6 June 2015

HBsAg loss: an achievable treatment target?

Pietro Lampertico

Gastroenterology and Hepatology Division

Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico

University of Milan

Financial disclosures

► Advisory Board/Speaker Bureau for

- BMS, ROCHE, GILEAD SCIENCES, GSK, MSD

Outline of the presentation

• PEG-IFN and NUC therapy

• De-novo PEG and NUC combination

• Switch to PEG in NUC responders

• Add-on PEG in NUC responders

• New drugs/strategies

More highlights on sustained “off-therapy”

response in 2012 EASL guideline

EASL 2012

2012 EASL Guidelines

Ideal end-point: sustained off-therapy HBsAg clearance

with/without seroconversion

Satisfactory end-point: sustained off-therapy virological

and biochemical response without HBsAg loss

Next desirable end-point: maintained virological remission

(undetectable HBV DNA by a sensitive PCR assay)

Interferon therapy (Peg-IFN)

Studies in patients and humanized mice indicate that combination treatments suppressing both HBV replication (NUCs) and cccDNA transcription (IFNα) may trigger significant antigen decline (HBe and HBs) – combination needs to be done in a smart way

NUC IFN NUC + IFN

Adapted from Thimme & Dandri, J Hepatol 2012;58:205-9

PEG and NUC have different mechanisms of action

Treatment aims to enable patients to achieve inactive CHB with

sustained immune control

Peg-IFN alfa-2a treatment can also result in off-treatment immune

control2,3

Potential long-term clinical benefits of sustained immune control after a

finite course of Peg-IFN alfa-2a therapy:

What can we achieve with Peg-IFN alfa-2a in CHB?

1. Lau GK, et al. N Engl J Med 2005;352:2682–95; 2. Marcellin P, et al. Hepatol Int 2013;7:88–97

3. Marcellin P, et al. Gastroenterology 2009;136:2169–79; 4. Perrillo RP, et al. Hepatology 2006;43:S182–93

5. EASL clinical practice guidelines. J Hepatol 2012;57:167–85; 6. Liaw YF, et al. Antivir Ther 2010;15:25–33

Approximately 30% of patients respond to

treatment with Peg-IFN alfa-2a1,2

Approximately 30% of patients respond to

treatment with Peg-IFN alfa-2a1,2

Freedom from potentially life-long

treatment4

Freedom from potentially life-long

treatment4

No long-term safety concerns4

No long-term safety concerns4

Decreased risk of cirrhosis and liver cancer5,6

Decreased risk of cirrhosis and liver cancer5,6

HBsAg clearance

(clinical cure)2

HBsAg clearance

(clinical cure)2

48-week efficacy of HBV therapy

Aghemo A, Lampertico P, Colombo M, J Hepatol 2012

11/230

5%

1

14/230

6%

2

20/230

9%

3

25/230

11%

4

28/230

12%

5

Follow up (years)

0

2

4

6

8

10

12

14

5 years follow-up of Peg-IFN treated

HBeAg negative patients- HBsAg loss

Marcellin et al. EASL 2009

e-

Patients

with H

BsA

g

cle

ara

nce (

%)

230 patients with HBeAg-negative CHB treated Peg-IFN alfa 2a with ± lamivudine

11%

Genotype

D

5

5/47

All genotypes

Probability of HBsAg loss in IFN treated

HBeAg negative patients

HBsAg loss: 28 patients

(95%CI: 21-42%)

Lampertico P et al, EASL 2015

126 HBeAg neg patients, 90% geno D, IFN for 22 months, followed for 11 years

e-

IFN

Other biomarkers (including IP10) are under investigation; data from recent

studies investigating the relationship between IL28B and response have been

controversial and are currently under discussion9–14

Baseline predictors of response: accurate

prediction of response allows more informed

treatment decisions

IL28B = interleukin 28B

IP10 = interferon gamma-inducible

protein-10

ULN = upper limit of normal

1. Moucari R, et al. J Gastroenterol 2010;25:1469–75; 2. Buster EH, et al. Gastroenterology 2009;104:2449–57

3. Sonneveld MJ, et al. Hepatology 2012;56:67–75; 4. Piratvisuth T, et al. Hepatol Int 2013;7:429–36

5. EASL clinical practice guidelines. J Hepatol 2012;57:167–85; 6. Jansen L, et al. EASL 2013

7. de Niet A, et al. EASL 2013; 8. Bonino F, et al. Gut 2007;56:699–705; 9. Sonneveld MJ, et al.

