hepatitis b: epidemiology and...
TRANSCRIPT
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
1
Mitchell L. Shiffman, MD, FACG
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.
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
2
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
3
Mitchell L. Shiffman, MD, FACG
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.
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
4
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
5
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
6
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
7
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
8
Mitchell L. Shiffman, MD, FACG
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.
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
9
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
10
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
11
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
12
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
13
Mitchell L. Shiffman, MD, FACG
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.
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
14
Mitchell L. Shiffman, MD, FACG
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%)
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
15
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
16
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
17
Mitchell L. Shiffman, MD, FACG
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
ACG's Hepatitis School - Nashville, TN Copyright 2013 American College of Gastroenterology
18