2/20/2018

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Pimsiri Sripongpun, MD.

Division of Gastroenterology,

Department of Internal Medicine,

Faculty of Medicine, PSU.

Ott JJ. Vaccine. 2012;30:2212–9.

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Recover

Subclinical Hepatitis

FulminantHepatitis

Acute Hepatitis

ACUTE INFECTION

Chronic InfectionDEATH

< 1%

0.1-2.7%

5-20%

Risk is Related to Age at Infection

Outcome Neonates, % Children, % Adults, %

Chronic carrier 90 20 < 5

Recover 10 80 > 95

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

Phase Immune Tolerant Immune Clearance Inactive Carrier State

Reactivation

LiverMinimal

inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Anti-HBe

HBV DNA

ALT activity

HBeAg

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

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Parameter ImmuneTolerance

Immune Active/HBeAg-Positive

CHB

Nonreplicative(Inactive Carrier)

HBeAg-Negative CHB

Typical HBV DNA, IU/mL

> 200,000 200,000 - 2 x 109 < 2000 2000 - 2 x 107

HBeAg Positive Positive Negative Negative

ALT NormalElevated or fluctuating

NormalElevated or fluctuating

Other observations

Liver biopsy typically normal

or minimal findings

Active inflammation on

liver biopsy

HBsAg may become

undetectable

Active inflammation

on liver biopsy

New nomenclature (EASL 2017)

HBeAg positive chronic infection

HBeAg positive chronic hepatitis

HBeAg negative chronic

infection

HBeAg negative chronic

hepatitis

Lok AS, et al. Hepatology. 2009;50:661-662.

Liver cancer(HCC)

Cirrhosis

Liverfailure

Livertransplantation*

Death

5% to 10%

30%

Acute flare

10% to 15% in 5 yrs

23% in 5 yrs

Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Seeff LB, et al. Hepatology. 2001;33:455-463. Torresi J, et al. Gastroenterology. 2000;118:S83-S103. Fattovich G, et al. Hepatology. 1995;21:77-82.

Chronic infection

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Hx & PE Lab Serology

Imaging &

Liver specific

measurementAll patients -S/S of cirrhosis

-Family hx. HCC

-Alcohol

-Risk factors of

other diseases

-CBC w/ platelet

-LFT

-PT, INR

-HBeAg/ anti-

HBe

-HBV DNA

-anti-HAV IgG

USG abdomen

Individual

patient(s)

Work up other

cause of chronic

liver diseases: eg. Tsat, ferritin,

ceruloplasmin

-Work up other

cause of chronic

liver diseases:eg. anti-HCV, anti-

HDV, ANA, IgG level

-anti-HIV

-HBV genotype

-liver biopsy

-liver stiffness

measurement e.g. transient

elastography

APASL, AASLD, EASL guidelines

• Not a question of who to treat, but when : treat now or monitor and treat later when indicated

• All HBV carriers are potential treatment candidates

• A patient who is not a treatment candidate now can be a treatment candidate in the future • Changes in HBV replication status and/or activity/stage

of liver disease

• Availability of new or improved treatments

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Benefits Risks

Patient’s age and preference

Costs

Likelihood of

Adverse outcome

without treatment

Long-lasting response

Adverse effectsDrug resistance

Likelihood of adverse outcome without treatmentActivity and stage of liver disease at presentation

Risk of cirrhosis/HCC in the next 10-20 yrs

Likelihood of long-term benefit with treatment

Uncontrolled viral replication

No/ineffective treatment

Prevention of disease progression and improved liver histology are among the ultimate goals of CHB therapy1–3

1. Liaw YF, et al. Hepatol Int 2008;2:263–283. 2. Lok ASF & McMahon B. Hepatology 2007;45:507–539.3. Keeffe E. Clin Gastroenterol Hepatol 2008;6:1315–1341.

