Using Hepatitis B Surface Antigen Quantification to the Management of Hepatitis B

(1)

Using Hepatitis B Surface Antigen

Quantification to the Management of

Hepatitis B

中國醫藥大學附設醫院

消化系內科賴學洲

(2)

Hepatitis B: Epidemiology

• 350 million people chronically infected

• 2 billion with evidence of past or present infection

• Country of origin is THE major risk factor

World Health Organization. Hepatitis B Fact Sheet. Centers for Disease Control and Prevention. CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012.

Prevalence of HBsAg

High ≥ 8%

Intermediate 2% to 7% Low < 2%

(3)

The HBV Iceberg

• Clinical populations are

the tip of the iceberg

• Individuals in

treatment are the tip

of the tip

• Population-based

studies allow us to look

at the whole iceberg

–

Asia has been the place

for these

Cohen C, et al. J Viral Hepatitis. 2011;18:377-383. Graphic reproduced with permission.

2 million individuals in the US

have chronic HBV infection

1.4 million are unaware of their chronic HBV infection

50,000 receive treatment 150,000 are diagnosed in care and meet treatment

guidelines

600,000 are aware of their chronic HBV infection 500,000 are potentially

eligible for treatment 300,000 are diagnosed in care

(4)

Natural History of Chronic HBV

Infection

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

HBeAg+

HBeAg- HBeAb+

Immune Clearance

Immunotolerance

ALT

HBV DNA

Mos-Yrs

Immune Control

(Nonreplicative)

HBsAg+

HBsAg- HBsAb+

Infection

Mos-Yrs

5-30 Yrs

(5)

Assess HBsAg

Positive

CHB*

Evaluate for

treatment

Negative

Assess anti-HBs

Negative

(No antibodies)

(Antibodies

Positive

present)

Vaccinate

Immune to HBV

*Time from positive HBsAg test to diagnosis of CHB is 6 mos.

HBV Screening Algorithm

(6)

Hepatitis B Serology: First Phase

Testing

• AASLD guidelines recommend HBsAg and anti-HBs testing for all patients

–

HBsAg

–

Protein on surface of HBV detected during acute or chronic HBV infection

–

Presence indicates an individual is

INFECTED OR INFECTIOUS

–

Anti-HBs



Presence indicates recovery and

IMMUNITY

from HBV infection

–

Also develops following vaccination against hepatitis B

• Total anti-HBc can be used as alternative; those testing positive should be

tested for HBsAg and anti-HBs

–

Appears at the onset of symptoms in acute hepatitis and persists for life

–

Presence indicates

EXPOSURE

(previous or ongoing infection with HBV)

(7)

Geographic Distribution of HBV

Genotypes

Liaw YF, et al. Liver Int. 2005;25:472-489. Chu CJ, et al. Gastroenterology. 2003;125:444-451.

A, B, C,

D, G

F

A, D, E

D

B, C

A, B,

C, D

A

(8)

HBV Classified Into 10 Genotypes

Genotype

Geographic distribution

A

North America, northern Europe, India, and Africa

B and C

Asia

D

Southern Europe, Middle East, and India

E

West Africa and South Africa

F

Central and South America

G

United States and Europe

H

Central America and California

I

Vietnam

J

Japan

Fung SK, et al. 2004;40:790-792. Norder H, et al. Intervirology. 2004;47:289-309. Tuan Huy TT, et al. J Virol. 2008;82:5657-5663. Tatematsu K, et al. J Virol. 2009;83:10538-10547.

(9)

HBV Variants

• Wild type

–

Unmutated HBeAg-positive hepatitis

–

Mixed infection with

• Basal core promoter mutations (44%

of US patients)

[1,2]

• Precore mutations (27% of US

patients)

[2]

• Precore and core promoter

mutations

[3]

–

Eventually abolishes HBeAg

production (HBeAg-negative CHB)

• Genotypes

• Treatment-induced mutations

1. Buckwold VE, et al. J Virol. 1996;70:5845-5851. 2. Chu CJ, et al. Gastroenterology. 2003;125:444-451. 3. Hunt CM, et al. Hepatology. 2000; 31:1037-1044.

(10)

(11)

High Risk of Cirrhosis in Asians &

Patients With Vertically Transmitted

Disease

• The lifetime risk of cirrhosis or cancer in a

person who is HBsAg positive is 20% to 30%

–

Risk is lower for women

–

Risk is highest for men

Fattovich G, et al. Am J Gastroenterol. 2002;97:2886-2895. Fattovich G, et al. Gastroenterology. 2004;11;27:S35-S50. McMahin BJ. Hepatology. 2009;49:S45-S55.

