Zoulim fz traitement vhb du16

Traitement antiviral des hépatites B
et bénéfices à long terme
Fabien Zoulim
Service d’hépatologie, Hospices Civils de Lyon
INSERM Unité 1052
Université 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 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.

6.9
Mean 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
Proportionwithundetectable
HBVDNA(%)
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
MeanHBVDNAreduction
(log10copies/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

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.
8
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
Virologicresponse*,patients(%)
405418 391
Patients
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.

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/ rtL80I
rtL180M
rtM204V/I
LdT resistance
rtA181T/V
ADV resistance rtA181T/V rtN236T
TDF resistance* ?
ETV resistance rtL180M rtM204I/V
rtT184*** rtS202**** rtM250I/V
rtl169T
***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
0
5
10
15
20
25
0 6 12 18 24 30 36
Time after randomization (Months)
%Withdiseaseprogression
Placebo (N=215)
YMDDm (N=209) (49%)
Wild Type (N=221)
YMDDm
WT
Placebo
5%
13%
21%
Liaw YF et al. N Engl J Med. 2004;351:1521-1531

ALT flares in patients with lamivudine
resistance over time
Lok et al Gastroenterology 2003; 125 : 1714-1722

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
HBVreplication
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)
HBVDNA(copies/ml)
entecavirIFN
adefovir
lamivudine
Genotype H
lamivudine
Drugs sharing cross-resistance characteristics:
Switching strategy  emergence of MDR mutant
L180M+S202G+M204V
L180M+M204V
Villet et al, J Hepatol 2007

Liu et al, Antivir Ther. 2010;15(8):1185-90.
Sequential therapy with NUCs and the risk of MDR
Accumulation of multiple
mutations on the same
viral genome
Complete change of the
viral quasi-species

A single a.a. substitution at position rt181
may be responsible for multidrug resistance
Villet S, et al. J Hepatol. 2008;48:747-55.
wt
A181V
A181T
A181V + N236T
A181T + N236T
N236T
N236T + N238T
M204V
M204I
L80V
L80V + M204I
LVD
LVD+TDF LVD+ADV+TDF
Patient #1
(67 months)
Patient #7
(30 months)
Patient #2
(23 months)
Patient #3
(37 months)
Patient #10
(7 months)
Patient #5
(44 months)
Patient #4
(31 months)
Patient #6
(36 months)
Patient #9
(19 months)
Patient #8
(47 months)
LVD+ADVADV

Impact of rtA181 and rtN236 mutations on antiviral
drug efficacy and cross-resistance
Villet et al, J Hepatol 2008

0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BL W4 W12 W24 W36 W48
N236T
A181V + N236T
A181V
A181S + N236T
A181T + N236T
A181T
wt
#1051 (L180L/M,A181A/V/T,A194A/T,S202S/I,N236N/T)
Week
0 4 8 12 16 20 24 28 32 36 40 44 48
HBVDNA(log10cp/mL)
0
1
2
3
4
5
6
7
8
9
10
BL viral load = 8.75log
Treatment: TDF
Adherence : 95.2%
Patient 1051 data:
LLOD
Evolution of viral genome during Tenofovir therapy
in patients who previously failed ADV
Impact of persisting low viremia levels on treatment outcome ?
Impact of persisting resistant mutants ?
Lavocat et al, AASLD 2010 & Ms submitted

Virologic response to TDF according to ADV
resistance mutations at baseline
The Australian Experience
Patterson S J et al. Gut 2011;60:247-254

ADV rtN236T +/or rtA181V
Wild-type virus
ADV-resistant virus
LAM-resistant virus
LAM rtM204V/I ± rtL180M
ETV-resistant virus
rtT184 or rtS202 or rtM250
ETV
rtM204V/I rtL180M+/-
TDF
TDF: what can
we expect?
rtM204V/I +/- rtL180M
LAM
then ETV
rtT184 or rtS202 or rtM250
LAM + TDF –
what do we see?
Maximising the barrier to resistance