Gastroenterology 2012;142:513–20; 10. Lampertico P, et al. Hepatology 2013;57:890–6

11. Lee IC, et al. PLoS One 2013;8:e58071; 12. Wei L, et al. AASLD 2013

13. Brouwer WP, et al. EASL 2013; 14. Papatheodoridis G, et al. AASLD 2013

HBeAg-positive patients1–7

Low HBsAg

High ALT (2 × ULN)

Low viral load (HBV DNA <2 × 108 IU/mL)

HBV genotype (A > B > C > D)

Female gender

Wild-type vs precore/core promoter

mutations

HBeAg-positive patients1–7

Low HBsAg

High ALT (2 × ULN)

Low viral load (HBV DNA <2 × 108 IU/mL)

HBV genotype (A > B > C > D)

Female gender

Wild-type vs precore/core promoter

mutations

HBeAg-negative patients5–8

Similar to those observed in HBeAg-

positive patients but less well defined

HBeAg-negative patients5–8

Similar to those observed in HBeAg-

positive patients but less well defined

Baseline factors associated with sustained response

in patients receiving Peg-IFN alfa-2a

Baseline factors associated with sustained response

in patients receiving Peg-IFN alfa-2a

HBsAg loss by IL28B 917 and HLA-DPB1

535 polymorphisms in IFN treated

By HLA-DPB1 535*

Lampertico P et al, EASL 2015

126 HBeAg neg patients, 90% geno D, IFN for 22 months, followed for 11 years

e-

By HLA-DPB1 and IL28B 917

*HR 6.94 (95%CI: 2.8-16.8), p<0.0001

How can we improve PEG-IFN efficacy ?

• baseline predictors of response

• on-treatment predictors of response

• duration of therapy

• de-novo PEG+NUC combination therapy

De-novo PEG+NUC combination

Start TDF during follow-up if prespecified safety criteria met

De-novo combination of PEG-IFN +TDF

Randomized, controlled, open-label study (N=740)

– Stratified by screening HBeAg status and HBV genotype

Inclusion criteria

– HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL

– ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)

– No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography

15

0 48 120 72

TDF + PEG

TDF+PEG → TDF

24

n=186

n=184

n=185

n=185 PEG

16

TDF

Week

Marcellin P et al, AASLD 2014

Start TDF during follow-up if prespecified safety criteria met

De-novo combination of PEG-IFN +TDF

Randomized, controlled, open-label study (N=740)

– Stratified by screening HBeAg status and HBV genotype

Inclusion criteria

– HBeAg+ and HBV DNA ≥20,000 IU/mL; HBeAg- and HBV DNA ≥2,000 IU/mL

– ALT >54 and ≤400 U/L (men); ALT >36 and ≤300 U/L (women)

– No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography

16

0 48 120 72

TDF + PEG

TDF+PEG → TDF

24

n=186

n=184

n=185

n=185 PEG

16

TDF

Week

Marcellin P et al, AASLD 2014

HBsAg Loss Over Time (Week 72)

17

Pa

tie

nts

w

ith

HB

sA

g L

oss,

Ka

pla

n-M

eie

r E

stim

ate

(%

)

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

48 weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Week

0.15

0.14

0.13

0.12

0.11

72 weeks

7 patients had HBsAg seroreversion on or after Week 48 (4 in TDF+PEG 48 wk,

3 in TDF+PEG 16 wk →TDF 32 wk)