ChronicHBV

infection

Progression to cirrhosis/

HCC

Regression offibrosis

Long-term

viral suppression

Improved liver histology

Effective antiviral therapy

Sustainedviral suppression

Reduced HCC risk

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Peg-IFNADVTDF

Peg-IFN TDF LdT

0%0% 0%

24% 49% 67%38%

0% 3% 11% 18%

70%

4% 17%

29%

0.2% 1.2% 1.2%0.5% 1.2% 1.2%

Yr 3 Yr 4Yr 2Yr 1 Yr 5 Yr 6

LAM

ETV

LdT

ADV

TDF

EASL. J Hepatol. 2009;50:227-242. Tenney DJ, et al. EASL 2009. Abstract 20. Snow-Lampart A, et al. Hepatology. 2011;53:763-773. Snow-Lampart A, et al. AASLD 2010. Abstract 1365.

Not head-to-head trials; different patient populations and trial designs

Drug Generation

1st

2nd

3rd0%

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• HBeAg

• HBV DNA

• ALT

• Liver histology / Cirrhosis status

• Family history

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Prospective study in Taiwan

– 11,893 men without evidence of hepatocellular carcinoma

Newly diagnosed HCC

– 111 cases during 92,359 person-years of follow-up

Incidence rate per 100,000 person-years

– HBsAg-, HBeAg-: 39.1

– HBsAg+, HBeAg-: 324.3

– HBsAg+, HBeAg+: 1169.4

HBeAg positivity at enrollment was associated with an increased risk of HCC

Yang HI, et al. N Engl J Med. 2002;347:168-174.

Cu

mu

lati

ve In

cid

ence

(%)

0 1 2 3 4 5 6 7 8 9 10

Follow-Up (Yrs)

HCC

HBsAg+, HBeAg+RR: 60.2 (P < .001)

HBsAg+, HBeAg-RR: 9.6 (P < .001)

HBsAg-, HBeAg-RR: 1.0

0

2

4

6

8

10

12

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Ad

just

ed R

R*

0

2.0

4.0

6.0

8.0

10.0

Baseline HBV DNA predicted progression to cirrhosis : R E V E A L

Chen CJ, et al. EASL 2005. Abstract 476. Chen G, et al. Am J Gastroenterol 2006;101:1797–803.

*With 42,115 patient-yrs of follow-up and adjusted for sex, age, anti-HCV levels, smoking, and alcohol use.†1 IU/mL equals approximately 5.6 genomes/mL.

P = NS

HBeAg-Positive Patients

P < .01

P < .001

2.6

6.2

8.6

Cases of Cirrhosis: 2 3 135

< 104

(n = 22)≥ 105

(n = 520)≥ 104 to < 105

(n = 18)BL HBV DNA, c/mL†:

Correlation Between ALT and Histology in HBeAg+ Patients

Inflammation*

*Knodell necroinflammatory score ≥ 7. †Ishak fibrosis score ≥ 4.

Fibrosis†

Terrault N. DDW 2007. Abstract 94.

ALT (x ULN)

68

80

95

0

20

40

60

80

100

< 2 2-5 > 5

Pro

po

rtio

n o

f Pat

ien

ts (

%)

ALT (x ULN)

1115

20

0

20

40

60

80

100

< 2 2-5 > 5

234 305 113n = 234 305 113n =

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guidelines HBV ALT or Liver information

THASL 2015 2,000 IU/mL> 2x or sig. inflammation/ sig. fibrosis

(liver biopsy/LSM in age >40 if ALT <2x)

APASL 2015 20,000 IU/mL> 2x or sig. inflammation/ sig. fibrosis

(liver biopsy/LSM in age >35 if ALT <2x)

AASLD 2016 20,000 IU/mL> 2x or sig. inflammation/ sig. fibrosis

(liver biopsy/LSM in age >40 if ALT <2x)

EASL 2017 2,000 IU/mL

> 1x or sig. inflammation/ sig. fibrosis

(age For evaluation =?)

or age > 30

or family hx HCC

1387 asymptomatic HBsAg-positive patients with ≥ 1-yr follow-up

– 189 with persistently normal ALT (PNALT)* included in analysis (HBeAg negative: 116 /189, 61%)

Kumar M, et al. Gastroenterology. 2008;134:1376-1384.

