HEPATITIS B: EPIDEMIOLOGY AND...

Mitchell L. Shiffman, MD, FACG

HEPATITIS B:EPIDEMIOLOGY

AND TREATMENT

Mitchell L Shiffman, MDDirector

fLiver Institute of VirginiaBon Secours Health SystemRichmond and Newport News, Virginia

CHRONIC HBV INFECTIONDEMOGRAPHICS IN THE USA

Estimated 1.25 million persons in USA infected Vast majority are immigrants or first generation

Americans:• Southeast Asia, China• Sub-Saharan Africa• Eastern Europe• Likely acquired HBV via vertical transmission

African Americans account for 20% of persons with chronic infection

ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology

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CHRONIC HBVWHAT IS E-NEGATIVE HBV

• E-gene located in the pre- Core geneE-geneg pcore region of HBV

• Not necessary for replication• Target of the immune

response to inactivate HBVE-antigen

Coreantigen

Core geneE**gene • Mutation of the E-gene

Coreantigen

• No detectable E-antigen• Does not prevent replication• Prevents the immune response

from inactivating HBV

Ahn S, et al. Gastroenterol 2003;125:1370-1378.

E-ANTIGEN NEGATIVE CHRONIC HBVEVOLUTION

Acute HBV

E-Antigen (+) E-Antigen (-)E-Antigen (+)E**Antigen (-)

Seroconversion of E-Antigen (+) Strain:

E-antigen (-)Anti-E (+)

Inactive HBV

E**antigen (-)Anti-E (+)

Active E**negative HBV

E antigen (-)Anti-E (-)

Active E-negative HBV

Hoofnagle JH, et al. Hepatology 2007;45:1056-1075.


2


HCC IN PATIENTS WITH CHRONIC HBVE-ANTIGEN STATUS

100

20

40

60

80

% o

f Pat

ient

s

eAg (+)eAg (-)

eAg (+)

eAg (-)

0

20

ChronicHBV

Risk ofHCC

Total number of HCCs

Colombo M, et al. Clin Liv Dis 2001;5:109-125.

PHASES OF HBVALT, SEROLOGY AND HBV DNA

AcuteImmuneTolerant

eAg+Active

eAg-Active Inactive Resolved

HB

V D

NA

sAg

eAg Anti-E

Anti-s

Hoofnagle JH, et al. Hepatology 2007;45:1056-1075.

ALT


3


CHRONIC HBV – REVEAL STUDYHBV DNA AND HCC

20ce

4

8

12

16

um

ula

tive

In

cid

en

co

f H

CC

N=3,653

0

UD

HBV DNA at Baseline (copies/ml)

Cu

<104 104-105 105-106 >106

Chen CJ, et al. JAMA 2006;295:65-73.

HEPATITIS B VIRUSDISEASE STATUS AND TREATMENT

Immune T l t

ActiveGray

InactiveTolerant

ActiveZone

Inactive

ALT (IU/l) Elevated Elevated High/Normal Normal

HBsAg + + + +

HBeAg + +/- +/- -

Anti-HBe - +/- +/- +

HBV DNA (IU/ml) >1 Million>20,000 </> 20,000 <20,000

HBV DNA (IU/ml) >1 Million>2,000 </> 2,000 <2,000

Histology Normal Active Variable Normal

Treatment NO YES NO

Tong MJ, et al. Dig Dis Sci 2011;56:3143-3162.Keeffe EB, et al. Dig Dis Sci 2011;56:3106-3108.McMahon BJ. Am J Gastroenterol 2006;101 (suppl 1):S7-12.


4


CHRONIC HBV – REVEAL STUDYHBV DNA CIRRHOSIS AND HCC

16

S

4

8

12

RIS

K o

f CIR

RO

SIS

OR

HC

C

At what level of HBV DNAis the risk of progression and HCC significantly increased

0UD

R

HBV DNA (copies or IU (x1000)/ml)

<104 104-105 105-106 >106

<2 2-20 >20020-200

Chen CJ, et al. JAMA 2006;295:65-73.

CHRONIC HBVIMMUNE TOLERANT HBV

20

40

60

80

100

tient

s in

Im

mun

e le

rate

Sta

te (

%) • Normal ALT

• Very high HBV DNA• Absence of inflammation• None–minimal fibrosis• No treatment indicated• Likely to be ineffective• Monitor

0

20

0 10 20 30 40 50 60 70

Pat To

Months

Hui CK, et al. Hepatology 2007;46:395-401.

• 50% active over 5 years


5


IMMUNE TOLERANT HBVNATURAL HISTORY

Baseline 5 years

ALT (IU/l) 17 (6-24) 14 (4-23)

Log HBV DNA (IU/ml) 9.74 9.81

Inflammation Score 3 (1-6) 3 (1-5)

Fibrosis:

F0

F1

F2

15

33

0

16

31

1

Hui CK, et al. Hepatology 2007;46:395-401.