– 5/7 had ≤1 week of therapy after HBsAg loss

TDF + PEG 16 wk →TDF 32 wk

TDF + PEG 48 wk 9.0%

0%

2.8%

2.8%

p=0.003

p<0.001

p=NS

p=NS PEG 48 wk

TDF 120 wk

Marcellin P et al, AASLD 2014

‡

18 Chan et al, EASL 2015, O117

Baseline and On-Treatment Predictors of HBsAg Loss at Week 72

Univariate

P-value

Multivariate

P-value

Hazard ratio

Multivariate

Baseline

Predictors

Genotype A vs B 0.024 <0.001 7.32

Genotype A vs C <0.001 <0.001 16.76

Genotype A vs D 0.004 0.007 8.64

Arm A vs B (Peg+NUC short) 0.030 0.017 3.78

Arm A vs C (TDF) 0.018 0.070 15.68

Arm A vs D (Peg-IFN) 0.031 0.014 4.19

On-Treatment

Predictors

HBsAg decrease >1 log10 IU/mL by Week

12 (yes vs no) <0.001 <0.001 17.8

Anti-HBs >10 mIU/mL at Week 12 (yes vs

no) 0.138 0.003 9.97

ALT >400 U/L (males) or >300 U/L

(females) during first 12 weeks (yes vs no) <0.001 0.031 2.85

Arm A: PEG+NUC for 48 wks

On-Treatment Predictors of HBsAg Loss at Week 72

19

‡

Chan et al, EASL 2015, O117

Sensitivity Specificity

Positive

Predictive

Value

Negative

Predictive

Value

HBsAg decline from baseline

> 1 log10 at Week 12 71% 92% 43% 97%

TDF + PegIFN 48 wk

High negative predictive values are seen among patients treated

with TDF + PegIFN combination if they have:

HBsAg decline < 1 log10 IU/mL at Week 12

On-Treatment Predictors of HBsAg Loss at Week 72

20

‡

Chan et al, EASL 2015, O117

Sensitivity Specificity

Positive

Predictive

Value

Negative

Predictive

Value

HBsAg decline from baseline

> 1 log10 at Week 12 71% 92% 43% 97%

TDF + PegIFN 48 wk

High negative predictive values are seen among patients treated

with TDF + PegIFN combination if they have:

HBsAg decline < 1 log10 IU/mL at Week 12

87% of PEG-IFN +TDF treated should stop combo at

week 12 because of low chance (3%) of HBsAg loss

PegIFN vs PegIFN + TDF in CHB

21 Marcellin P et al, EASL 2015, P0657

Efficacy of combination of TDF+PegIFN compared to PegIFN monotherapy

PegIFN

(n=30)

PegIFN + TDF

(n=32)

HBsAg loss at week 48 (EOT) 2 (6.6%) 4 (12%)

HBsAg loss at year 3 (follow-up) 6 (20%) 6 (19%)

PegIFN + TDF (n=45)

PegIFN monotherapy (n=43)

Wk 0 Wk 48

CHB patients • HBeAg-negative, n=62

• HBeAg-positive, n=26

HBeAg-Negative patients

HBeAg-negative patients receiving PegIFN+TDF experienced higher EOT HBsAg loss than PegIFN monotherapy, but both groups had similar HBsAg loss 3 years after EOT

‡

Oral therapy (NUC)

Studies in patients and humanized mice indicate that combination treatments suppressing both HBV replication (NUCs) and cccDNA transcription (IFNα) may trigger significant antigen decline (HBe and HBs) – combination needs to be done in a smart way

NUC IFN NUC + IFN

Adapted from Thimme & Dandri, J Hepatol 2012;58:205-9

PEG and NUC have different mechanisms of action

8 years TDF for naïve CHB – Efficacy summary

1Missing/addition of FTC = failure [LTE-TDF]); 2Missing=excluded/addition of FTC = included.; 3Kaplan-Meier

(KM-ITT); NA = not applicable

%

HBeAg-

n=375

HBeAg+

n=266

HBV DNA ITT1 Observed2 ITT Observed

<69 IU/mL 75 99.6 58 98

<29 IU/mL 74 99 58 97

HBeAg loss / seroconversion NA NA 32 / 21 47 / 31

HBsAg loss / seroconversion 1.1 / 0.7 1.1 / 0.7 12.9 / 10.3 11.5 / 8.5

No resistance to TDF detected

Marcellin P et al, AASLD 2014

8 years TDF for naïve CHB – Efficacy summary

1Missing/addition of FTC = failure [LTE-TDF]); 2Missing=excluded/addition of FTC = included.; 3Kaplan-Meier