*≥ 3 ALT values in the previous 1 yr prior to baseline liver biopsy that were all ≤ 40 IU/L and remained so until the start of treatment or the last follow-up.

60.3

39.735.3

13.8

0

20

40

60

80

100

HBV DNA ≥ 5 log copies/mL Histologic Fibrosis Stage ≥ 2

HBeAg positive

HBeAg negative

Pat

ien

ts (%

)

Patients With Normal ALT May Have Significant Fibrosis

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483 patients with spontaneous HBeAg seroconversion were follow up long-term ; Taiwan

Chen YC, et al. HEPATOLOGY 2010;51:435-44.

Phase Immune Tolerant Immune Clearance Inactive Carrier State

Reactivation

LiverMinimal

inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Anti-HBe

HBV DNA

ALT activity

HBeAg

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

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•Not all CH-B HBeAg negative individuals is an only CH-B carrier

•Every CH-B patients need to be followed up even no antiviral need yet

Phase Immune Tolerant Immune Clearance Inactive Carrier State

Reactivation

LiverMinimal

inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Anti-HBe

HBV DNA

ALT activity

HBeAg

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

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Inactive carrier

(Not healthy carrier)

HBeAg-negative CHB

10% to 20% have reactivation after yrs of quiescence disease

Serial testing is necessary during the “inactive carrier state”

After spontaneous HBeAg seroconversion, 67% to 80% of carriers remain in inactive carrier phase

Lok AS, et al. Hepatology. 2009;50:661-662.

Prospective, multicenter, observational cohort study

1. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. 2. Chen CJ, et al. JAMA. 2006;295:65-73.

1991-1992: 7 Taiwanese townships Individuals aged 30-65 yrs eligible

(N = 89,293 invited)

HCC Analysis[2]

(n = 3653)2004: 41,779 PYs follow-up164 new HCC cases (4.5%)

HCC-free individuals enrolled(n = 23,820) HBsAg+=4155

Cirrhosis Analysis[1]

(n = 3582)2004: 40,038 PYs follow-up

365 new cirrhosis cases (10.2%)

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Baseline HBV DNA predicted progression to cirrhosis : REVEAL

*With 42,115 patient-yrs of follow-up and adjusted for sex, age, anti-HCV levels, smoking, and alcohol use.†1 IU/mL equals approximately 5.6 genomes/mL.

HBeAg-Negative Patients

< 104

(n = 2132)

Cases of Cirrhosis: 104 55 96

≥ 104 to < 105

(n = 631)≥ 105

(n = 451)BL HBV DNA, c/mL†:

Ad

just

ed R

R*

P < .001

P < .001

1.01.9

4.9

0

2.0

4.0

6.0

8.0

10.0

1. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. 2. Chen CJ, et al. JAMA. 2006;295:65-73.

HCC risk

Terrault N. DDW 2007. Abstract 94.

7583 81

17 1721

*Knodell necroinflammatory score ≥ 7. †Ishak fibrosis score ≥ 4.

Inflammation* Fibrosis†

ALT (x ULN)

0

20

40

60

80

100

< 2 2-5 > 5

Pro

po

rtio

n o

f Pat

ien

ts (

%)

ALT (x ULN)

0

20

40

60

80

100

< 2 2-5 > 5

217 283 101n = 217 283 101n =

Correlation Between ALT and Histology in HBeAg-Negative Patients

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1387 asymptomatic HBsAg-positive patients with ≥ 1-yr follow-up

– 189 with persistently normal ALT (PNALT)* included in analysis (HBeAg negative: 116 /189, 61%)

Kumar M, et al. Gastroenterology. 2008;134:1376-1384.

