zoulim fz traitement hépatite b 2015 du

Traitement antiviral des hépatites B et bénéfices à long terme

Fabien ZoulimService d’hépatologie, Hospices Civils de Lyon

INSERM Unité 1052Université de Lyon

HBeAg(+) HBeAg(-) / anti-HBe(+)

ALT

HBV DNA

Minimal CH Moderate to severe CH Moderate to severe CHRemission

Cirrhosis

Immunotolerant

phase

Immuno-active

phase

Inactive phase

Low replication Reactivation phase

Cirrhosis

109-1012 IU/mL >2000-<109 IU/mL <2000 IU/mL >2000 IU/mL

Inactive cirrhosis

Treatment indicated Treatment indicated

HBsAg

Occult infection

EASL Clinical Practice Guidelines, J Hepatol 2012

Antivirals approved for the treament of

chronic hepatitis B

Drug Type Approved

Nucleoside analogs • Lamivudine

• Entecavir

• Telbivudine

Nucleotide analogs • Adefovir dipivoxil

• Tenofovir disoproxilfumarate

Cytokines • Interferon alfa

• Pegylated Interferon alfa-2a

Zoulim & Locarnini, Gastroenterology 2009; Zoulim Antiviral Research 2012; Mico et al J Hepatol 2013; Lucifora et al Science 2014

NK cells

Innate responses

CD8+ cells

B cells

CD4+ cells

Adaptive immune

responses

Nucleos(t)ide analogues

Interferon

alphaNTCP

Efficacité virologique

6.9Mean baseline

HBV DNA 9.7 9.6 9.59.5 8.68.99.9 10.1 7.6 7.6 7.77.4 7.07.1

93

TDF

Pro

po

rtio

n w

ith

un

dete

cta

ble

HB

V D

NA

(%

)

0

20

40

60

80

100

LVD vs.

LdT18†

LVD vs.

ETV16†

ADV vs.

TDF14*

PEG vs.

LVD19*

36

LVD

67

ETV

60

LdT

40

LVD

76

TDF

13

ADV

25

PEG

40

LVD

72

LVD

90

ETV

88

LdT

71

LVD

63

ADV

63

PEG

73

LVD

7.2

-8

-6

-4

-2

0

Me

an

HB

V D

NA

re

du

cti

on

(lo

g10

co

pie

s/m

L)

LVD vs.

LdT18†

LVD vs.

ETV17†

ADV vs.

TDF14*

PEG vs.

LVD20*

HBeAg-positive HBeAg-negative

-4.6

-5.4

-6.9-6.5

-5.5

-6.2

-3.9-4.5

-5.8

-4.5-5.0 -5.2

-4.4-4.1-4.1

-5.0

Gish, Jia, Locarnini & Zoulim, Lancet Infect Dis 2012

Response

HBeAg- Patients

(Study 102)

HBeAg+ Patients

(Study 103)

Year 5 Year 6 Year 5 Year 6

HBV DNA < 400 copies/mL

Intent-to-treat*, % (n/N)

83

(291/350)

81

(281/345)

65

(160/248)

63

(157/251)

HBV DNA < 400 copies/mL

On treatment†, % (n/N)

99

(292/295)

99.6

(283/284)

97

(170/175)

99

(167/169)

* LTE-TDF (missing = failure/addition of FTC = failure)† Observed (missing = excluded/addition of FTC = included)

♦ 80% of 585 patients entering the open-label phase remained on study at Year 6; 73% of

enrolled patients remained on study

♦ HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years

♦ 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion)

♦ No resistance to TDF was detected through 6 years

TDF administration: Virologic Suppression at Year 6

Marcellin P, et al. AASLD 2012; Boston. #374.7

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

Italian ETV cohort: 100% of naive patients achieved HBV-DNA undetectability at 60 months

*Undetectable HBV-DNA† A 78-year-old woman with AH and a 48-year-old renal-transplanted woman with compensated cirrhosis

Adapted from Lampertico P, et al. AASLD 2012, poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013].

Safety

• Favourable safety profile after 53 months of treatment

• Renal safety profile: two patients reduced ETV dose due to eGFR decline†

Resistance

• One patient (0.2%) developed resistance

0

67

85

95 96 98 100

0

20

40

60

80

100

Baseline 6 12 24 36 48 60

Vir

olo

gic

resp

on

se*,

pat

ien

ts (

%)

405418 391Patients

on follow-up 344 307 259 97

Management of partial response – The case of Entecavir

Zoutendijk et al, HepatologyVolume 54, Issue 2, pages 443-451, 25 JUL 2011

Kaplan-Meier curve for the probability of achieving virological response for 243 NA-naïve patients according to HBeAg status at baseline. P value was determined using log-rank testing.

http://onlinelibrary.wiley.com/doi/10.1002/hep.v54.2/issuetoc

Entecavir treatment for chronic hepatitis B: Adaptation is not needed for the majority of naïve patients with a partial virological response

