Hepatitis B Virus therapy

Maria Buti Hospital Universitario Valle Hebron Barcelona Spain

Disclosures

Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis

Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Roche

Immune tolerance Immune active Immune control HBeAg Anti-HBe

HBV DNA log10 IU/ml

ALT (U/L)

HBeAg or anti-HBe

HBsAg log10 IU/ml

5 4 3 2

500

100 20

Natural history of CHB

Janssen, et al. Gut 2012

Treatment indicated

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Liaw Y-F, et al. Hepatol Int 2012;11:163645 ALT: alanine aminotransferase; HBV: hepatitis B virus

Treatment indicated Chronic hepatitis

ALT elevated HBV DNA >2000 IU/mL Fibrosis

Cirrhosis Decompensated cirrhosis

Treatment not indicated Immune tolerant HBV HBV carrier state

Chronic hepatitis B infection

What can be achieved now

In immune tolerant patients

In patients with CHB and cirrhosis

In decompensated patients

CHB: chronic hepatitis B

Long-term follow-up of immune tolerant patients

Consecutive immune tolerant patients HBsAg- and HBeAg- for

> 6 months Normal ALT levels on

3 consecutive readings over 6 months

HBV DNA >107 copies/mL 57 patients followed up

for 5 years 84% of patients remained

immune tolerant at Year 5 No HCC

0

5

10

15

20

25

30

35

F0 F1 F2

BaselinebiopsyBiopsy at5 years

Hui CK, et al. Hepatology 2007;46:395401 HBsAg: hepatitis B surface antigen;

HBeAg: hepatitis B e antigen; HCC: hepatocellular carcinoma

Pat

ient

s (%

)

What can be achieved now in immune tolerant patients?

Chan HL, et al. Gastroenterology 2014;146:12408 FTC/TDF and FTC are investigational agents and not licensed for use in CHB; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; UNL: upper normal limit

HBV DNA 108 copies/mL ALT ULN

(N=126)

Randomised to TDF for 192 weeks

(n=64)

Completed study through Week 192

(n=54; 87%)

Randomised to FTC/TDF for 192 weeks

(n=62)

Completed study through Week 192

(n=53; 83%)

Discontinued treatment before Week 192

(n=11; 17%)

Discontinued treatment before Week 192

(n=8; 13%)

TDF and FTC/TDF in patients with normal ALT and high HBV DNA Phase 2, randomised, double-blind study in HBeAg-positive patients

HBV DNA suppression in immune tolerant patients

Chan HL, et al. Gastroenterology 2014;146:12408

100

80

60

40

20

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

Study week

Pat

ient

s (%

)

FTC/TDF 76%

TDF 55%

6% TDF patients and 2% TDF/FTC achieved HBeAg loss 5% TDF patients and 0% TDF/FTC achieved HBeAg seroconversion There were no cases of HBsAg loss/seroconversion No patients developed HCC or clinical events

What can be achieved now?

In immune tolerant patients

In patients with CHB and cirrhosis

In decompensated patients

Liaw Y-F, et al. Hepatol Int 2012;11:163645

Treatment indicated Chronic hepatitis

ALT elevated HBV DNA >2000 IU/mL Fibrosis

Cirrhosis Decompensated cirrhosis

Treatment not indicated Immune tolerant HBV HBV carrier state

Chronic hepatitis B infection

Approved Agents used to Treat HBV

Lamivudine

Telbivudine

Entecavir

Adefovir

Interferon alpha-2a

Peginterferon alpha-2b

Tenofovir

Chart1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2007

0

0

0

0

Year

Number of FDA-Approved Agents

Sheet1

19921993199419951996199719981999200020012002200320042005200620072008200920102011

Number of FDA-Approved Agents0000000000000000000

Therapeutic strategies for chronic hepatitis B

Short-term "curative" treatment

Years

HBV DNA < 2000 IU/ml ALT < UNL (anti-HBe)

On treatment response

HBsAg Loss

Follow-up (mo/yrs) IFN

Long-term "suppressive" treatment

HBV DNA undetectable by PCR (

Therapeutic Strategies for Chronic Hepatitis B

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients

HBeAg-POSITIVE Patients: Week 72 Treatment Response

Lau GKK, et. al. N Engl J Med. 2005;352:2682-95.