*≥ 3 ALT values in the previous 1 yr prior to baseline liver biopsy that were all ≤ 40 IU/L and remained so until the start of treatment or the last follow-up.

60.3

39.735.3

13.8

0

20

40

60

80

100

HBV DNA ≥ 5 log copies/mL Histologic Fibrosis Stage ≥ 2

HBeAg positive

HBeAg negative

Pat

ien

ts (%

)Normal ALT May Have Significant Fibrosis

0

100

200

300

4000

100

200

300

400

0

100

200

300

400

0 12 24months

With flares and normalization

Without flares

With flares and without normalization

73 pts (44.5%)

59 pts (36%)

32 pts (19.5%)

ALT

16

4 u

ntreated

patien

ts,2

3 m

on

ths (ran

ge 12

-36

) mo

nth

ly mo

nito

ring

Brunetto MR, J Hepatol, 2002

Annual frequency of flares: < Once : 23%, once : 57%, twice : 20%Spontaneous resolution rare only 1/61 in untreated

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guidelines HBV DNA (IU/mL) ALT or liver information

THASL 2015 2,000 > 2x or sig. inflammation/fibrosis

APASL 2015 2,000 > 2x or sig. inflammation/fibrosis

AASLD 2016 2,000 > 2x or sig. inflammation/fibrosis

EASL 2017 2,000 > 1x or sig. inflammation/fibrosis

Phase Immune Tolerant Immune Clearance Inactive Carrier State

Reactivation

LiverMinimal

inflammation and fibrosis

Chronic activeinflammation

Mild hepatitis and minimal

fibrosis

Active inflammation

Optimal treatment times

Anti-HBe

HBV DNA

ALT activity

HBeAg

Yim HJ, et al. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology. 2006;43:S173-S181. Copyright © 1999–2012 John Wiley & Sons, Inc. All Rights Reserved.

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Guideline Cirrhosis stage HBV DNA (IU/mL)

THASL 2015Both compensated and

decompensated

Detectable

(consider OLT listing if

decompensated)

APASL 2015

Compensated cirrhosis> 2,000 or

< 2,000 + ALT elevation

Decompensated

cirrhosis

Detectable

(+OLT listing if decompensated)

AASLD 2016Both compensated and

decompensated

Detectable

(consider OLT listing if

decompensated)

EASL 2017Both compensated and

decompensated

Detectable

(consider OLT listing if

decompensated)

Subgroup HCC Incidence per Yr

Asian male HBV carriers > 40 yrs of age 0.4% to 0.6%

Asian female HBV carriers > 50 yrs of age 0.3% to 0.6%

Hepatitis B carrier with HCC family history Higher than no family history

African/N American blacks with HBV HCC occurs at younger age

Cirrhotic HBV carriers 3% to 8%

Bruix J, et al. AASLD HCC guidelines. July 2010.

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Meta-analysis of 26 prospective clinical studies

3428 CHB patients, 73.6% non-Asian descent

1 2 3 54

4

3

2

1

0

–1

–2

Median log10 HBV DNA level decrease from baseline

Me

dia

n h

isto

logi

cal a

ctiv

ity

ind

ex

imp

rove

me

nts

fro

m b

ase

line

P < 0.000003

r = 0.96

Mommeja-Marin H, et al. Hepatology 2003;37:1309–1319.

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2.8

6.4

0

1

2

3

4

5

6

7

antiviral Rx no Rx

2.7

12.5

17.8

33.7

0

5

10

15

20

25

30

35

40

IFN treated no Rx

p<0.05p<0.05 all

Meta-analysis 2010 : 3881 patients Meta-analysis 2007 : 466 patients

Papatheodoridis GV. J Hepatol. 2010;53:348-56.Lin SM. J Hepatol. 2007;46:45-52.