Zoutendijk et al Hepatology Volume 54, Issue 2, pages 443-451, 25 JUL 2011

.Kaplan-Meier curve for the probability of achieving a VR for NA-naïve patients with a PVR according to HBV DNA atweek 48. Three patients were switched to TDF plus emtricitabine, and one patient received TDF add-on therapy. P value was determined using log-rank testing.

http://onlinelibrary.wiley.com/doi/10.1002/hep.v54.2/issuetoc

6

3

LVD ADV LdT ETV TDF

0

10

20

30

40

50

60

70

80

23

Pro

port

ion o

f patients

(%

)

46

55

71

80

0

11

18

29

5

25

0.2 0.51.2

0

1 2 3 4 5 1 2 3 4 5 1 2 1 2 3 4 5 1 2 3

0 0

Option to add

emtricitabine

at week 72*

*Patients confirmed to be viraemic at Week 72 or beyond could add emtricitabine to TDF at the discretion of the

investigator. Clinical data on the safety and efficacy of emtricitabine and TDF in CHB are pending

Rates of resistance with lamivudine (LVD), adefovir (ADV), telbivudine

(LdT), entecavir (ETV) and tenofovir (TDF) among NA-naïve patients

4

0

High barrier to resistance

Gish, Jia, Locarnini & Zoulim, Lancet ID 2012

5

0

6

3

LVD ADV LdT ETV TDF

0

10

20

30

40

50

60

70

80

23

Pro

port

ion o

f patients

(%

)

46

55

71

80

0

11

18

29

5

25

0.2 0.51.2

0

1 2 3 4 5 1 2 3 4 5 1 2 1 2 3 4 5 1 2 3

0 0

Option to add

emtricitabine

at week 72*

*Patients confirmed to be viraemic at Week 72 or beyond could add emtricitabine to TDF at the discretion of the

investigator. Clinical data on the safety and efficacy of emtricitabine and TDF in CHB are pending

Rates of resistance with lamivudine (LVD), adefovir (ADV), telbivudine

(LdT), entecavir (ETV) and tenofovir (TDF) among NA-naïve patients

4

0

High barrier to resistance

Gish, Jia, Locarnini & Zoulim, Lancet ID 2012

5

0

57% in lamivudineresistant patients

Drug and patient population

Resistance at year of therapy expressed as

percentage of patients

1 2 3 4 5 6

Lamivudine 23 46 55 71 80 -

Telbivudine HBeAg-Pos 4.4 21 - - - -

Telbivudine HBeAg-Neg 2.7 8.6 - - - -

Adefovir HBeAg-Neg 0 3 6 18 29 -

Adefovir (LAM-resistant) Up to 20% - - - - -

Tenofovir 0 0 0 0 0 0

Entecavir (naïve) 0.2 0.5 1.2 1.2 1.2 1.2

Entecavir (LAM resistant) 6 15 36 46 51 57

Incidence of drug resistance over time

CL Lai Clin Infect Dis 2003; CL Lai NEJM 2007; Hadzyiannis Gastroenterology 2006;Marcellin NEJM 2008; CL Lai & Chang NEJM 2006; Zoulim & Locarnini Gastroenterology 2009

Cross-resistance data for the main mutants and the commercially available drugs

Zoulim & Locarnini Gastroenterology 2009; J Hepatol 2012

Pathway Amino Acid

Substitutions in

the rt Domain

LMV LdT ETV ADV TFV

Wild-type S S S S S

L-Nucleoside

(LMV/LdT)

M204I/V R R I S S

Acyclic

phosphonate

(ADV)

N236T S S S R I

Shared (LMV, LdT,

ADV)

A181T/V R R S R I

Double (ADV, TFV) A181T/V + N236T R R S R R

D-Cyclopentane

(ETV)

L180M+M204V/I

± I169 ± T184

± S202 ± M250

R R R S S

Multi-Drug

Resistance

A181T+N236T+

M250V

R R R R R

Tenofovir rescue of Adefovir failure

• 105 Patients with chronic hepatitis B refractory to ADVrandomized in a controlled trial of TDF versus TDF + FTC.

• 63 Patients had been exposed to lamivudine before the trial.

RA

ND

OM

IZA

TIO

N 1

:1

Tenofovir DF 300 mg

FTC 200mg/Tenofovir DF 300 mg

Total Study Duration = 168 Weeks (Blinded or Open Label)

Week 24Roll over to open label FTC/TDF or discontinue if confirmed

(within 4 weeks) plasma HBV DNA 400 copies/mL

Double Blind

Blinded Study Medicationor

Open Label FTC/TDF

Week 48Primary Analysis

Week 168

Berg et al, Gastroenterology 2010

Manns M, et al., EASL 2008; Oral # 1587.