P < 0.001

P < 0.001

P = 0.006

P = 0.002

P = 0.02

P < 0.001

Chart1

0.140.140.05

0.410.390.28

0.320.270.19

Peg-INF alfa-2a

Peg-INF alfa-2a + Lamivudine

Lamivudine

Patients (%)

Sheet1

Peg-INF alfa-2aPeg-INF alfa-2a + LamivudineLamivudine

HBV DNA < 400 copies/ml14%14%5%

ALT Normalization41%39%28%

HBeAg Seroconversion32%27%19%

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients

HBeAg-NEGATIVE Patients: Week 72 Treatment Response

Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.

P=0.007

P=0.003 P=0.849

P=0.004

P=0.003 P=0.915

Chart1

0.430.440.29

0.590.60.44

Peg-INF alfa-2a

Peg-INF alfa-2a + Lamivudine

Lamivudine

Patients (%)

Sheet1

Peg-INF alfa-2aPeg-INF alfa-2a + LamivudineLamivudine

HBV DNA < 20,000 copies/ml43%44%29%

ALT Normalization59%60%44%

Impact of (peg)-IFN therapy on CHB

Safety profile well known

Progression to cirrhosis prevented

Clinical decompensation prevented

HCC reduced (?)

Improved patient survival

Immune control status in 30% of patients

How can we improve PEG-IFN efficacy ?

pretreament predictors of response High ALT levels

Low levels HBV DNA

Genotype A

Young people

on-treatment predictors of response

Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients:

to identify non responders

Week 12:

- No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C)

Week 24:

- HBsAg >20,000 IU/ml (A,B,C,D)

Week 12:

- No decline in HBsAg +

Response-guided therapy by HBsAg levels in Peg-IFN-treated patients: to identify non

responders

Week 12:

- No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C)

Week 24:

- HBsAg >20,000 IU/ml (A,B,C,D)

Week 12:

- No decline in HBsAg +

Therapeutic Strategies for Chronic Hepatitis B

High virological responses with long-term ETV or TDF

Response

ETV TDF

HBeAg+ patients Year 51

HBeAg- patients Year 32,a

HBeAg+ patients Year 83

HBeAg- patients Year 83

HBV DNA suppressionb 94% (88/94) 95%

(54/57) 98%

(159/160) 99%

(271/273)

Resistance 1% (n=1) NR 0% 0%

HBsAg loss (seroconversion) NR NR

12.9% (10.3%)

1.1% (

91 94 100 100

88 95 91

100

0

20

40

60

80

100

Week 48 Week 96 Week 144 Week 192

% P

atie

nts

with

VR

, H

BV

DN

A <

69 IU

/mL

TN TE

CIBERHEP: Efficacy of TDF in Treatment nave and Treatment Experienced patients

74 84 86

100

74 82 85

100

0

20

40

60

80

100

Week 48 Week 96 Week 144 Week 192

% P

atie

nts

with

VR

, H

BV

DN

A <

69 IU

/mL

Tabernero D. EASL 2014; Poster 1058 TE: treatment experienced; TN: treatment nave

Viral suppression was similar between TN and TE patients, with HBeAg loss

occurring more in TN patients

HBsAg loss: n=4 (1 HBsAg seroconversion)

HBeAg-negative HBeAg-positive

23 19

TN, N TE, N

19 17

14 13

3 8

65 48

TN, N TE, N

50 40

26 33

13 25

Patients (N=370) from 48 Spanish centres treated for 12295 weeks

0 48 96 144 192 0

30

60

90

120

150

180

210

MD

RD

(ml/m

in/1

.73m

2 )

Week

VIREAL study: high rates of virological response, regardless of age Subgroup (n=48) of elderly patients (65 years)

Incidence of comorbidities in elderly patients: 35% hypertension 17% diabetes 58% F3F4 (METAVIR) at baseline

Causse X. EASL 2014; Poster 1062

TDF has not been studied in patients >65 years. As elderly patients are more likely to have decreased renal function, caution is required

in these patients (Viread SmPC, March 2014)

Patie

nts

with

HBV

DN

A

Liver fibrosis regression and cirrhosis reversal over 5 years of treatment with TDF

N=348 had biopsies at baseline and Year 5 (96 with cirrhosis)

Marcellin P, et al. Lancet 2013;381:46875 Histologically evaluable patients in the

long-term histology cohort

0

20

40

60

80

100

Baseline Year 1 Year 5

Missing6543210

Pat

ient

s (%

)

