Optimising therapy in chronic hepatitis B: Switch or add treatment

Teerha Piratvisuth

NKC Institute of Gastroenterology and Hepatology

Prince of Songkla University,Thailand

Optimising therapy in chronic hepatitis B:

Switch or add treatment

NA

Viral Resistance at 2 Years vs. Antiviral

Effect at Week 24

n =

Serum HBV DNA Level at Week 24

HBeAg Positive

HBeAg Negative

Pe

rce

n

t

w

ith

res

is

ta

n

c

e

Liaw YF. et al. Gastroenterology 2009;136:486-495.

4 9 25 24 29 41 30 45 2 5 12 6 20 50 60 56

0

10

20

30

40

50

60

70

80

90

100

Telbivudine

Lamivudine

GLOBE Results based on the baseline

and early virological response

Zeuzem S, et al. J Hepatology 71% of Telbivudine Treated Patients Achieve PCR Negativity (≤300 copies/mL) at Week 24 N=57/80 89% PCR Negative Week 104 N=51/57 52% Seroconversion Week 104 N=25/48 1.8% Resistance Week 104 N=1/57 Baseline HBV DNA <9 Log₁₀, ALT ≥ 2 x ULN N=80

HBeAg

Positive

Patients

95% of Telbivudine Treated Patients Achieve PCR Negativity (≤300 copies/mL) at Week 24 N=86/91 91% PCR Negative Week 104 N=76/86 83% ALT normalization Week 104 N=57/69 2.3% Resistance Week 104 N=2/86 Baseline HBV DNA <7 Log₁₀, N=91

The Roadmap Concept

Keeffe E,Piratvisuth T. et al. Clinical Gastroenterology and Hepatology 2007;5:890–897.

Inadequate response

≥2,000 IU/mL or

≥10,000 copies/mL

Start treatment

Complete response

PCR negative

Partial response

60 to <2,000 IU/mL or

300 to <10,000 copies/mL

Add a more

potent drug

Continue

Add another drug

without cross resistance,

or continue monitor

every 3 months

“Telbivudine Roadmap Strategy” Prospectively

Investigated in Study CLDT600A2410

Key Inclusion Criteria

 Male or female, ≥18 years of age

 Documented HBeAg-positive chronic hepatitis B

 Serum HBV DNA level ≥5 log₁₀ copies/mL at screening

 Elevated serum ALT level (1.3–10 x ULN) at screening

 Evidence of chronic liver inflammation

 For patients with cirrhosis, clinically and biochemically compatible with compensated liver disease Screening ≤6 weeks prior to baseline Telbivudine, N=105 Week 0→24 weeks

≥300 copies/mL

Telbivudine + Tenofovir

Week 24→104

<300 copies/mL

Telbivudine

Week 24→104

Off-treatment

Follow-up

Week 104→120

Off-treatment

Follow-up

Week 104→120

Road Map: HBeAg/HBsAg Response

Rates at Weeks 52 and 104

43

39

6

3

51

44

7

4

0

10

20

30

40

50

60

HBeAg clearance

HBeAg

seroconversion

HBsAg clearance

HBsAg

seroconversion

%

o

f

pa

ti

ent

s

Week 52, N=100

Week 104, N=99

Tenofovir in ADV nonresponders

Berg T, et al. Gastroenterology. 2010;139:1207-1217.

Tenofovir 300 mg QD*

(n = 53)

Fixed-Dose Emtricitabine/Tenofovir

200/300 mg QD

(n = 52)

Patients receiving

adefovir for chronic

HBV infection with

HBV DNA > 1,000

cps/mL after treatment

> 24 upto 96 weeks

(N = 105)

*If HBV DNA ≥ 400 copies/mL at or after Wk 24, patients could add emtricitabine (as open-label, fixed-dose emtricitabine/tenofovir) for ≥ 12 wks or discontinue study and start commercially available HBV treatment.

Wk 48

(current analysis)

Stratified by lamivudine

experience (< vs ≥ 12 wks)

and screening HBeAg status

(positive vs negative)

Wk 168

Berg T, et al. Gastroenterology. 2010;139:1207-1217.