(12)

Why Test for HBV Genotype?

• Differences in natural history and treatment

responsiveness

–

B is associated with less active disease, slower

progression, and lower incidence of HCC than C

–

C has higher risk of HCC and cirrhosis

–

A and B respond better to IFN than C and D

–

F is associated with fulminant liver disease; rare

(13)

Interferon alfa-2b

Lamivudine

Adefovir

Peginterferon alfa-2a

Telbivudine

Tenofovir

1990

1998

2002

2005

2006

2008

Entecavir

HBV Treatment Landscape in 2010

(14)

HBV life cycle

(15)

(16)

(17)

HBsAg less than 100 IU/mL with a

higher rate of HBsAg loss

(18)

(19)

HBsAg level less than 10 IU/mL is

strong predictor of HBsAg loss

(20)

HBV DNA level less than 2000 IU/ml

with HBsAg level less than 10 IU/ml

related HBsAg loss

(21)

(22)

Lowest HBsAg levels at

week 12

are associated with

highest rate of sustained immune control

HBsAg at week 12 (IU/mL)

HB

eA

g

ser

oc

on

ver

sio

n

6 mo

nt

hs

p

os

t-tr

ea

tm

en

t (

%)

60

50

40

30

20

10

0 Low

(<1500)

(1500–20,000)

Medium

(>20,000)

High

57%

32%*

16%*

51/90 72/223 14/86 * P<0.0001 vs <1500 IU/mL

HBeAg-positive patients (N=399) treated with Peginterferon alfa-2a ± lamivudine

(23)

HBsAg at week 24 (IU/mL)

Lowest HBsAg levels at

week 24

are associated with

highest rate of sustained immune control

HB

eA

g

ser

oc

on

ver

sio

n

6 mo

nt

hs

p

os

t-tr

ea

tm

en

t (

%)

60

50

40

30

20

10

0 Low

(<1500)

(1500–20,000)

Medium

(>20,000)

High

54%

26%*

15%*

74/136 55/211 8/52 * P<0.0001 vs <1500 IU/mL

HBeAg-positive patients (N=399) treated with Peginterferon alfa-2a ± lamivudine

(24)

HBsAg decline at

week 12

is an early

sign of future HBsAg clearance

* 23% (90/399 patients) achieved HBsAg <1500 IU/mL at week 12

HBsAg

CLEARANCE

ON-TREATMENT

SUSTAINED

IMMUNE

CONTROL

Among patients who achieved HBsAg <1500 IU/mL at week 12 of treatment* achieved HBeAg seroconversion 6 months post- treatment (N=51/90) of those achieved HBsAg clearance at 6 months post-treatment (N=9/51)

57%

18%

(25)

NEPTUNE: On-Treatment HBsAg Level

as Marker of Response to PegIFN

• HBeAg-positive patients: pegIFN alfa-2a 180 µg/wk for 48 wks

–

HBsAg analyzed at baseline and every 12 wks

Gane E, et al. EASL 2011. Abstract 69. Graphic used with permission.

HBsAg levels (IU/mL) at Wk 12

100 80 60 40 20 0 Re sp on se 6 M os Po st tr ea tm en t ( % ) P < .0001 P = .0004 19% 27% 54% HBeAg

Seroconversion < 2000 IU/mL HBV DNA Clearance HBsAg < 1500 (n = 31) < 1501-20,000 (n = 62) > 20,000 (n = 21) P = .2866 58 42 0 52 31 0 10 0 0

HBsAg levels (IU/mL) at Wk 24

100 80 60 40 20 0 P = .0003 P = .0015 14% 40% 46% HBeAg

Seroconversion < 2000 IU/mL HBV DNA Clearance HBsAg < 1500 (n = 46) < 1501-20,000 (n = 52) > 20,000 (n = 16) P = .3819 57 35 0 54 19 0 7 0 0

(26)

NEPTUNE: On-Treatment HBsAg as

Marker of Response to PegIFN

• HBsAg < 20,000 IU/mL identified as key marker of response

• HBsAg > 20,000 IU/mL at Week 12 or 24 predicts lack of HBeAg seroconversion

– Negative predictive value: 100%

• Combination of ALT level and HBsAg decline improves positive predictive value

Gane E, et al. EASL 2011. Abstract 69.