Tenofovir efficacy in LAM Experienced vs. Naïve

Study 103:N=176

Study 102: N=250 Total

LAM-Naïve, n

LAM-Experienced, n168

8

209

41

377

49

• Study 102 actively

enrolled both

LAM experienced and

LAM-naïve patients

• Study 103 enrolled

eight LAM experienced

patients despite

LAM-naïve inclusion

criteria

P=0.718

88%

86%P=0.718

Naive (N=377)

Lam Exp (N=49)P

erc

enta

ge (

%)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 16 20 24 28 32 36 40 44 48

88%

86%P=0.718

Naive (N=377)

Lam Exp (N=49)P

erc

enta

ge (

%)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 16 20 24 28 32 36 40 44 48

ITT Missing=Failure

Combined data includes both HBeAg +/- patients

Reijnders, JGP et al. J Hepatol 2010

Virologic response to Entecavir according to Lamivudine exposure

% C

um

ula

ted

re

spo

nse

2 80 10 124 60

20

60

80

40

100LVD-naïve (N=118)

LVD-experienced without development of LVD-resistance (N=20)

LVD-experienced with a prior history of LVD-resistance (N=14)

LVD-experienced with LVD-resistant mutations at baseline (N=9)

P = 0.007

2 80 10 124 60

100

20

60

80

40

Reijnders, JGP et al.. J Hepatol. 2010

Virologic response to Entecavir

according to Adefovir exposure

ADV-naïve (N=119)

ADV-experienced without development of ADV-resistance (N=30)

ADV-experienced with ADV-resistant mutations at baseline (N=12)

% C

um

ula

ted

re

spo

nse

P = NS

P

e

r

c

en

t

age

(

%

)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Treatment

TDFFTC/TDF

P

e

r

c

en

t

age

(

%

)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168

P

e

r

c

en

t

age

(

%

)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 4 8 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Treatment

TDFF

Treatment

TDFFTC/TDF

Virologic Response to TDF vs TDF + FTC in patients with

previous failure to ADV (study # 106)

82% FTC/TDF

82% TDF

ITT: NC=F*

Two patients on study at Week 168 had HBV DNA ≥400 copies/mL

Berg T, et al., AASLD 2010; Oral# 136.

Perc

en

tag

e (

%)

*NC=F, Non-completer counted as failure in this ITT analysis, including patients who switched to open-label FTC/TDF fixed-dose combination

% of Patients with HBV DNA < 400 copies/mL (69 IU/mL)

29 29 29 29 27 26 24 24

33 33 33 31 30 29 27 26

14 14 14 14 14 14 14 14

11 11 11 11 10 10 10 10

17 16 16 16 16 16 16 16

12 12 12 12 12 11 10 10

n =n =n =n =n =n =

Response by Baseline Resistance at Week 168

TDF vs. FTC/TDF for Treatment-Experienced Patients:

Weeks on Study

Berg et al, Gastroenterology 2010; J Heaptol 2014

Suggested treatment adpatation in patients with treatment failure

Type of failure Treatment adaptation

Lamivudine resistance 1) switch to TFV

2) add TFV in difficult cases (add ADV if TFV not available)

Adefovir resistance 1) switch to TFV (if available)

2) if no history of LMV, switching to ETV is also effective.

3) If rtN236T substitution, consider adding ETV to the TFV or switch

to TFV plus FTC

4) If rtA181V/T substitution, alone or in combination with rtN236T,

switch to TFV plus ETV

Telbivudine resistance 1) switch to TFV

2) add TFV

3) a switch to ADV is not recommended

Entecavir resistance 1) add TFV

Tenofovir resistance 1) not been confirmed so far

2) genotyping and phenotyping required

3) may add ETV

EASL CPG, J Hepatol 2009 & 2012; Zoulim & Locarnini Liver Int 2013

Management algorithm

Antiviral treatment

Treatment failure

Viral load asssessment

Second line therapybased on cross-resistance data(switch or add-on)

Check compliance Primary non response

Switch to more potent drug

Viral genome sequence analysis

Wild type virus HBV drug resistant mutant

Check compliance

Zoulim and Perrillo, J Hepatol, 2008; EASL CPG J Hepatol 2012

Management algorithm

Antiviral treatment

Treatment response

Viral load asssessment

Zoulim and Perrillo, J Hepatol, 2008; EASL CPG J Hepatol 2009

Check for HBe/HBs seroconversion on a regular basis (6 monthly)

Bénéfice histologique et clinique

Histology: long-term ETV therapy and regression of fibrosis and cirrhosis

88% of patients had regression of fibrosis†, including 10/57 patients with advanced fibrosis or cirrhosis (Ishak score ≥ 4) at phase 3 study baseline

• 57 NUC-naive HBeAg(+) and HBeAg(-) CHB patients from phase 3 studies who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes

• Liver biopsy after median 6 years of ETV (range 3–7 years)

Adapted from Chang TT, et al. Hepatology 2010;52:886–93.