66

81

69

81

0

20

40

60

80

100

Wk 24

Wk 48 (Intent to Treat)

Tenofovir (n = 52)

Emtricitabine/tenofovir (n = 53)

H

B

V

D

N

A

<

40

0

copi

es

/m

L

(

%

)

Tenofovir ± FTC in patients with persistent

viraemia on ADV (study 016)

Berg T, et al Gastroenterology 2010;139:1207-17 Manns M et al., APASL 2011 #PS 01-03

1

TDF

FTC/TDF

Res

po

ns

e

a

t w

e

e

k

1

6

8

HBV DNA

<400 cps/ml

HBeAg loss

seroconversion

HBeAg

HBsAg loss

53 52 38 39 _{38 39} 53

%

Role of Interferon in patients on long term

Nucleoside therapy

Theoretical background : NA and IFN

combination therapy

Moraleda G. et al. J Virol. 1997. Dandri M. et al. Hepatology 2000. Chisari FU. et al Annu Rev Immunol 1995. Boni C. et al Hepatology. 2001.

• Different mechanism of action

• NAs has little or no effect on intrahepatic cccDNA

• High HBV DNA load is associated with an inefficient

T Cell response to HBV-related antigen

Boglione L. et al. J Viral Hepatitis 2013; 20; e11-19.

Induction

ETV 0.5 mg/day

12 weeks

Association

ETV 0.5 mg/day + PEG-IFN

alfa-2a 180 μg/week

12 weeks

Maintenance

PEG-IFN alfa-2a

180 μg/week

36 weeks

Stopping rule at 12 weeks of PEG-IFN

<0.5 Log qHBsAg decline and < 2 Log HBV DNA decline

ETV alone

Sequential therapy with entecavir and PegIFN in CHB

with high HBV DNA

Sequential therapy with Entecavir and PegIFN in CHB

with high HBV DNA

0

10

20

30

40

50

60

70

80

90

100

Sequential

PegIFN monotherapy

cSVR

pSVR

HBeAg

seroconversion

HBsAg

seroconversion

cSVR:

pSVR:

Boglione L. et al. J Viral Hepatitis 2013; 20; e11-19.

60%

10%

20

20

80%

30%

20

20

76.9%

15%

11

20%

0%

13

20

%

(history control)

Sequential therapy with Adefovir dipivoxil and

PegIFN alfa-2a for HBeAg-negative patients

0 20 40 60 80 100

SVR 24

Week

Moucari R. et al. J Viral Hepatitis 2011. 18; 580-6.

50%

20

20%

cSVR 24

20

ADV

20

24

68

92

genotype D 45%

cSVR 24: HBV DNA < 70 cps/ml 24 weeks post-treatment SVR 24: HBV DNA < 10,000 cps/ml 24 weeks post-treatment

PegIFN:

response in patients who failed

prior LAM therapy

1. Piratvisuth T et al. (APASL 2006) J Gastroenterol Hepatol 2006; 21 (Suppl 1): A32. Abstract 100. 2. Xu DZ et al. (EASL 2008) J Hepatology 2008; 48 (Suppl 2): S266. Abstract 712. 3. Shi XF et al. (APASL 2007) Hepatol Int 2007; 1: 18. Abstract O-90.

P

a

ti

e

nt

s

w

it

h

H

B

e

A

g

s

e

roc

onve

rs

ion

(

%

)

PegaLAM cohort

31%

23/58

0

10

20

30

40

50

39%

31%

Chinese study

Naïve

LAM-R

31%

Chinese data

HBsAg

seroconversion in

13% of patients

p = ns

12 weeks PEG + LAM

then 12 weeks of PEG alone

48 weeks PegIFN

5/16

36/91

25/81

HBsAg

clearance in

9% of patients

11 patients with stable HBV DNA suppression (< 200 IU/mL)*

with long-term NA treatment (five ETV/six TDF ± LAM/FTC)

Add-on Peg-IFNα + long-term NA enhances HBeAg and

HBsAg decline

Arends P, et al. EASL 2013 *Patients remained HBeAg+ve with elevated HBsAg.

Five patients received 24 weeks of

Peg-IFNα-2b add-on treatment

Six patients continued

NA monotherapy

Arends P, et al. EASL 2013.

EOT = end of treatment.