100 80 60 40 20 0 HBe Ag Se roc on ve rs ion 6 M os P os ttr ea tm en t ( % ) 47 0 0 45 Week 12 Week 24 HBsAg (IU/mL) (n = 93) < 20,000 (n = 21) > 20,000 (n = 98) < 20,000 (n = 16) > 20,000 100 80 60 40 20 0 HBe Ag Se roc on ve rs ion 6 M os P os ttr ea tm en t ( % ) 46 0 0 45 1-2 x ULN > 2 x ULN

HBsAg Levels at Week 12 < 1500 IU/mL 1500-20,000 IU/mL > 20,000 IU/mL 68 31 ALT

(27)

HBsAg level as predicted at week 12

and week 24

(28)

Quantitative HBsAg and HBV DNA Predict SVR in

HBeAg-Negative CHB on PegIFN

Rijckborst V, et al. Hepatology. 2010;52:454-461.

102 patients on PegIFN ± RBV x 48 wks

No

(n = 54; 53%)

Yes

(n = 48; 47%)

< 2 logs

(n = 20; 20%)

≥ 2 logs

(n = 28; 27%)

≥ 2 logs

(n = 34; 33%)

< 2 logs

(n = 20; 20%)

0%

24%

25%

39%

HBsAg decline

at Wk 12

HBV DNA decline at

Wk 12

Chance of

sustained response

(HBV DNA < 4 logs at

Wk 72)

Stopping Rule

(29)

HBsAg decline : HBeAg-negative patient

(30)

CMUH ETV-Real Word Data

中國醫大附設醫院

消化系內科

賴學洲醫師

(31)

Predictors of Serum HBsAg Decline in Chronic

Hepatitis B Patients Undergoing Entecavir

Therapy

慢性B型肝炎病患接受貝樂克治療血清B型肝炎表面抗原濃度下降的

預測因子

賴學洲彭成元蘇文邦莊伯恒高榮達陳昇弘

中國醫藥大學附設醫院

內科部消化系

(32)

Background

• On-treatment decline in quantitative serum hepatitis

B surface antigen (qHBsAg) levels are predictors of

therapeutic efficacy in chronic hepatitis B (CHB)

patients treated with peginterferon

Aliment Pharmacol Ther 2012 ;35:458-68

Hepatology 2009;49:1141-1150

Hepatology 2009;49:1151-1157

• The decline in qHBsAg level and its predictors in CHB

patients undergoing entecavir (ETV) therapy remain

unclear

(33)

(34)

Methods

Exclude

1.Acute Decompensation (N=31)

2.Decompensated Cirrhosis (N=23)

Between

Jun 2006 and Nov 2011

,

299 treatment-naïve

CHB patients

have been treated with Entecavir for at least 1 year

245 HBV patients:

1.HBeAg(+): N=86; HBeAg(-): N=159

2.Treatment duration:

(1) Mean: 36.5 months

(35)

Factors associated with VR in CHB patients at year 1

VR(-)

VR(+)

p

uni

p

multi

OR(95%CI)

Total patients

N=24

N=221

HBeAg - + 5(20.8) 19(79.2) 154(69.7) 67(30.3) <0.001 0.003 7.491(1.948-28.813) 1.000

BL HBV DNA: Log₁₀ copies/mL <8 ≧8 6(28.6) 15(71.4) 167(77.0) 50(23.0) <0.001

BL HBsAg: Log₁₀ IU/mL <3.7 ≥3.7 7(35.0) 13(65.0) 167(80.3) 41(19.7) <0.001 0.024 3.429(1.180-9.968) 1.000

HBeAg(+)

N=19

N=67

ALT: IU/L <110 ≥110 14(73.7) 5(26.3) 31(46.3) 36(53.7) 0.041 0.005 1.000 7.275(1.817-29.126)a

BL HBsAg: Log₁₀IU/mL <3.7 ≥3.7 5(29.4) 12(70.6) 37(56.9) 28(43.1) 0.043 0.005 6.520(1.738-24.455) a 1.000 BL HBV DNA: Log₁₀ copies/mL

<8 ≥8 3(17.6) 14(82.4) 31(48.4) 33(51.6) 0.022 0.004 8.038(1.931-33.457)b 1.000 BL-3M HBsAg decline <10% ≥10% 15(88.2) 2(11.8) 35(57.4) 26(42.6) 0.023 0.006 1.000 10.118(1.966-52.079)b

(36)

Factors associated with HBeAg loss after 3 years of treatment

Median or N(%)

HBeAg loss (-)

N=35

HBeAg loss (+)