IMMUNE TOLERANT HBVLACK OF AN IMMUNE RESPONSE


6


IMMUNE SYSTEM AND HBVBALANCING THE IMMUNE RESPONSE

ImmuneResponse

HBVAntiviral

CHRONIC HBVLOSS OF IMMUNE TOLERANCE

12

0

3

6

9

12

HB

V D

NA

(IU

/ml)

150

200

T L)

3 log decline in HBV DNA

0

50

100

ALT

(IU

/L

TIME


7


CHRONIC HBVMONITORING

S ALT

E-antigen status

Serum ALTLiver function

HBV DNA

Every 3-6 months

Every 6-12 months ?Depending upon changes in:Serum ALTHBV DNA

AFPUltrasound

HBV DNA

Every 6-12 months

Lok AS, McMahon BJ. Hepatology 2009;50:1-36.

TREATMENT OF CHRONIC HBVGOALS OF THERAPY

E-antigen (+) E-antigen (-)g ( )

• Loss of E-antigen• Appearance of anti-E• Conversion to inactive status

g ( )

• Normalization in serum liver aminotransferases• Loss of detectable HBV DNA• Improvement in liver histology• Reduce the risk of hepatocellular carcinoma• Loss of S-antigen


8


TREATMENT OF CHRONIC HBVPEGINTERFERON

60HBV DNA < 2000IU

10

20

30

40

50

% o

f P

atie

nts

HBV DNA < 2000IUE Antigen LossNormal ALT

0

10

90/24 90/48 180/24 180/48

mcg per week/weeks of treatment

Liaw YF, et al. Hepatology 2011;54:1591-1599.

E-ANTIGEN SERCONVERSION EFFECT OF GENOTYPE

60

10

20

30

40

50

% o

f Pat

ient

s

PegIFN-2a

Lamivudine

0A B C D

GENOTYPE

Lau GKK, et al. N Engl J Med 2005;352:2682-2695.


9


CHRONIC HBV GENOTYPES DISTRIBUTION IN U.S. POPULATION

A27%D

10%

Other13% - Non-Asian

B19%C

31%

GKK Lau, et al. N Engl J Med 2005;352:2682-2695.

ANTI-VIRAL THERAPY FOR HBVSTUDY DESIGNS

Placebo

Lamivudine 100 QD

Entecovir 0.5 mg/dayRCT

Telbivudine 600 mg/day

Adefovir 10 mg/dayRCT

Telbivudine 600 mg/day

Adefovir 10 mg/dayRCT

Adefovir 10 mg QD

Tenofovir 300 mg QDRCT


10


TREATMENT OF CHRONIC HBV eAg(+)VIROLOGIC RESPONSE

100

40

60

80

% H

BV

DN

A (

-)

PlaceboLamivudineAdefovirEntecovirTelbivudineTenofo ir

0

20

% Tenofovir

Marcellin P, et al. N Engl J Med 2003;348:808-816Chang TT, et al. N Engl J Med 2006;354:1001-1010Chen HLY, et al. Ann Int Med 2007;147:745-754Marcellin P, et al. N Engl J Med 2008;359:2442-2455

TREATMENT OF CHRONIC HBV eAg(+)E-ANTIGEN SEROCONVERSION

50

%)

20

30

40

eroc

onve

rsio

n (%

PlaceboLamivudineAdefovirEntecovirTelbivudineTenofo ir

0

10

eAg

se Tenofovir

Marcellin P, et al. N Engl J Med 2003;348:808-816Chang TT, et al. N Engl J Med 2006;354:1001-1010Chen HLY, et al. Ann Int Med 2007;147:745-754Marcellin P, et al. N Engl J Med 2008;359:2442-2455


11


TREATMENT OF CHRONIC HBV eAg(-)VIROLOGIC RESPONSE

100

40

60

80

% o

f Pat

ient

s

PlaceboLamivudineAdefovirEntecovirTelbivudine

0

20

% TelbivudineTenofovir

Hadziyannis S, et al. N Engl J Med 2003;348:800-807Lai CL, et al. N Engl J Med 2006;354:1011-1020Chen HLY, et al. Ann Int Med 2007;147:745-754Marcellin P, et al. N Engl J Med 2008;359:2442-2455

TREATMENT OF CHRONIC HBV eAg (-)FLAIR WHEN TREATMENT STOPS

8

ml) Adefovir stopped

2

3

4

5

6

7

Cha

nge

in L

og

V D

NA

(co

pies

/m

Adefovir

ADV stopped

Adefovir stopped

0

1

0 12 24 36 48 60 72 84 96

HB

V

WEEKS

Hadziyannis SJ, et al. N Engl J Med 2005;352:2673-2681


12


CHRONIC HBVMONITORING TREATMENT

Serum ALT

E-antigen status

Liver functionHBV DNA

Every 3-6 months

Every 6 months in E-Antigen (+) Patients once HBV DNA undetectable

Every 3 months after E-Antigen lost

AFPUltrasound

Every 6-12 months

Lok AS, McMahon BJ Hepatology 2009;50:1-36.