P

Characteristics of patients shown to be associated with reversal of cirrhosis with TDF

Marcellin P, et al. Lancet 2013;381:46875 BMI: body mass index; SD: standard deviation

Characteristic No cirrhosis at Year 5 (n=71)

Cirrhosis at Year 5 (n=25)

P value

Mean BMI at baseline, kg/m2 (SD)

25.7 (3.7) 29.0 (4.4) 0.0007

BMI (kg/m2) at baseline, %

Japanese cohorts: significantly reduced HCC incidence with ETV compared with controls

in cirrhotic patients

Hosaka T, et al. Hepatology 2013;58:98107 LAM: lamivudine

Control ETV LAM

HCC

79 49 85

79 49 85

72 41 76

17 29 47

ETV LAM

Control

Treatment duration (years)

Cum

ulat

ive

HC

C ra

te (%

)

0 1 2 3 4 5

0

20

30

40

50

10

No. at risk 53 35 65

35 32 64

Control

LAM

11.4%

20.9%

2.6%

28.5%

4.3%

19.7%

7.0%

6

ETV 7.0%

22.2%

38.9%

4.8%

12.2%

Cirrhotics Log-rank test:

ETV vs LAM: P=0.043 ETV vs control: P

Lower risk of death/transplantation with ETV than with LAM

Death or transplantation HCC

Lim Y-S, et al. Gastroenterology 2014:doi: 10.1053/j.gastro.2014.02.033

1792 1792

1778 1777

1740 1436

1660 966

1601 563

1531 224

LAM ETV

No. at risk

Est

imat

ed c

umul

ativ

e in

cide

nce

of

dea

th o

r tra

nspl

anta

tion

(%)

0 1 3 5 2 4 6

0

40

60

80

100

20

Years after starting treatment

1389 21

P

When to stop NA therapy?

EASL 2012 guidelines

HBeAg positive

A) Confirmed anti-HBe seroconversion (and undetectable 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

Adapted from EASL Clinical Practice Guidelines. J Hepatol 2012;57:16785

*A proportion of patients who discontinue nucleos(t)ide analogue (NA) therapy after anti-HBe seroconversion may require retreatment,

since they fail to sustain their serological and/or virological response; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen

Off-therapy durability of response to ETV in HBeAg-negative CHB from Taiwan

95 patients (39 cirrhotic) treated with ETV for 24 (1359) months

Stopping rule: undetectable HBV DNA on 3 occasions at least 6 months apart

Response after treatment discontinuation compared with LAM or LdT from historical data

Cumulative relapse rates in Year 1: Virological relapse: 58% Clinical relapse: 45%

No good predictors of relapse

Jeng WJ, et al. Hepatology 2013;58:188896

0 90 180 270 360 Time to relapse (days)

0

20

40

60

80

100

Off

ther

apy

cum

ulat

ive

rela

pse

(%)

LAM or LdT

P=0.027

ETV

HBsAg loss

qHBsAg predicts HBsAg loss and HBV relapse after LAM discontinuation in HBeAg -ve

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 1201000 IU/mL 60

40

20

0

0 52 104 156 208 260 312 364 C

umul

ativ

e in

cide

nce

of H

BsA

g lo

ss

Duration of follow-up (weeks)

HBsAg

Stopping TDF After Long-Term Virologic Suppression in

HBeAg-Negative CHB

32

FINITE CHB, a randomized study in non cirrhotic HBeAg-ve patients with 4 yrs TDF therapy and undetectable HBV DNA

Randomized N=45

Withdrew consent n=3

Week 48 TDF-Restart

n=3

Week 48 TDF-Stop

n=18

Week 48 TDF-Continue

n=21

TDF-Stop n=21

TDF-Continue n=21

86% of TDF-Stop subjects did not restart TDF by Week 48

Berg, EASL, 2015, O119

33

TDF-Stop: HBsAg loss, HBV DNA, ALT, TDF-Restart

FINITE CHB study 48 weeks outcome after therapy discontinuation

5%

24%

10%

10%

52% 48%

38%

10%

5%

57%

19%

14%

10%

Berg, EASL, 2015, O119

Grfico1

9.52380952389.523809523823.80952380954.761904761952.3809523810

9.5238095238038.0952380952047.6190476194.7619047619

14.2857142857019.0476190476057.14285714299.5238095238

TDF-Restart

HBV DNA >2000, ALT >2 x ULN

HBV DNA >2000, ALT 2000, ALT 2000, ALT

34

* TDF-Restart

-1 1 3 5HBsAg (log10 reduction)