(KM-ITT); NA = not applicable

%

HBeAg-

n=375

HBeAg+

n=266

HBV DNA ITT1 Observed2 ITT Observed

<69 IU/mL 75 99.6 58 98

<29 IU/mL 74 99 58 97

HBeAg loss / seroconversion NA NA 32 / 21 47 / 31

HBsAg loss / seroconversion 1.1 / 0.7 1.1 / 0.7 12.9 / 10.3 11.5 / 8.5

No resistance to TDF detected

Marcellin P et al, AASLD 2014

8 years TDF for naïve CHB – Efficacy summary

1Missing/addition of FTC = failure [LTE-TDF]); 2Missing=excluded/addition of FTC = included.; 3Kaplan-Meier

(KM-ITT); NA = not applicable

%

HBeAg-

n=375

HBeAg+

n=266

HBV DNA ITT1 Observed2 ITT Observed

<69 IU/mL 75 99.6 58 98

<29 IU/mL 74 99 58 97

HBeAg loss / seroconversion NA NA 32 / 21 47 / 31

HBsAg loss / seroconversion 1.1 / 0.7 1.1 / 0.7 12.9 / 10.3 11.5 / 8.5

No resistance to TDF detected

Marcellin P et al, AASLD 2014

For HBeAg positive:

HBsAg loss: ~19% in white vs 0% in Asians

Indicators of future HBsAg loss: early HBeAg

loss and a fast decline in HBsAg levels

Multivariate models: HBeAg+ve; genotype A and D1

Characteristic Odds Ratio (95% CI) P-value

HBeAg loss in first 24 weeks 13.460

(2.159 - 83.927) 0.0054

Log10 slope of HBsAg: baseline to Week 12 12.440

(1.888 - 81.961) 0.0088

Years from diagnosis of HBV: ≤4 vs. >5 6.944

(1.119 - 43.478) 0.0375

1. Adapted from Marcellin P, et al. EASL 2011; Poster #740.

Summary of Efficacy Endpoints at Week 144

Chinese TDF vs. ADV Registration Study

a. Virological breakthrough was defined as HBV DNA level increase ≥ 1 log10 copies/mL above the treatment nadir and be confirmed on two consecutive

visits at least 1 month apart

b. Detected only at one visit and HBsAg became positive at subsequent visits

Table includes all randomized study subjects who received at least one dose of study medication (ITT population).

28

‡

Response

HBeAg+ Patients

P-value

HBeAg- Patients

P-value TDF-TDF

(n=103)

ADV-TDF

(n=99)

TDF-TDF

(n=154) ADV-TDF

(n=153)

Patients with HBV DNA < 400

copies/mL, n (%) 97 (94.2) 95 (96.0) 0.5571 144 (93.5) 145 (94.8) 0.6370

Log10 copies/mL decline from

baseline in HBV DNA, mean (SD) -6.6 (0.86) -6.5 (0.80) 0.7944 -4.9 (1.16) -4.9 (1.09) 0.8855

Virological breakthrougha, n (%) 0 6 (6.1) 0.0115 3 (1.9) 4 (2.6) 0.6958

ALT normalization, n (%) 92 (90.2) 87 (89.7) 0.9057 123 (90.4) 119 (90.2) 0.9362

HBeAg loss, n (%) 37 (35.9) 24 (24.2) 0.0678 NA NA -

HBeAg seroconversion, n (%) 33 (32.0) 20 (20.2) 0.0530 NA NA -

HBsAg loss, n (%) 1 (1.0)b 0 0.3149 0 1 (0.7)b 0.3157

HBsAg seroconversion, n (%) 0 0 - 0 1 (0.7)b 0.3157

Hou et al, APASL 2015, Oral #1292

Summary of Efficacy Endpoints at Week 144

Chinese TDF vs. ADV Registration Study

a. Virological breakthrough was defined as HBV DNA level increase ≥ 1 log10 copies/mL above the treatment nadir and be confirmed on two consecutive

visits at least 1 month apart

b. Detected only at one visit and HBsAg became positive at subsequent visits

Table includes all randomized study subjects who received at least one dose of study medication (ITT population).