† ≥1-point decrease in Ishak fibrosis score.

0

10

20

30

40

50

60

Baseline Week 48 Long-term

Missing

6

5

4

3

2

1

0

Ishak Fibrosis Score

51% of patients had regression of fibrosis†, including 71/96 patients with cirrhosis (Ishak score ≥ 5) at phase 3 study baseline

• 348 HBeAg(+) and HBeAg(-) CHB patients from phase 3 studies who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes

• Liver biopsy after 5 years of TDF

Histology: long-term TDF therapy and regression of fibrosis and cirrhosis

Adapted from Marcellin P, et al. Lancet 2013;381:468–75.

† ≥1-point decrease in Ishak fibrosis score.

Ishak Score

0

20

40

60

80

100

Baseline Year 1 Year 5

6

5

4

3

2

1

0

VIRGIL European cohort: compared with no response, avirological response to ETV is significantly associated with

lower probability of disease progression in cirrhotics

Patients with compensated cirrhosis (n = 89) and decompensated cirrhosis (n = 9)

0 48 96 1440

20

40

60

80

100

p = 0.04

Time (weeks)

Pro

bab

ility

of

even

t* %

HR: 0.22, 95% CI 0.05–0.99

**VR defined as HBV-DNA <80 IU/mL.

No virological response

Virological response**

Cirrhotic patients had previously received:

• ADV: 31%• LAM: 34%

*Primary outcome was occurrence of a

clinical event defined as a composite

endpoint of development of

hepatic decompensation, HCC

or death

Adapted from Zoutendijk R, et al. Gut 2013;62:760–5.

Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013]

Prospective real-world study, assessing 5-year efficacy and safety of ETV in NUC-naive CHB

Italian ETV cohort: complication-free survival in patients with compensated cirrhosis

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 Months

Decompensation rate/year: 0%

HCC rate/year: 2.8%

86%

100%

HCC

Decompensation

Patients

at risk155 153 149 145 135 125 115 105 92 58 20

*Kaplan–Meier estimates.

Baseline characteristics (418 NUC-naive patients): • Median (range)

age: 58 (18–82) • Cirrhosis: 49%• Concomitant

diseases: 56%• HBeAg(-)ve: 83%

Italian ETV cohort: overall and liver-related survival in patients with compensated cirrhosis

*Kaplan–Meier estimates.OLT = death.

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 Months

Patients

at risk155 154 151 147 142 133

91%Overall survival*

124 111 98 61 21

Liver–related survival*95%

Death for HCC: 2 patients

OLT for HCC: 4 patients

Adapted from Lampertico P, et al. AASLD 2012, Boston, MA. Poster 366. Available at http://liverlearning.aasld.org/aasld/2012/thelivermeeting/22910/pietro.lampertico.entecavir.treatment.for.nuc.na.field.practice.patients.with.html?history_id=78126. [Accessed April 2013]

BE-LOW (ETV-110): study design

• Randomized, open-label, Phase IIIb trial

• NA-naïve CHB, HBeAg(+) or HBeAg(–)

• HBsAg levels were quantified (Abbott Architect assay at a central laboratory) at baseline and Weeks 12, 48 and 96

RA

ND

OM

IZA

TIO

N 1

:1

ETV 0.5 mg + TDF 300 mg, once daily (N=197)*

Week 96Baseline

ETV 0.5 mg, once daily(N=182)*

Primary endpointHBV DNA <50 copies/mL#

Further anti-HBV therapy at discretion

of investigator –up to 24 weeks

follow-up

Dosing x 100 weeks

*Modified intent-to-treat population: received at least one dose of study medication#HBV DNA assayed by Roche COBAS™ TaqMan-HPS assay

. Lok A, et al. Gastroenterology 2012

HBV DNA <50 IU/mLat Weeks 48 and 96: overall

*Primary endpoint

Difference 6.9% (95% CI –1.0, 14.9)

P=NS

Number of patients:

HB

V D

NA

<5

0 I

U/m

L(%

pat

ien

ts)

0

20

40

60

80

100

158197

80.2

128182

70.3

Week 48164197

83.2

139182

76.4

Week 96*

ETV

ETV+TDF

Difference 9.9%

(95% CI 1.5, 18.4)

Non-completer = failure

Change in quantitative HBsAgthrough Week 96: overall

0

0.2

0.4

0.6

0.8

1

1.2

0 12 24 36 48 60 72 84 96

ETV

ETV+TDF

Mean decline in HBsAg level from baseline to Wk 96 = 0.67 (±0.1) log10 IU/mLin both groups

Me

an H

BsA

gd

ecl

ine

fro

m b

ase

line

, lo

g 10

IU/m

L (S

E)

Duration of treatment (weeks)

Zoulim et al, J Hepatol 2015

HBsAg decline through Week 96 by baseline HBeAg status and baseline ALT

0

0.2

0.4

0.6

0.8

1

1.2

0 12 24 36 48 60 72 84 96

ETV HBeAg(-)

