HBV NATURAL HISTORY AND MANAGMENTs3.gi.org/meetings/mn2016/16ACG_Hep_School_Midwest_0001.pdf ·...

Mitchell L. Shiffman, MD, FACG

Liver Institute of VirginiaEducation, Research and Treatment for Patients with Liver Disease

IVerBon SecoursHealth System

HBVNATURAL HISTORY AND MANAGMENT

Mitchell L. Shiffman, MD, FACGDirectorLiver Institute of VirginiaBon Secours Health SystemRichmond and Newport News, Virginia

IVer

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 or

from contaminated medical equipment in their homeland

African Americans account for 20% of persons with chronic infection

ACG 2016 Midwest Hepatitis School Copyright 2016 American College of Gastroenterology

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ACUTE HBV INFECTIONAGE AT RISK

0

5

10

15

20

25

0-14 15-19 20-29 30-39 >40

AGE (years)

Ca

ses/

10

0,0

00

ML ShiffmanClin Liv Dis 2010; 14:75-91.

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ACUTE HBVSPONTANEOUS RESOLUTION

TIME

AL

T (

IU/L

)

HBV DNAHBVeAgHBVsAgHBVcAb IgMHBVcAb

Anti-HBs

Window

Anti-HBe


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RISK OF DEVELOPING CHRONIC HBVAGE AND SYMPTOMS

ML ShiffmanClin Liv Dis 2010; 14:75-91.

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CHRONIC HBVIMMUNE TOLERANT STATE

HBV DNAHBVeAg

HBVcAb IgMHBVcAb

HBVsAg

• Normal ALT• Very high HBV DNA• Absence of inflammation• None–minimal fibrosis• No treatment indicated


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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

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

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CHRONIC HBVLOSS OF IMMUNE TOLERANCE

TIME

Decline in

HBV DNA

Increase inSerum ALT

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

• Do not treat• Monitor• 50% will convert

to active HBV in 5 years


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CHRONIC HBVSPONTANEOUS LOSS OF eAg

HBV DNAHBVeAg

HBVcAb IgMHBVcAb

HBVsAgAnti-HBVe

IgM

Anti-Hbcore IgMMay become positive

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CHRONIC HEPATITIS B VIRUSSPONTANEOUS SEROCONVERSION

0

10

20

30

40

50

60

0 1 2 3 4 5 6

YEARS

% o

f P

atie

nts

YF Liaw et al.Gastroenterol 1983; 84:216-219.

Factors associated with seroconversion: Duration of infectionBUT NOT: HBV DNA level Serum ALT Histology


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CHRONIC HBV SEROCONVERSIONFIBROSIS RESOLUTION

• Fibrosis progression occurs with active HBV

• Fibrosis regression occurs after seroconversion

• Factors which affect the rate of fibrosis regression:• Decline in HBV DNA• Decline in ALT• Patient age• HBV genotype

CK Hui et al.Hepatology 2007; 46:690-698.

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CHRONIC HBVWHAT IS E-NEGATIVE ACTIVE HBV

• E-gene located in the pre-core region of HBV

• Not necessary for replication• Target of the immune response to

inactivate HBV

Core geneE-gene

E-antigenCore

antigen

Core geneE**gene

Coreantigen

• Mutation of the E-gene• No detectable E-antigen• Does not prevent replication• Prevents the immune response from

inactivating HBV

S Ahn et alGastroenterol 2003; 125:1370-1378.


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E-ANTIGEN NEGATIVE CHRONIC HBVEVOLUTION

Chronic HBVsAg (+)

E-Antigen (+)

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

Inactive HBV

JH Hoofnagle et al.

Hepatology 2007; 45:1056-1075.

Seroconversion of E-Antigen (+) Strain:

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Chronic HBVsAg (+)

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


Inactive HBV

E antigen (-)Anti-E (-)

Active E-negative HBV

JH Hoofnagle et al.

Hepatology 2007; 45:1056-1075.



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Chronic HBVsAg (+)

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


Inactive HBV

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

Active E**negative HBV

E antigen (-)Anti-E (-)

Active E-negative HBV

JH Hoofnagle et al.

Hepatology 2007; 45:1056-1075.


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CHRONIC HBVREACTIVATION OF INACTIVE HBV

HBV DNA

HBVcAb IgMHBVcAb

HBVsAgAnti-HBVe

Risk Factors for Reactivation• Immune suppression• Cancer Chemotherapy


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HEPATITIS B VIRUSOTHER MUTATIONS

• Surface mutation• Core mutation

• Lamivudine• Adefovir

HBsAgAnti-HB

coreAnti-HBsurface

HBVDNA

Surface Antigen - + + +

Core + - - +

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HEPATITIS B VIRUSGENOTYPES

Genotype

A North America, Northern Europe, Central Africa

B Asia

C Asia

D Mediterranean, Middle East, South Asia

E Western Africa

F South and Central America

G France, USA

CT Wai, RJ FontanaClin Liver Dis 2004; 8:321-352.


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HCC IN PATIENTS WITH CHRONIC HBVIMPACT OF IMMUNE STATUS

Total number

of HCCsM Colombo et al.

Clin Liv Dis 2001; 5:109-125.

Inactive

eAg +/-

eAg -

HCCStatus

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CHRONIC HBV – REVEAL STUDYHBV DNA CIRRHOSIS AND HCC

<104 104-105 105-106 >106

<2 2-20 >20020-200

CJ Chen et al.

JAMA 2006; 295:65-73.

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


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CHRONIC HBVMONITORING

E-antigen status

AFPUltrasound

Serum ALTLiver function

HBV DNAEvery 3-6 months

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

Every 6-12 months

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

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CHRONIC HEPATITIS B VIRUSPHASES

Immune Tolerant

ActiveGray

ZoneInactive

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

HBsAg + + + +

HBeAg + +/- +/- -

Anti-HBe - +/- +/- +

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

>2,000

</>20,000

</>2,000

<20,000

<2,000

Histology Normal Active Variable Normal

Treatment NO YES NO

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


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HBV NATURAL HISTORY AND MANAGMENTs3.gi.org/meetings/mn2016/16ACG_Hep_School_Midwest_0001.pdf ·...

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