29

‡

Response

HBeAg+ Patients

P-value

HBeAg- Patients

P-value TDF-TDF

(n=103)

ADV-TDF

(n=99)

TDF-TDF

(n=154) ADV-TDF

(n=153)

Patients with HBV DNA < 400

copies/mL, n (%) 97 (94.2) 95 (96.0) 0.5571 144 (93.5) 145 (94.8) 0.6370

Log10 copies/mL decline from

baseline in HBV DNA, mean (SD) -6.6 (0.86) -6.5 (0.80) 0.7944 -4.9 (1.16) -4.9 (1.09) 0.8855

Virological breakthrougha, n (%) 0 6 (6.1) 0.0115 3 (1.9) 4 (2.6) 0.6958

ALT normalization, n (%) 92 (90.2) 87 (89.7) 0.9057 123 (90.4) 119 (90.2) 0.9362

HBeAg loss, n (%) 37 (35.9) 24 (24.2) 0.0678 NA NA -

HBeAg seroconversion, n (%) 33 (32.0) 20 (20.2) 0.0530 NA NA -

HBsAg loss, n (%) 1 (1.0)b 0 0.3149 0 1 (0.7)b 0.3157

HBsAg seroconversion, n (%) 0 0 - 0 1 (0.7)b 0.3157

Hou et al, APASL 2015, Oral #1292

HBsAg kinetics in HBeAg-negative patients

treated with TDF for 4 years

• Asians have lower baseline levels of HBsAg than non-Asians

• In both groups, the overall 192 week declines were modest

Mean

HB

sA

g(L

og

10 IU

/mL

)

5.0

4.5

4.0

3.5

3.0

2.5

2.0

0 12 24 36 48 64 80 96 1 08 120 132 144 156 168 180 192

Weeks on treatment

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

Fung S, et al. APASL 2012; Poster #PP09-043.

Non-Asians (N = 281)

Asians (N = 94)

HBsAg kinetics in HBeAg-negative patients

treated with TDF for 4 years

• Asians have lower baseline levels of HBsAg than non-Asians

• In both groups, the overall 192 week declines were modest

Mean

HB

sA

g(L

og

10 IU

/mL

)

5.0

4.5

4.0

3.5

3.0

2.5

2.0

0 12 24 36 48 64 80 96 1 08 120 132 144 156 168 180 192

Weeks on treatment

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

Fung S, et al. APASL 2012; Poster #PP09-043.

Non-Asians (N = 281)

Asians (N = 94)

HBsAg decline: 0.35 -0.50 log/4 years

0

20

40

60

80

100

Pati

en

ts %

5 years ETV for real life, naive CHB patients

Virological summary

97%

n=744

97%

n=222

99%

n=418

96%

n=535

Europe1 Hong-Kong3 Italy2 Thailand5

100%

n=252

Japan4

1)Arends P, et al Gut. 2014 in press 2) Lampertico P, et al. J Hepatol 2013;58:S306. 3) Seto WK, et al J Gastroenterol

Hepatol 2014;29:1028-34. 4)Ono A, et al J Hepatol 2012;57:508–14. 5)Tanwandee T, et al. Hepatology 2013;58:672A

0

20

40

60

80

100

Pati

en

ts %

5 years ETV for real life, naive CHB patients

Virological summary

97%

n=744

97%

n=222

99%

n=418

96%

n=535

Europe1 Hong-Kong3 Italy2 Thailand5

100%

n=252

Japan4

1)Arends P, et al Gut. 2014 in press 2) Lampertico P, et al. J Hepatol 2013;58:S306. 3) Seto WK, et al J Gastroenterol

Hepatol 2014;29:1028-34. 4)Ono A, et al J Hepatol 2012;57:508–14. 5)Tanwandee T, et al. Hepatology 2013;58:672A

