Zoulim fz traitement vhb du16

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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

Transcript of Zoulim fz traitement vhb du16

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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

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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

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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

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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

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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.

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Efficacité virologique

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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

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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. #374.8

Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed for use to treat CHB

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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

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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.

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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.

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Résistances aux antiviraux

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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 ?

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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

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ALT flares in patients with lamivudine resistance over time

Lok et al Gastroenterology 2003; 125 : 1714-1722

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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

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Zoulim & Locarnini, Gastroenterology, 2009

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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

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?

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

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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

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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

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A single a.a. substitution at position rt181 may be responsible for multidrug resistance

Villet S, et al. J Hepatol. 2008;48:747-55.

wtA181VA181TA181V + N236TA181T + N236TN236T

N236T + N238TM204VM204IL80VL80V + 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

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Impact of rtA181 and rtN236 mutations on antiviral drug efficacy and cross-resistance

Villet et al, J Hepatol 2008

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BL W4 W12 W24 W36 W480%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

N236TA181V + N236TA181VA181S + N236TA181T + N236TA181Twt

#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

HB

V D

NA

(lo

g 10 c

p/m

L)

0

1

2

3

4

5

6

7

8

9

10

BL viral load = 8.75logTreatment: 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

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Virologic response to TDF according to ADV resistance mutations at baseline

The Australian Experience

Patterson S J et al. Gut 2011;60:247-254

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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)

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Bénéfice histologique et clinique

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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

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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

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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.

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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%

Page 50: Zoulim fz traitement vhb du16

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]

Page 51: Zoulim fz traitement vhb du16

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

Page 52: Zoulim fz traitement vhb du16

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

Page 53: Zoulim fz traitement vhb du16

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

Page 54: Zoulim fz traitement vhb du16

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)

Page 55: Zoulim fz traitement vhb du16

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

Page 56: Zoulim fz traitement vhb du16

Prévention du CHC par le traitement antiviral

Page 57: Zoulim fz traitement vhb du16

*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

Page 58: Zoulim fz traitement vhb du16

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

Page 59: Zoulim fz traitement vhb du16

*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

Page 60: Zoulim fz traitement vhb du16

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

Page 61: Zoulim fz traitement vhb du16

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

Page 62: Zoulim fz traitement vhb du16

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

Page 63: Zoulim fz traitement vhb du16

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.

Page 64: Zoulim fz traitement vhb du16

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)

Page 65: Zoulim fz traitement vhb du16

Vers un traitement plus précoce de l’hépatite B: le cas du patient

immunotolérant

Page 66: Zoulim fz traitement vhb du16

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

Page 67: Zoulim fz traitement vhb du16

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

Page 68: Zoulim fz traitement vhb du16

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

Page 69: Zoulim fz traitement vhb du16

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

Page 70: Zoulim fz traitement vhb du16

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

Page 71: Zoulim fz traitement vhb du16

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

Page 72: Zoulim fz traitement vhb du16

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

Page 73: Zoulim fz traitement vhb du16

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

Page 74: Zoulim fz traitement vhb du16

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

Page 75: Zoulim fz traitement vhb du16

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

Page 76: Zoulim fz traitement vhb du16

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

Page 77: Zoulim fz traitement vhb du16

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

Page 78: Zoulim fz traitement vhb du16

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

Page 79: Zoulim fz traitement vhb du16

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

Page 80: Zoulim fz traitement vhb du16

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

Page 81: Zoulim fz traitement vhb du16

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

Page 82: Zoulim fz traitement vhb du16

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

Page 83: Zoulim fz traitement vhb du16

Wong et al, Clin Gastroenterol Hepatol 2013Werle et al, Gastroenterology 2004

Slow decay of cccDNA and HBsAg

Page 84: Zoulim fz traitement vhb du16

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 »

Page 85: Zoulim fz traitement vhb du16

Maynard et al, J Hepatol 2005

Persistence of cccDNA after HBs seroconversion

Page 86: Zoulim fz traitement vhb du16

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

Page 87: Zoulim fz traitement vhb du16

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

Page 88: Zoulim fz traitement vhb du16

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

Page 89: Zoulim fz traitement vhb du16

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

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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

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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

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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

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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

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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

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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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