ETV+TDF HBeAg(-)

ETV HBeAg(+)

ETV+TDF HBeAg(+)

0

0.2

0.4

0.6

0.8

1

1.2

0 12 24 36 48 60 72 84 96

ETV ALT<2*ULNETV+TDF ALT<2*ULNETV 2*ULN<=ALT<5*ULNETV+TDF 2*ULN<=ALT<5*ULNETV ALT=>5.0*ULNETV+TDF ALT=>5.0*ULN

By HBeAg status By baseline ALT


Me

an H

BsA

gd

ecl

ine

fro

m

bas

elin

e, l

og 1

0IU

/mL

(SE)

Me

an H

BsA

gd

ecl

ine

fro

m

bas

elin

e, l

og 1

0IU

/mL

(SE)


HBsAg decline through Week 96 by baseline HBV Genotype

0

0.4

0.8

1.2

1.6

2

0 12 24 36 48 60 72 84 96

0

0.4

0.8

1.2

1.6

2

0 12 24 36 48 60 72 84 96

ETV ETV + TDF

Duration of treatment (weeks) Duration of treatment (weeks)

Me

an H

BsA

gd

ecl

ine

fro

m

bas

elin

e, l

og 1

0IU

/mL

(SE)

Me

an H

BsA

gd

ecl

ine

fro

m

bas

elin

e, l

og 1

0IU

/mL

(SE)

A A

BB

C

C

D D

O

Genotype

O = Other

Genotype

O

Prévention du CHC par le traitement antiviral

*Marcellin P, et al. Lancet. 2013 Feb 9;381(9865):468-75.

Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral #43

Studies 102/103

Long Term TDF Therapy and Risk of HCC

Phase 3, randomized, double-blind, placebo-controlled

All patients received open-label TDF after Year 1 for total study duration of 8 years

Previously reported 5-year data showed no resistance and reversal of fibrosis*

Study Aim: To compare the observed incidence of HCC in patients treated with TDF in

Studies 102/103 with the predicted HCC incidence based on the REACH-B risk calculator

TDF 300 mg

(n=426)

ADV 10 mg

(n=215)

Open-label TDF 300 mg QD

85430 1 2Year

Chronic HBV: (HBeAg– and +)

7

HCC data analysis

Neither Truvada (TVD = TDF + FTC) or emtricitabine (FTC) are licensed

for use to treat CHB

Emtricitabine (FTC) could be added at/after week 72

REACH-B Model

Hypothetical Patient:

• 60-year-old HBeAg+ male, ALT 60, HBV DNA 100,000 copies/mL

• REACH-B score: 17

Year

HC

C R

isk (

%)

Variable Data Score

Sex Male/female 0‒2

AgeEvery 5 y

>300‒6

ALT, U/L

<15

15‒44

>45

0‒2

HBeAg +/– 0‒2

HBV DNA,

copies/mL

Und.

~104

~105

~106

>106

0‒5

Prediction model to estimate HCC risk in non-cirrhotic patients up to 10 years

Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral #43

Yang et al, Lancet Oncology. 2011;12(6):568-74

REACH-B is a risk calculator developed in non-cirrhotic pts

so It may underestimate the risk

*Patients completing 336 weeks in study as defined by protocol

Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral#43

Studies 102/103

HCC Incidence Based on Cirrhosis Status at BaselineH

CC

dia

gn

os

is (

%)

No. at risk

Non-cirrhotic 482 453 425 396 377 360 343 324*

Cirrhotic 152 146 137 132 126 120 115 109*

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0 48 96 144 192 240 288 336

Week

Cirrhotic

Non-cirrhotic

n=6

4.5%

n=8

1.5%

REACH-B is a risk calculator developed in non-cirrhotic pts so

It may underestimate the risk

SIR = 0.50* 95% CI (0.294, 0.837)

1st significant difference

All Patientsn=634

*Statistically significant at nominal -level of 0.05.

Kim WR, et al. J Hepatol 2013 Supp 1;58(43):S19 - Oral#43

Studies 102/103

Observed vs. Predicted HCC Cases

Incidence of HCC in patients on TDF in Studies 102/103 was lower than predicted by the

REACH-B model

In non-cirrhotic patients, the effect of TDF becomes noticeable between 2–3 years of therapy

and became statistically significant (55% reduction) at 6 years of therapy

SIR = 0.45*

95% CI (0.227, 0.909)

1st significant difference

Non-cirrhoticsn=482

REACH-B is a risk calculator developed in non-cirrhotic pts so

It may underestimate the risk

Propensity score (PS) matching for age, sex, pre-existing cirrhosis, HBeAg,

HBV-DNA, AST, ALT, GGTP, bilirubin, albumin, platelet counts

ETV groupNUC-naive CHB patients

Treated with ETV 0.5 mg, 2004–2010 n = 472

316 matched patients

Historical control groupUntreated CHB patients*Followed up, 1973–1999

n = 1143

316 matched patients analysed

• Retrospective cohort study from Toranomon Hospital, Tokyo, Japan

• Aim: to compare HCC incidence with ETV† vs no NUC therapy

Japanese cohorts: study design

Created from Hosaka T, et al. Hepatology 2013; [Epub ahead of print].

doi: 10.1002/hep.26180.