-1 1 3 5HBsAg (log10 reduction)

TDF-Stop (n=21) TDF-Continue (n=20)

*

*

*

HBsAg Log10 Reduction: Median 0.283 Mean 0.773 HBsAg loss n=2

HBsAg Log10 Reduction: Median 0.088 Mean 0.109 HBsAg loss n=0

Week 48 HBsAg log10 Reduction (Individual Patients)

FINITE CHB. HBsAg levels between Patients who

TDF stopped and those who TDF continued

Stopping TDF was associated with a more profound decline in HBsAg levels compared to continuous TDF

HBsAg loss HBsAg loss

Berg, EASL, 2015, O119

HBsAg Clearance After Addition of PegIFN for 48 Weeks in HBeAg-Negative CHB Patients on NUCs

35 Bourliere, EASL, 2015, O112

Multicenter, randomized, controlled study in 183 patients with documented undetectable HBV DNA while on NUCs for at least 1 year

ANRS-HB06 PEGAN Study

NUC alone (n=93)

NUC + PegIFN

Wk 0 Wk 144

HBeAg- undetectable HBV DNA

on NUCs (n=183)

Wk 96 Wk 48

NUCs Alone N=93

PegIFN + NUCs N=90 P-value

HBsAg loss (Week 48, %) 0 (0) 7 (8) 0.0057 HBsAg loss (Week 96, %) (1 endpoint) 3 (3) 7 (8) 0.1521

HBs seroconversion (Week 96, %) 1 (1) 6 (7) 0.0465

NUC alone (n=90)

Patients receiving add-on PegIFN experienced higher HBsAg loss than NUC monotherapy at W48, but without statistical difference at W96

HBsAg loss with TDF plus PEG in chronic hepatitis B (CHB): Results of a global randomized controlled trial at week 72

Start TDF during follow-up if prespecified safety criteria met

0 48 120 72

TDF + PEG

TDF+PEG TDF

24

n=186

n=184

n=185

n=185 PEG

16

TDF

Week

from Asian No cirrhosis and bridging fibrosis were excluded

HBsAg HBeAg Loss Loss 9% 29% 2.8% 25% 0% 15% 2.8% 25%

Marcellin P, et al. AASLD 2014

37

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

Study 149.-On-Treatment Predictors of HBsAg Loss at Week 72

38 Chan, 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

What can be achieved now?

High rates of virological response with low/no risk of resistance

Histological improvement

Stop progression of disease (decompensation) and reduced liver transplant

Reduced risk of HCC

?

Hepatitis B Virus therapyDisclosuresSlide Number 3Slide Number 4What can be achieved nowLong-term follow-up of immune tolerant patientsWhat can be achieved now inimmune tolerant patients?HBV DNA suppression inimmune tolerant patientsWhat can be achieved now?Slide Number 10Approved Agents used to Treat HBVSlide Number 12Therapeutic Strategies for Chronic Hepatitis BPeginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive PatientsPeginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative PatientsSlide Number 16Slide Number 17Slide Number 18Slide Number 19Therapeutic Strategies for Chronic Hepatitis BHigh virological responses withlong-term ETV or TDFCIBERHEP: Efficacy of TDF in Treatment nave and Treatment Experienced patientsVIREAL study: high rates of virological response, regardless of ageLiver fibrosis regression and cirrhosis reversal over 5 years of treatment with TDFCharacteristics of patients shown to be associated with reversal of cirrhosis with TDFRisk of HCC is predicted to be decreased with long-term therapyJapanese cohorts: significantly reduced HCC incidence with ETV compared with controlsin cirrhotic patientsLower risk of death/transplantation with ETV than with LAMWhen to stop NA therapy?Off-therapy durability of response toETV in HBeAg-negative CHB from TaiwanqHBsAg predicts HBsAg loss andHBV relapse after LAM discontinuation in HBeAg -veStopping TDF After Long-Term Virologic Suppression in HBeAg-Negative CHBSlide Number 33Slide Number 34HBsAg Clearance After Addition of PegIFN for 48 Weeks in HBeAg-Negative CHB Patients on NUCsHBsAg loss with TDF plus PEG in chronic hepatitis B (CHB): Results of a global randomized controlled trial at week 72Slide Number 37Slide Number 38What can be achieved now?