6
3
LVD ADV LdT ETV TDF
0
10
20
30
40
50
60
70
80
23
Proportionofpatients(%)
46
55
71
80
0
11
18
29
5
25
0.2 0.5
1.2 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
Proportionofpatients(%)
46
55
71
80
0
11
18
29
5
25
0.2 0.5
1.2 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 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 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

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, n
168
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=
Naive (N=377)
Lam Exp (N=49)
Percentage(%)
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=
Naive (N=377)
Lam Exp (N=49)
Percentage(%)
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%Cumulatedresponse
2 80 10 124 6
0
20
60
80
40
100
LVD-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 6
0
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)
%Cumulatedresponse
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.
RANDOMIZATION1:1
Tenofovir DF 300 mg
FTC 200mg/
Tenofovir DF 300 mg
Total Study Duration = 168 Weeks (Blinded or Open Label)
Week 24
Roll over to open label FTC/TDF or discontinue if confirmed
(within 4 weeks) plasma HBV DNA  400 copies/mL
Double Blind
Blinded Study Medication
or
Open Label FTC/TDF
Week 48
Primary 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 Study
0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168
Treatment
TDF
FTC/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
TDF
F
Treatment
TDF
FTC/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.
Percentage(%)
*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

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
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
Baseline 3 6 9 12 15 18 21 24
10 6
Δ 3 log10 c/mL reduction
P=0.0001
LLoD
HBVDNA[IU/ml]
Months

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 therapy
based 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, a
virological 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 96 144
0
20
40
60
80
100
p = 0.04
Time (weeks)
Probabilityofevent*%
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 risk
155 153 149 145 135 125 115 105 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 risk
155 154 151 147 142 133
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
RANDOMIZATION1:1
ETV 0.5 mg + TDF 300 mg, once daily
(N=197)*
Week 96Baseline
ETV 0.5 mg, once daily
(N=182)*
Primary endpoint
HBV 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/mL
at Weeks 48 and 96: overall
*Primary endpoint
Difference 6.9%
(95% CI –1.0, 14.9)
P=NS
Number of patients:
HBVDNA<50IU/mL
(%patients)
0
20
40
60
80
100
158
197
80.2
128
182
70.3
Week 48
164
197
83.2
139
182
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
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/mL
in both groups
MeanHBsAgdeclinefrombaseline,
log10IU/mL(SE)
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*ULN
ETV+TDF ALT<2*ULN
ETV 2*ULN<=ALT<5*ULN
ETV+TDF 2*ULN<=ALT<5*ULN
ETV ALT=>5.0*ULN
ETV+TDF ALT=>5.0*ULN
By HBeAg status By baseline ALT
MeanHBsAgdeclinefrom
baseline,log10IU/mL(SE)

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)
A A
B
B
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
HCCRisk(%)
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 #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 BaselineHCCdiagnosis(%)
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 Patients
n=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-cirrhotics
n=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 group
NUC-naive CHB patients
Treated with ETV 0.5 mg, 2004–2010
n = 472
316 matched patients
Historical control group
Untreated 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.
CumulativeHCCrates(%)
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 risk
ETV
Control
316
316
316
316
264
277
185
246
101
223
44
200
2
187
2
170
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%
237
231 231
237 192
201 181
132 66
169 143
27ETV
Control
No at risk
Treatment duration (years )
CumulativeHCCrate(%)
50
40
30
20
10
0
Cirrhosis
79
85 85
79 72
76 65
53 35
54 47
17ETV
Control
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

Japanese cohorts: HCC incidence lower with ETV than with
LAM in cirrhotic patients
LAM
No at risk
Cirrhosis
0 1 3 52 4
20.9%
38.9%
4.3%
7.0%
22.2%
12.2%
50
40
30
20
10
0
Log-rank test:
ETV vs LAM: p = 0.043
ETV vs control: p < 0.001
LAM vs control: p = 0.019
49
79
85
49
85
79
41
72
76
35
65
53
32
35
54
29
47
17ETV
Control
ETV
Control
LAM
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
Characteristic
TDF
(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
NeitherTruvada(TVD=TDF+FTC)oremtricitabine(FTC)arelicensedforusetotreatCHB

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

Mean Viral Decline From Baseline
Study week
TDF
FTC/TDF
ChangeinHBVDNA(log10IU/mL)
0 16 32 48 64 80 96 112 128 144 160 176 192
–8
–6
–4
–2
0

Proportion of Patients With HBV DNA < 69
IU/mL at Week 192*
FTC/TDF 76%
TDF 55%
Patients(%)
Study week
*Proportion (95% confidence interval [CI]); missing data = failure analysis.