HBsAg loss

Anti-HBe seroconv. 33% 33% 38% 67% 55% 58%

1.5% 0.2% 0.4% 3.5% 4.1%

* Kaplan-Meier estimates

0

20

40

60

80

100

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

Patients

at risk 72 68 52

55%

43 36 28

HBeAg seroconversion: 31 patients

25 22 16 11 7

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60

34%

HBsAg loss: 15 patients

72 69 65 55 49 42 38 34 29 23 14

5-years ETV in naive, field practice CHB

Serological response in HBeAg pos

Lampertico et al , EASL 2013

NUC-experienced patients

0

5

10

15

20

Pati

en

ts (

%)

5 years TDF for LAM-ADV-exp CHB patients

HBsAg levels

7.8%

N=25

HBsAg

10-100 IU/ml

4.7%

N=15

HBsAg

loss

8.1%

N=26

HBsAg

0.05-10 IU/ml

320 patients, 59 yrs, 78% male, 85% HBeAg neg, 85% geno D, 97% LAM

exp, 88% ADV exp, 74% HBV-DNA neg, 60% cirrhotics

Lampertico P et al , EASL 2015

21%

HBsAg

<100 IU/ml

N=66

To improve HBsAg response in long-

term NUC treated patients

2013

“Switch to PEG” in long-term ETV treated pts:

OSST study 1-year follow-up e+

Ning Q et al, J Hepatol 2014

Mean duration of ETV at randomization: 20 months

Switching from long-term ETV to PegIFN 2a:

Results at week 48 (EOT for PEG) - mITT

Response, n (%) PegIFN alfa2a (n=94)

ETV (n=98)

P value

HBeAg loss 16 (38%) 16 (33%) NS

HBeAg seroconversion 14 (15%) 6 (6%) 0.046

HBsAg <100 IU/ml 22 (27%) 4 (4.4%) <0.0001

HBsAg <10 IU/ml 13 (16%) 0 <0.0001

HBsAg loss 8 (8.5%) 0 <0.01

HBsAg seroconversion 4 (4.3%) 0 NS

HBV DNA <1000 cp/mL 59 (72%) 90 (98%) <0.0001

ALT normal 48 (58%) 84 (94%) <0.0001

Ning Q, et al, J Hepatol 2014

e+

ANRS

26/07/2013

EASL 2015 / April 22-26 - Vienna 40

* Log10 IU/ml decrease between W0/W48 and W0/W96. Error bars represent 95% confidence intervals.

1.5

2.0

2.5

3.0

3.5

W0 W12 W24 W36 W48 W60 W72 W84 W96

Weeks

NUC alone (n=93)

PEG-IFN + NUC (n=90)

P=0.0001 P=0.006

-0.19*

-0.35*

-0.91* -0.89*

Bourliere M. et al, EASL 2015

A RCT of 48-week add-on Peg-IFN in NUC responders

185 HBeAg negative French patients, 40% Caucasians, neg HBV-DNA >1 year M

ea

n H

Bs

Ag

tit

ers

(lo

g IU

/ml)

HBsAg loss:

Week 48: 0% vs 8%, p<0.01

Week 96: 3% vs 8%, p=015

ANRS

On-treatment changes in HBsAg levels

26/07/2013

EASL 2015 / April 22-26 - Vienna 41

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

W0 W12 W24 W36 W48 W60 W72 W84 W96

Me

an H

BsA

g ti

ter

log 1

0 (

IU/m

l)

Weeks

W96 non responder N=83

W96 PEG-IFN responder N=7

In the PEG-IFN + NUC group

P<0.0001 P<0.0001

-0.70* -0.62*

-3.27*

-3.74*

* Log10 IU/ml decrease between W0/W48 and W0/W96. Error bars represent 95% confidence intervals.

Bourliere M. et al, EASL 2015

0

200

400

600

800

1000

1200

1400

1600

-12 0 12 24 36 48

Med

ian

HB

sA

g l

evels

(IU

/ml)

Weeks

PEG

48 week Add-on Peg-IFN in HBeAg neg, geno D,

NUC responders - HERMES study

Lampertico P. et al, EASL 2015

Patients:

50 yr, 81% male, 100% Caucasian, 100% geno D

100% with HBV- DNA negative and normal ALT levels

Undetectable HBV DNA for 3.2 years (1.1-8) before add-on PEG

NUC

1160

308

P<0.001

Overall, 73% qHBsAg decline

43% pts with >50% decline

One HBsAg loss (1.4%)