Anti-E status Stop treatment 6-12 months afterappearance of Anti-E

TREATMENT OF CHRONIC HBVWHEN TO ALTER TREATMENT

Suboptimal Loss of

4

6

8

DN

A (

IU/m

l) Add orswitch

4

6

8

DN

A (

IU/m

l) Add orswitch

Response Response

0

2

0 2 4 6 8 10 12

HB

V

MONTHS

0

2

0 2 4 6 8 10 12

HB

V

MONTHS


13


TREATMENT OF CHRONIC HBV

RESISTANCE TO TREATMENT

Lamivudine – 70% after 5 years

Adefovir – 30% after 5 years

Telbivudine – 25% after 3 years

Entecovir – 1% after 5 years

Tenofovir – 0% after 5 years

Treat utilizing agents with the lowest rate of resistance unless cost is the primary issue

Use whatever availableMonitor responseChange therapy if resistance develops

TREATMENT OF CHRONIC HBVHEPATIC DECOMPENSATION

10

2

4

6

8

% o

f Pat

ient

s

Wild TypeYMDD mutationPlacebo

0

2

Increase CTP HCC

Liaw YF, et al. N Engl J Med 2004;351:1521-1531.


14


TREATMENT OF HBV WITH TENOFOVIRRESOLUTION OF FIBROSIS

100 E-Ag( )

E-Ag ( )

40

60

80

OF

PA

TIE

NT

S

Cirrhosis

Bridging

Portal

(+) (-)

N 266 375

Normalized ALT 73% 85%

HBV DNA <80 IU/mlITTOn treatment

65%97%

83%99%

HBeAg loss 49%

0

20

Baseline 5 Years

%

HBeAgseroconversion

40%

HBsAg loss 10%

HBsAgserconversion

8%

Marcellin P, et al. Lancet 2013;381:468-475

PREVENTING VERTICAL TRANSMISSIONPROPHYLAXIS WITH HIGH DNA

Telbivudine Placebo

N 35 35

Mother Log HBV DNA (IU/ml)At Randomization (Start of 3rd trimester)At birth

7.381.98

7.386.90

Infant at Birth:sAg (+)HBV DNA (+)

2 (4%)0 (0%)

8 (23%)3 (9%)

CQ Pan, et al. Clin Gastroenterol Hepatol 2012;10:520-526.

HBV DNA (+)Infant at day 28sAg (+)HBV DNA (+)

0 (0%)

0 (0%)0 (0%)

3 (9%)

3 (9%)3 (9%)


15


HBV REACTIVATIONCANCER CHEMOTHERAPY

50

10

20

30

40

% o

f P

atie

nts

Control

LAM

0

10

Reactivation Hepatitis Disruption of chemotherapy

Yeo W, et al. J Clin Oncol 2004;22:927-934.

HBV REACTIVATIONCANCER CHEMOTHERAPY

N 626 ti tN 626 patients

HBsAntigen 12%

Elevation in ALT 44%

Hepatotoxicity from chemotherapy drugs 32%

Malignant infiltration of liver 6%

Risk of reactivation:L hLymphomaE-Antigen positiveMale

Yeo W, et al. J Med Virol 2000;62:299-207


16


CHRONIC HBVPROPHYLAXIS FOR REACTIVATION

100010

200

400

600

800

2

4

6

8

ALT

(IU

/L)

BV

DN

A (

IU/m

l)

Tenofovir

Serologic status:sAg (+)E-antigen (-)

0

200

0

2

0 2 4 6 8 10 12 14 16 18 20

H

MONTHS

CHRONIC HBVSUMMARY

All patients with surface antigen have chronic HBVp g

All patients with chronic HBV are at risk for HCC

There is no such thing as a “healthy” carrier

The risk of HCC is related to HBV DNA

Although the immune tolerant state of HBV is associated with very high HBV DNA the vast majority of these

ti t h ld b b dpatients should be observed

Peginterferon is best utilized in patients without cirrhosis and HBV genotype A

Treatment reduces disease progression, HCC and leads to fibrosis regression


17


CHRONIC HBVANTI-VIRAL THERAPY

• Treat:Treat:• Active HBV: HBV DNA >2,000 - 20,000 IU/ml• Prior to starting cancer chemotherapy• Pregnancy with HBV DNA > 200,000 IU/ml• Use anti-viral agents with low resistance Tenofovir or Entecovir

• If use inferior therapy convert when resistance starts pyto emerge

• No treatment – Just monitor:• Immune tolerant HBV• Inactive HBV: HBV DNA < 2,000 – 20,000 IU/ml


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HEPATITIS B: EPIDEMIOLOGY AND...

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