Multivariate Analysis of Treatment Response
Odds ratio† CI
Female 6.0 1.9‒18.2
FTC/TDF treatment 3.9 1.4‒11.1
Week192responserate*(%)
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.

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.

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

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 AdministrationCumulativeProbabilityFunctionEstimate
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
CumulativeProbabilityFunctionEstimate
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 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§
Patients(%)
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

 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 cccDNA
Werle 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
Baseline Week 48

Wong et al, Clin Gastroenterol Hepatol 2013

Persistence of intrahepatic viral DNA synthesis
during Tenofovir therapy
(HIV-HBV cohort)
Boyd et al, in revision
New round of infection and/or replenishment of the cccDNA pool occur
despite « viral suppression »

Maynard et al, J Hepatol 2005
Persistence of cccDNA after HBs seroconversion

Therapy
HBVDNAchangefrombaseline(log10c/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 1 2 1 6 2 0 2 4
0
2
4
6
8
1 0
HBeAg positive (n=4)
HBVDNA(Log10IU/mL)
HBeAg negative (n=37)
Follow-up Week
Buti et al AASLD 2015
ALT,MultipleofULN
Follow-up Week
0 4 8 1 2 1 6 2 0 2 4
0
1
2
3
1 0
2 0
3 0
4 0
5 0
Stopping TDF therapy after long-term viral
suppression
High rates of viral replapse & ALT elevations
3 patients with HBsAg loss out of 41

Therapy
HBVDNAchangefrombaseline(log10c/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
Therapy
0.0
-1.0
-2.0
-3.0
-4.0
+1.0
Time
HBsAg
HBVDNA
cccDNA
Immune
restoration
SERUM
LIVER
Decay 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 2014
Zoulim, et al, Clin
Gastroenterol Hepatol 2013
Belloni et al, JCI 2012
Koeniger etal, PNAS 2014
Tropberger 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 degradation
IFNalpha /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.1003784
http://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 therapy
Transgene, 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 HBsAg
Mab, Gilead
Release, Replicor
RNA interference,
Arrowhead, Arbutus,
Alnylam, GSK
Cyclophilin
inhibitors
Arbutus

Acknowledgements
Hepatology Unit INSERM U1052 Collaborations
David Durantel
Barbara Testoni
Julie Lucifora
Malika Ait-Goughoulte
Souphalone Luangsay
Marion Gruffaz
Nathalie Isorce
Fanny Lebossé
Maelenn Fournier
Maud Michelet
Judith Fresquet
LabEx
C. Caux, Lyon CRCL
FL. Cosset, Lyon CIRI
K. Lacombe, Paris
M. Levrero, Rome/Lyon
JP Quivy, Institut Curie
IHU
Maelle Locatelli
Valentina d’Arienza
Pascal Jalaguier
Thomas Lahlali
Dulce Alafaiate
Lucyna Cova
Romain Parent
Anna Salvetti
Birke Bartosch
Eve Pecheur
Boyan Grigorov
Christophe Combet

Third ANRS “HBV cure” Workshop
HBV pathobiology and target discovery
Scientific coordination: Fabien Zoulim
Tuesday, May 31st, 2016
Union internationale des chemins de fer (UIC)
16, rue Jean Rey - 75015 PARIS
HBV cure 2014: Zeisel, M. B. et al. Towards an HBV cure: state-of-the-art and unresolved
questions-report of the ANRS workshop on HBV cure. Gut, doi:10.1136/gutjnl-2014-
308943 (2015).
HBV cure 2015: http://www.anrs-hbvcure2015.com/

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