Two HBsAg <10 IU/ml (3%)

(70 patients - Week 48 analysis)

e-

743

After NUC withdrawal

55

39

27

0

20

40

60

80

Patients

with s

usta

ined r

esponse

after

5.5

years

(%

)

Durability of response to ADV in

HBeAg-negative patients from Greece

Hadziyannis SJ, et al. Gastroenterology 2012;143:629–36

*Persistently HBV DNA undetectable and

persistently normal ALT;

ADV: adefovir; ALT: alanine aminotransferase

Sustained

responders*

HBsAg

loss

HBsAg

seroconversion

18/33 13/33 9/33

• 33 patients with undetectable HBV

DNA levels who had discontinued

ADV therapy were followed for 67–

72 months

• Initially all sustained responders,

had a

virological relapse and

76% had a hepatitis flare

• The 5.5-year rate of HBsAg loss in

sustained responders was 72%

• No patient with HBsAg loss

seroreverted

Stopping LAM treatment in

HBeAg-negative patients from Taiwan

• 105 HBeAg-negative patients

stopped LAM

(52% GT B; 48% GT C)

• Stopping rule: undetectable HBV

DNA for 12 months*

• Median follow up: 49 months

• Durable response: undetectable

HBV DNA (<2000 IU/mL)

57

40

32

3.2

12.6

30.3

0

20

40

60

80

100

1 3 6 1 3 6

Pa

tie

nts

(%

)

Years off treatment

Chen CH, et al. J Hepatol 2014;

doi.org/10.1016/j.jhep.2014.04.029 (epub ahead of print)

*2 consecutive assessments at least 6 months apart †Percentages are a proportion of the total population

not of those with a durable response

Durable response HBsAg loss†

HBsAg loss

qHBsAg predicts HBsAg loss and

HBV relapse after LAM discontinuation

Chen CH, et al. J Hepatol 2014;

doi.org/10.1016/j.jhep.2014.04.029 (epub ahead of print)

*defined as serum HBV DNA >2,000 IU/mL in

2 measurements at least 3 months apart

HBsAg 120–1000 IU/mL

60

40

20

0

0 52 104 156 208 260 312 364

Cum

ula

tive

incid

en

ce

of H

BsA

g loss

Duration of follow-up (weeks)

HBsAg <120 IU/mL P<0.001

HBsAg >1000 IU/mL

80

100

24 20 19 14 9 8 4 4

42 31 24 20 16 10 8 4

39 35 26 21 17 14 8 2

<120

120‒1000

>1000

No. at risk HBsAg (IU/mL)

HBV DNA relapse*

100

60

40

20

0

0 52 104 156 208 260 312 364

Duration of follow-up (weeks)

HBsAg <200 IU/mL

P<0.001

Cum

ula

tive

incid

en

ce

of H

BV

rela

pse

HBsAg >1000 IU/mL

HBsAg 200–1000 IU/mL

80

39 19 10 8 7 5 2 1

36 19 9 7 4 3 3 1

30 29 28 25 20 16 10 9

>1000

200‒1000

<200

No. at risk HBsAg (IU/mL)

Stopping TDF After Long-Term Virologic Suppression in HBeAg-Negative CHB

47 Berg T et al, EASL 2015, O119

FINITE CHB

Open-label, multicenter, randomized, controlled trial, Week 48 interim analysis

TDF-Continue (n=21)

TDF-Stop (n=21)

Primary endpoint:

HBsAg loss by Week 144

Wk 0 Wk 48 Wk 144

CHB patients • HBeAg-negative

• ≥ 4 years TDF therapy

• HBV DNA <400

cp/mL for ≥3.5 years

Wk 48

Interim Analysis

No cirrhosis (Fibroscan ≤10 kPa), normal ALT, HBeAg-, anti-HBe+, HBsAg+

No history of decompensated liver disease

“Stop and Relapse” approach to induce HBsAg loss

TDF restart criteria based on viral load, ALT, prothrombin time, and bilirubin

‡

48

TDF-Stop (n=21): HBsAg loss, HBV DNA, ALT, TDF-Restart

FINITE CHB

0

20

40

60

80

100

Week 12 Week 24 Week 48

Pa

tie

nts

(%

)