Median follow-up: 3.3 years

HCC cases: 6(5.63 cases/1000 patient-years)

Median follow-up: 7.6 years

HCC cases: 72(24.1 cases/1000 patient-years)

Cirrhosis was determined by laparoscopy, liver biopsy, imaging modalities or portal hypertension

*NUCs not available at this time in Japan.†ETV is not indicated for the prevention of HCC in CHB patients

Japanese cohorts: ETV reduced HCC incidence, compared with controls

PS-matched cohort multivariate cox regression analysis:*

HR 0.37 (95% CI 0.15–0.91) p = 0.030

*Adjusted for age, sex, alcohol, smoking, cirrhosis, HBV genotype, HBeAg status, HBV-DNA, ALT, albumin, γGTP, total bilirubin and platelet count.

Cu

mu

lati

ve H

CC

rat

es (

%)

Log-rank test: p<0.001

Treatment duration (years)

0

10

20

30

7.2%

13.7%

3.7%

1.2%

0 1 3 5 72 4 6

No. at riskETVControl

316316

316316

264277

185246

101223

44200

2187

2170

Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180. HR, hazard ratio; PS, propensity score

Control

ETV

Japanese cohorts: significantly reduced HCC incidence with ETV compared to controls in cirrhotic patients

50

40

30

20

10

0

Log-rank test: p = 0.440

No cirrhosis

1.6%3.6%

2.5%0%

237231 231

237 192201 181

132 66169 143

27ETVControl

No at risk

Treatment duration (years )

Cu

mu

lati

ve H

CC

rat

e (%

)

Treatment duration (years)

50

40

30

20

10

0

Cu

mu

lati

ve H

CC

rat

e (%

)

Cirrhosis

7985 85

79 7276 65

53 3554 47

17ETVControl

No at risk

0 1 3 52 4

Log-rank test: p < 0.001

20.9%

4.3%

38.9%

7.0%

0 1 3 52 4

Control

ETV

Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180.

Japanese cohorts: HCC incidence lower with ETV than with LAM in cirrhotic patients

LAM

No at risk

Cirrhosis

0 1 3 52 4Treatment duration (years)

20.9%

38.9%

4.3%7.0%

22.2%

12.2%

50

40

30

20

10

0

Cu

mu

lati

ve H

CC

rat

e (%

)

Log-rank test:

ETV vs LAM: p = 0.043ETV vs control: p < 0.001LAM vs control: p = 0.019

497985

49

8579

417276

35

6553

323554

29

4717ETV

Control

ETV

Control

LAM

Adapted from Hosaka T, et al. Hepatology 2013 [Epub ahead of print]. doi: 10.1002/hep.26180.

ETV vs LAM sub analysis:

• Additional cohort of 949 LAM-

treated patients were recruited

(1995–2007)

• Of 492 LAM-treated patients who

met the same inclusion criteria as

the ETV group (no rescue therapy),

PS-matching resulted in a cohort of

182 patients (49 had cirrhosis)

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

immunotolérant

Mason, W. S. et al. 2009 / 2010. J. Virol

Devons nous redéfinir la tolérance immunitaire et

repenser les indications thérapeutiques ?

Observation d’une expansion clonale des hépatocytes

- Cellules qui n’expriment pas les antigènes viraux

- Diminution de la charge virale malgré l’absence de lésion hépatique mesurable

- L’une des premières étapes du CHC

Tolérance Immunitaire

- Presque tous les hepatocytes sont infectés- Viremies > 10E9 copies/mL- Devrions nous réaliser une biopsie lorsque

la charge virale diminue sans élévation des ALAT ? Et penser à un traitement antiviral ?

Zoulim & Mason, W. S. Gut 2012

Baseline Characteristics

CharacteristicTDF

(n=64)

FTC/TDF

(n=62)

Mean age, years (SD) 33 (9.5) 33 (11.2)

Male, n (%) 31 (48.4) 31 (50)

Race, n (%)

Asian 56 (87.5) 56 (90.3)

Caucasian 4 (6.3) 1 (1.6)

Other 4 (6.3) 5 (8.0)

Region, n (%)

Asia/Pacific 37 (57.8) 43 (69.4)

Europe 9 (14.1) 8 (12.9)

North America 18 (28.1) 11 (17.7)

Mean HBV DNA, log10 IU/mL (SD) 9.2 (0.4) 9.2 (0.4)

HBV genotype, n (%)

B 33 (51.6) 32 (51.6)