-0.93

-0.29

-0.84

-0.14

Follow up [weeks]

Peg-IFNα treatment

Peg-IFNα addition (n = 5)

Patients who received Peg-IFN add-on therapy had

greater decline of HBeAg levels

-0.4 -0.3 -0.2 -0.1 0.0 0.1 0 12 24 36 48 H B s A g d e c lin e [ lo g 10 IU /mL ] NA monotherapy (n = 6) Peg-IFN α addition (n = 5)

Arends P, et al. EASL 2013

EOT = end of treatment.

-0.26

-0.18

-0.35

-0.12

HBsAg loss was not observed

Peg-IFNα treatment

HBsAg decline was more profound in patients who

received Peg-IFN add-on

N = 75

Non-random

classification

Patient

population

HBeAg+ve CHB

patients who had

achieved

undetectable HBV

DNA with at least

1 year of NA

therapy without

seroconverting

Combination

therapy with NAs

plus Peg-IFNα-2a

180 µg/week

Monotherapy group

remaining on NA

therapy

Li Q. et al. EASL 2013

No baseline difference between treatment groups (sex, age, ALT, qHBsAg, qHBeAg,

prior NA treatment duration)

Adding PegIFN alfa-2a on NAs therapy in HBeAg-positive

CHB patients who have achieved virological responses

Adding PegIFN alfa-2a on NAs therapy improves HBeAg seroconversion in

HBeAg-positive CHB patients who have achieved virological responses*

Li Q. et al. EASL 2013

฿0

10.5%

15.8%

36.8%

36.8%

฿0

฿0

฿0

0%

10%

20%

30%

40%

week 12

week 24

week 36

week 48

H

B

e

A

g

s

e

ro

c

o

n

v

e

rs

io

n

NA (n=56)

PegIFN + NA (n=19)

2.0 2.5 3.0 3.5 4.0 0 12 24 36 48 Weeks of therapy M e a n H B s A g [ lo g10 IU /mL ] NA (n=56) PegIFN + NA (n=19)

Adding PegIFN alfa-2a on NAs therapy improves qHBsAg decline in

HBeAg-positive CHB patients who have achieved virological responses*

Li Q. et al. EASL 2013 +0.09 log₁₀ IU/mL

-1.06 log₁₀ IU/mL

p<0.001

•

HBsAg seroconversion in 2 patients with combination therapy

•

No difference between 2 groups in AE rate

Improved serological response by additional

PegIFN in NAs treated CHB

0 20 40 60 80 100

Continuous HBsAg decline _{HBeAg seroconversion HBsAg < 10 IU/mL}

Wu Z. et al. AASLD 2012. 50% 0% 0% 31.3% 75% NA treated CHB HBV DNA <1,000 cps/mL Obvious decline of HBsAg

Additional PegIFN 16 pts 5 ve+ 16 pts 6 ve+ NA NA 48 wks 48 wks

*

Switched to Peg IFN therapy in ETV treated

CHB patients

HBeAg clearance _HBeAg seroconversion HBsAg clearance R es p o n se at we ek 48 Chen XF. EASL 2013. 40.7% 16.7% _13.3% 37% 0% 7.4% P>0.05 P<0.05 P<0.05 HBeAg-positive ETV > 96 weeks HBV DNA < 500 copies/ml HBeAg < 50 PEIU/mL. No HBeAg seroconversion

PegIFN alfa-2a 180 mcg weekly 48 weeks

ETV 12 wks

ETV 48 weeks 27 pts

•

Randomized, multicenter, open-label study

•

Primary endpoint: HBeAg seroconversion at end of treatment (Week 48)

•

Secondary endpoint: HBsAg loss at week 48

OSST Study, 200 Chineses HBeAg-positive CHB

Ning Q, et al. Hepatology 2012; 56 (Suppl.1): 35–88A.