HBsAg loss

HBV DNA <2000, ALT <2 x ULN

HBV DNA <2000, ALT >2 x ULN

HBV DNA >2000, ALT <2 x ULN

HBV DNA >2000, ALT >2 x ULN

TDF-Restart5%

24%

10%

10%

52% 48%

38%

10%

5%

57%

19%

14%

10%

‡

Berg T et al, EASL 2015, O119

Future HBV therapies: new targets, new drugs

Immunomodulation • Toll-like receptors

agonists, e.g. GS-9620

• Anti-PD-1 mAb, e.g. BMS-936559

• CYT107 • GI13000 • Vaccine therapy

Development stage: preclinical, clinical ; modified fand updated rom Zoulim, F, et al. Antiviral Res 2012;96(2):256–9; HBV Drug Watch, Available at: http://www.hepb.org/professionals/hbf_drug_watch.htm.

HBx

Endosome

rcDNA

cccDNA

Polymerase

pgRNA

Core

Surface proteins

Entry inhibitors (HBV/HDV) • Lipopeptides, e.g.

Myrcludex-B

Targeting cccDNA • HAPs • Chromatin-modifying

enzymes

Inhibition of Nucleocapsid Assembly, e.g. Bay 41-4109, NVR1221

Polymerase inhibitors • Nucleoside

analogues, e.g. • TAF, amdoxovir,

MIV-210 • Non-nucleoside,

e.g. LB80380

Inhibition of HBsAg release, e.g. REP 9AC

RNA interference, (siRNA) e.g. ARC-520

Inhibition of Prenylation (HDV) • Lonafarnib

What May a HBV Curative Regimen Look Like?

cccDNA inhibitor

NUC ±

Entry inhibitor

Agent to prevent viral spread, cccDNA re-amplification

Agents to activate antiviral immunity or relieve repression of the system

Selective agent to deplete or perturb cccDNA

Immune activator

+

+

HBV antigen inhibition

Agents to inhibit other components in the HBV life cycle [entry or cell-spread, capsid, HBX, HBsAg]

+

Adapted from S. Locarnini, 2014

HBsAg loss - Conclusions

• HBsAg loss is an achievable target today, however in

few patients only (duration of therapy)

• Genetic, disease and viral factors play a major role

• New strategies (de-novo combo, switch to or add-on)

with current drugs may improve HBsAg loss

• New strategies with new drugs aimed to HBsAg loss

• Is HBsAg loss a mandatory target ?

- NO, if the goal is to improve patient survival

- YES, if the goal is to shorten duration of NUC

Extended pegylated interferon alfa-2a therapy in Chinese

Patients with HBeAg-negative chronic hepatitis B: a

single-center, prospective, randomized open-label study

HBV-DNA suppression: <60 IU/ml

0

PegIFN

180 µg/week

96 48

Follow-up

RND

(n=66) PegIFN

180 µg/week Follow-up

60/72 108/120 weeks

n=36

n=30

Chen XP, et al. Poster 505. EASL 2012

HBsAg clearance at 48 weeks post-treatment significantly higher

in extended therapy group: 36.1% vs 13.3% (p<0.05)

HBsAg <1000 IU/ml and HBV DNA <60 IU/ml at end of treatment:

• PPV of 92% and NPV of 48.78% for achieving HBV DNA

suppression

e-

CHB Treatment

Guidelines EASL 2012 guidelines

HBeAg positive

A) confirmed anti-HBe seroconversion (and undectable

HBV DNA) after at least 12 months of consolidation*

B) confirmed HBsAg loss and anti-HBs seroconversion

HBeAg negative confirmed HBsAg loss and anti-HBs seroconversion

Cirrhotics confirmed HBsAg loss and anti-HBs seroconversion

When to stop NUC therapy ?

*A proportion of patients who discontinue NUC therapy after anti-HBe seroconversion may

require retreatment, since they fail to sustain their serological and/or virological response

adapted from EASL HBV Guidelines, J Hepatol 2012

Reijnders JG and Janssen HL. Hepatology 2013

Lampertico P. Gut 2014