C 24 (37.5) 28 (45.2)

Other 7 (10.9) 2 (3.2)

Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45-Oral #101

Nei

ther

Tru

vad

a (T

VD

= T

DF

+ FT

C)

or

emtr

icit

abin

e (F

TC)

are

licen

sed

fo

r u

se t

o t

reat

CH

B

Study Design

♦ Primary endpoint: HBV DNA < 69 IU/mL at Week 192

– Roche TaqMan® Real-Time Polymerase Chain Reaction Assay 2.0

♦ Key inclusion criteria:

– HBV DNA 1.7x107 IU/mL

– ALT ≤ upper limit of normal

♦ Key exclusion criteria:

– Decompensated liver disease

Patients with high HBV DNA and normal ALT (N=126)

TDF 300 mg/placebo

(n=64)

FTC 200 mg/TDF 300 mg

(n=62)

1:1 Randomization

Chan HLY, et al. J Hepatology 2013 Supp 1;58(101):S45 Oral #101


Mean Viral Decline From Baseline

Study week

TDFFTC/TDF

Ch

ange

in H

BV

DN

A (

log 1

0 IU

/mL)

0 16 32 48 64 80 96 112 128 144 160 176 192

–8

–6

–4

–2

0



Proportion of Patients With HBV DNA < 69

IU/mL at Week 192*

FTC/TDF 76%

TDF 55%Pati

en

ts (

%)

Study week*Proportion (95% confidence interval [CI]); missing data = failure analysis.


Nei

ther

Tru

vad

a (T

VD

= T

DF

+ FT

C)

or

emtr

icit

abin

e (F

TC)

are

licen

sed

fo

r u

se t

o t

reat

CH

B

Multivariate Analysis of Treatment Response

Odds ratio† CI

Female 6.0 1.9‒18.2

FTC/TDF treatment 3.9 1.4‒11.1

We

ek

19

2 r

es

po

ns

e r

ate

* (%

)

Male

Female

TDF FTC/TDF

*Proportion of patients with HBV DNA <69 IU/mL at Wk 192 among those with Wk 192 visit. †Multivariate logistic regression performed using forward selection model.


Nei

ther

Tru

vad

a (T

VD

= T

DF

+ FT

C)

or

emtr

icit

abin

e (F

TC)

are

licen

sed

fo

r u

se t

o t

reat

CH

B

Safety Analysis: Clinical Parameters

TDF

(n=64)

FTC/TDF

(n=62)

Serious adverse event, n (%)* 6 (9.4)* 3 (4.8)†

Study drug-related adverse event

Grade 2 4 (6.3) 5 (8.1)

Grade 3 or 4 0 0

Death 0 1 (1.6)‡

*Urinary tract infection, HBV, appendicitis, gastroenteritis, creatine kinase increase, uterine leiomyoma; †Urinary tract infection, spontaneous abortion, ovarian cyst; ‡Homicide.



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

Zoulim, Antiviral Research 2012

Current treatment: sustained disease control achieved with NUCs/IFN in majority of patients

Entecavir1,2 Tenofovir3 PEG-IFN α-2a4,5

HBeAg positive n = 354 n = 176 n = 271

HBV DNA undetectable 67% 76% 25%a

HBeAg seroconversion 21% 21% 27%

ALT normalisation 68% 68% 39%

HBsAg loss 2% 3.2% 2.9%b

HBeAg negative n = 325 n = 250 n = 177

HBV DNA undetectable 90% 93% 63%a

ALT normalisation 78% 76% 38%

HBsAg loss 0.3% 0% 0.6%b

1. Chang T-T, et al. N Engl J Med 2006;354:1001–10.2. Lai C-L, et al. N Engl J Med 2006;354:1011–20.3. Marcellin P, et al. N Engl J Med 2008;359:2442–55.

4. Lau GKK, et al. N Engl J Med 2005;352:2682–95.5. Marcellin P, et al. N Engl J Med 2004;351:1206–17.

Results at 48 weeks a HBV DNA < 400 copies/mL; b At 72 weeks

Cumulative Probability of HBsAg

Loss During TDF AdministrationC

umul

ativ

e P

roba

bilit

y F

unct

ion

Est

imat

e

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0.10

0.11

0.12

Weeks on Study

0 12 24 36 48 64 80 96 108 120 132 144 156 168 180 192

10.8%

8.5%

• TDF-TDF

• ADV-TDF

Switch to Open Label TDF

Cumulative probability of seroconversion to anti-HBs: 7.7% TDF-TDF

7.3% ADV-TDF*Kaplan-MeierHeathcote E-J, et al., AASLD 2010; Poster #477.