Switch to Peg-IFNα-2a 180 μg/week for 48 weeks

(n=100)

ETV 0.5 mg QD for 48 weeks

(n=100)

ETV 0.5 mg QD

(N=200)

~ 9–36 months

Demographic or baseline characteristic

Peg-IFNα-2a

(n=97*)

ETV

(n=100*

)

Males, n (%)

78 (80.4)

87 (87.0)

Age, years, mean (SD)

33.2 (8.2)

33.2 (8.9)

Asian race, n (%)

97 (100)

100 (100)

Body mass index, kg/m

_,

_{mean (SD)}

_{22.9 (2.7)}

_{22.9 (2.9)}

Duration of previous treatment with ETV, months,

mean (SD)

19.7 (8.2)

20.4 (8.4)

HBsAg, log

IU/mL, mean (SD)

3.3 (0.5)

3.3 (0.5)

HBV DNA by PCR, log

copies/mL, mean (SD)

3.0 (0.1)

3.0 (0.0)

ALT, U/L, mean (SD)

27.5 (21.3)

24.2 (13.6)

HBeAg, PEIU/mL, mean (SD)

15.6 (48.0)

7.5 (19.9)

HBeAg loss, n (%)

54 (55.7)

52 (52.0)

Ning Q, et al. Hepatology 2012; 56 (Suppl.1): 35–88A.

* Patients who received at least one dose of study drug

† _{Two patients had received adefovir prior to initial ETV therapy} ‡ _{Peg-IFNα-2a; n=93; ETV; n=95}

HBsAg decline significantly greater in responders than

non-responders in Peg-IFNα-2a arm

Ning Q, et al. Hepatology 2012; 56 (Suppl.1): 35–88A.

*P value for responders versus

non-responders at Week 48

No. of patients (responders/non-responders)

Peg-IFNα-2a 13/80 15/79 15/76 15/72 13/70 ETV 6/89 6/91 6/91 6/88 6/86 1 3 4 0 2 0 12 24 36 48 Weeks M e a n q u a n tita tive HB sA g ( log 10 IU/m L ) P = 0.0002* P = 0.3716*

Peg-IFNα-2a responders ETV responders Peg-IFNα-2a non-responders ETV non-responders

20 80 100 0 40 60

Response rates at Week 48 ofPeg-IFNα-2a:

ITT population

Ning Q, et al. Hepatology 2012; 56 (Suppl.1): 35–88A. * Fisher Exact test, other p-values are using Chi-Squared Test

† _{Updated data from time of abstract submission}

ITT = intention-to-treat Resp o n se r a te s a t w e e k 4 8 ( % )

HBeAg seroconversion HBsAg seroconversion 15.5 HBV DNA <1000 copies/mL HBsAg loss 6.0 9.3† 0 4.1 0 ETV (n=100) Peg-IFNα-2a (n=97) P = 0.0314 P < 0.0001 P = 0.0014* P = 0.0569* 90.0 63.9 62/97 90/100 15/97 6/100 9/97 4/97 n/N

Baseline HBsAg >1500 IU/mL BaselineHBsAg < 1500 IU/mL 0% 5% 10% 15% 20% 25% 30% 35%

HBsAg < 1,500 IU/mL at baseline is a predictor of

HBeAg seroconversion at Week 48

Ning Q, et al. APASL 2013.

6/9 2/12 3/29 P = 0.0153 P = 0.113 P a tie n ts (% )

Baseline HBeAg status while patients on ETV

HBeAg seroconversion _{HBsAg loss}

P = 0.2002 P = 0.6197

2/34 4/18 2/12 1/29

HBeAg-ve HBeAg+ve HBeAg-ve HBeAg+ve

33.3 5.9 16.7 10.3 22.2 0.0 16.7 3.4

0%

20%

40%

60%

80%

100%

HBsAg at Weeks 12 and 24 predicts response to

Peg-IFNα-2a therapy at Week 48

Ning Q, et al. APASL 2013.

HBsAg < 200 IU/mL at Week 12 provides optimal prediction of HBeAg

seroconversion (PPV = 67%) and HBsAg loss (PPV = 78%) at Week 48

6/9 <200 6/26 200 - <1499 3/59 > 1500 7/9 <200 1/26 200 - <1499 1/59 > 1500 77.8 3.8 66.7 23.1 5.1 P < 0.0001 P < 0.0001 P a tie n ts (% )

Week 12 HBsAg (IU/mL)

Conclusions

:

• Switch or add-on more potent non-cross resistant agent is

recommended in patients treated with lamivudine or

telbivudine with detectable HBV DNA at week 24

• Switch to tenofovir should be consider in patients with

suboptimal response to adefovir therapy

•

Add-on or switch to PegIFN in patients on long-term NA

may provide better sustained response

•

Further study to confirm the benefit and to identify the