belloni et al, JCI 2012Koeniger etal, PNAS 2014Tropberger et al, PNAS 2015
Hepatocyte turn-over
cccDNA silencing
cccDNA degradation
cccDNA formation
Targeting cccDNA
Lucifora et al, Science 2014; Shlomai & Rice, Science 2014
Model for cccDNA degradationIFNalpha /Lymphotoxin beta can induce APOBEC3A/B dependent degradation
of HBV cccDNA
Similar observation with IFNg and TNF – Xia et al, Gastroenterology 2015
Restoration of antiviral immunity
Bertoletti A, Gehring AJ (2013) Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or Inflammation Control?. PLoS Pathog 9(12): e1003784. doi:10.1371/journal.ppat.1003784http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003784
Target & drug discovery to cure HBV infection
Immune modulation• Toll-like receptors
agonists, Gilead, Roche
• PD1 blockade, BMS, Merck etc.
• Vaccine therapyTransgene, Gilead, Roche Innovio, Medimmune, ITS
Zoulim 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, AssemblyBiosc, Gilead, Janssen, Roche
Polymerase inhibitors • Nucleoside
analogues, e.g. Gilead, BMS
• Non-nucleoside, e.g. LB80380
• RNAseH inhibitors
Targeting HBsAgMab, GileadRelease, Replicor
RNA interference, Arrowhead, Arbutus, Alnylam, GSK
Cyclophilin inhibitors
Arbutus
AcknowledgementsHepatology Unit INSERM U1052 Collaborations
David DurantelBarbara TestoniJulie LuciforaMalika Ait-GoughoulteSouphalone LuangsayMarion GruffazNathalie IsorceFanny LebosséMaelenn FournierMaud MicheletJudith Fresquet
LabEx
C. Caux, Lyon CRCLFL. Cosset, Lyon CIRIK. Lacombe, ParisM. Levrero, Rome/LyonJP Quivy, Institut Curie
IHU
Maelle LocatelliValentina d’ArienzaPascal JalaguierThomas LahlaliDulce AlafaiateLucyna CovaRomain ParentAnna SalvettiBirke BartoschEve PecheurBoyan GrigorovChristophe Combet
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