• TDF-TDF

• ADV-TDF

0 12 24 36 48 64 80 96 108 120 132 144 156 168 180 192

Weeks

Cu

mu

lati

ve

Pro

ba

bil

ity F

un

cti

on

Es

tim

ate

0.12

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Percentage of

TDF-TDF Patients with HBsAg Loss

Key CharacteristicHBsAg Clearance by Year 4

n/N (%)

Genotype A or D 14/95 (15%)

HBV DNA ≥ 9 log10 copies/mL 12/75 (16%)

HBsAg ≥ 4.5 log10 IU/mL 14/90 (16%)

Knodell Necroinflammatory Score ≥ 9 13/114 (11%)

Heathcote E-J, et al., AASLD 2010; Poster #477.

No HBsAg loss in : Asian patients

HBeAg negative patients

Genotype B or C

High rate of HBsAg clearance among sustained

responders to PEG-IFN-2a± LAM

Marcellin et al. APASL 2009* Modified ITT analysis (missing = non response);§ last observation carried forward

5 years post-treatment with PEG-IFN-2a ± LAM (N=230)

<10,000 cp/mL* <400 cp/mL* Cleared HBsAg§

Pati

en

ts (

%)

21%

17%

12%

64%

0

5

10

15

20

25

30

Slow kinetics of HBV clearance

• Rate of cccDNA decline (liver)

< 1 log10 copie/cell at year one

Estimated time for clearance (in the absence of

hepatocyte turnover) > 15 years

Werle et al, Gastroenterology 2004; Wong et

al Clin Gastroenterol and Hepatol 2013

• HBsAg decline (serum)

• Rate of decline: 0.007 ± 0.007 Log

UI/mL/month

Evolution of viral markers during NUC therapy

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

0.01

0.1

1

10

100

2.00E+02

3.00E+02

4.00E+02

5.00E+02

6.00E+02

7.00E+02

8.00E+02

9.00E+02

No

v. 99

Jan

. 00

Sep

t. 0

0

Ma

r. 0

1

Ju

ly 0

2

Dec. 02

Dec. 03

Viral load

HBs Ag

Lamivudine 100 mg/day

Clinical example of HBsAg clearance

HBs AgPositivity cut off: 0.05

Viral loadDetection treshold

Viral loadLog Copies/ml

HBs Ag

IU/ml

* *

*: Anti-HBs antibody

Negativation of HBe Ag May 1987HBe Seroconversion between June 87 and November 1996?

Borgniet O et al., J Med Virol , 2009;81:1336-42.

Therapy

HB

V D

NA

ch

an

ge f

rom

baselin

e (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

Short-term therapy is associated with rebound of viral replication

HBsAg

HBVDNA

cccDNA

Therapy

HB

V D

NA

ch

an

ge f

rom

baselin

e (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

Long-term therapy is required to maintain viral suppression

HBsAg

HBVDNA

cccDNA

Therapy

HB

V D

NA

ch

an

ge f

rom

baselin

e (

log

10

c/m

L)

0.0

-1.0

-2.0

-3.0

-4.0

+1.0

Time

New treatment concepts for a functional cure of HBV infection

HBsAg

HBVDNA

cccDNA

Lucifora et al, Science 2014

Zoulim, et al,

Clinical Gastroenterology

and Hepatology 2013

Belloni et al, JCI 2012

Hepatocyte turn-over

cccDNA silencing

cccDNAdegradation

cccDNAformation

Bertoletti & Ferrari Gut 2012; Zoulim et al, Gastroenterology 2013

Concept of combination therapy for CHB

Innate

responses

Adaptive

responses

Viral

replication

Future directions: target & drug discovery to cure HBV infection

Immune modulation• Toll-like receptors

agonists, Gilead, Roche

• Anti-PD-1 mAb, BMS, Merck

• Vaccine therapyTransgene, Gilead, Roche Innovio, Medimmune, ITS

Development stage: preclinical, clinicalZoulim F, et al. Antiviral Res 2012;96(2):256–9; HBF Drug Watch, Available at: http://www.hepb.org/professionals/hbf_drug_watch.htm.

HBx

Endosome

rcDNA

cccDNA

Polymerase

pgRNA

Core

Surface

proteins

Entry inhibitors• Lipopeptides, e.g.

Myrcludex-B

Targeting cccDNA

Inhibition of nucleocapsid assembly, Novira, Assemblypharm, Gilead, Janssen, Roche

Polymerase inhibitors • Nucleoside

analogues, e.g. Gilead, BMS

• Non-nucleoside, e.g. LB80380

Inhibitors of HBsAg release, Replicor

RNA interference,Arrowhead, Tekmira, Alnylam, GSK

http://www.hepb.org/professionals/hbf_drug_watch.htm

The concept of combination therapy

Entry inhibition

cccDNA- formation- stability / destruction- epigenetic regulation

Viral core functions

Other viral targets

Stimulating innate responsesSpecific ligands

Stimulating adpative responsesCo-inhibitory signals

Co-stimulatory signals

Therapeutic vaccination

Functional cure / controlReal cure ?

Viral targets Immune modulation

zoulim fz traitement hépatite b 2015 du

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