N=23

p –value

Genotype

B

C

23(65.7)

12(34.3)

8(36.4)

14(63.6)

0.030 PT: seconds prolonged

0.42

1.45

0.020 AFP: ng/mL

<8.0

≧8.0

25(80.6)

6(19.4)

10(45.5)

12(54.5)

0.017 BL HBV DNA: Log

₁₀

copies/mL 8.250

8.27

0.099 VR (6M)

-

+

21(60.0)

14(40.0)

7(30.4)

16(69.6)

0.028 HBsAg (6M): Log

₁₀

IU/mL

<2.8

≧2.8

3(8.8)

31(91.2)

8(34.8)

15(65.2)

0.020 Cox regression analysis of factors associated HBeAg loss

Variable

HR(95% CI)

p-value

Genotype (C)

3.141(1.226-8.004)

0.017 VR 6M (+)

2.572(1.025-6.457)

0.044 HBsAg 6M: (<2.8 Log

₁₀

IU/mL)

4.124(1.604-10.606)

0.003

(37)

Multiple logistic regression analysis of factors associated HBsAg decline in HBeAg(+) patients

Variable OR(95% CI) p-value AFP: ≥8 ng/mL 4.936(1.677-14.528) 0.004 BL HBsAg: ≥3.7 Log₁₀IU/mL 2.952(1.026-8.496) 0.044

Factors associated with HBsAg decline in HBeAg(+) patients (BL-3M)

Characteristics Median or N(%) BL-3M <10% (N=50) BL-3M ≧10% (N=28) p-value Age: year <40 ≥40 19(38.0) 31(62.0) 18(64.3) 10(35.7) 0.026 Genotype B C 21(42.9) 28(57.1) 20(71.4) 8(28.6) 0.019 Cirrhosis No Yes 32(64.0) 18(36.0) 28(100) 0(0) <0.001 ALT: IU/L < 120 ≥120 41(82.0) 9(18.0) 5(17.9) 23(82.1) <0.001 Total bilirubin: mg/dL 0.87 1.44 <0.001 AFP: ng/mL <8 ≥8 37(78.7) 10(21.3) 13(46.4) 15(53.6) 0.004 BL HBV DNA: Log₁₀copies/mL 7.90 8.47 0.011 BL HBsAg: Log₁₀IU/mL

<3.7 ≥3.7 29(58.0) 21(42.0) 10(35.7) 18(64.3) 0.059

(38)

Factors associated with HBsAg decline in HBeAg(-) patients (BL-12M)

Characteristics

Median or N(%)

BL-12M<10%

(N=112)

BL-12M≧10%

(N=33)

p-value

ALT: IU/L

<120

≥120

85(75.9)

27(24.1)

12(36.4)

21(63.6)

<0.001

Inflammatory activity

0-1

2-3

59(69.4)

26(30.6)

9(37.5)

15(62.5)

0.004 Fibrosis stage

0-2

3-4

41(47.7)

45(52.3)

19(76.0)

6(24.0)

0.012 BL HBV DNA: Log

₁₀

copies/mL

5.86

6.56

0.003 BL HBsAg: Log

₁₀

IU/mL

<3.7

≥3.7

108(96.4)

4(3.6)

20(66.7)

10(33.3)

<0.001

Multiple logistic regression analysis of factors associated HBsAg decline in HBeAg(-)

patients

Variable

OR(95% CI)

p-value

ALT: ≥120 IU/L

4.980(1.964-12.629)

0.001 BL HBsAg

: ≥3.7 Log

₁₀

IU/mL

12.018(3.149-45.869)

<0.001

(39)

Univariate and multivariate analyses of characteristics predicting serum HBsAg

≦2 Log

₁₀

IU/mL after three years therapy

HBsAg>2 HBsAg≦2 p

uni

p

multi

OR(95%CI)

HBeAg(+)

45 4

BL HBsAg: Log₁₀ IU/mL 3.85 3.05 0.079 NA HBsAg BL-3M <10% ≧10% 26(66.7) 13(33.3) 0(0) 4(100) 0.019 NA

HBeAg(-)

67 20

BL HBsAg: Log₁₀ IU/mL 3.11 1.95 <0.001 <0.001 0.403 (0.273-0.594) HBsAg BL-12M <10% ≧10% 52(85.2) 9(14.8) 8(44.4) 10(55.6) <0.001 0.001 1.000 3.730(1.370-10.155)

Using Hepatitis B Surface Antigen Quantification to the Management of Hepatitis B