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3rd Paris Hepatitis Congress, 20/1/09
HBeAg-positive patient: Why do I
treat with nucleos/tide analogs?
Samuel S. Lee
University of Calgary
Calgary, Canada
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Speaker declarations
• Research support: Microgenix, Roche, Schering,
Johnson & Johnson, BMS, Gilead, Virochem,
Vertex, Merck, GSK, Novartis
• Consultant: Genentech, Microgenix, Roche, BMS,
Novartis, Virochem
• Speakers Bureau: Roche, Gilead
• Oui, I am a Francophile!
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A la recherche des nanas perdues
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Objectives of this presentation
•Why treat?
•Who and when to treat
•Nucleos/tide treatment
o efficacy
o monitoring
5
Multiple sexual partners is a risk factor
for HBV
6
Natural History of HBV
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“It was like déjà vu all over again”
- Yogi Berra
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NATURAL HISTORY OF CHRONIC HBV
•Initial stage of replicative immunetolerant, 15-25 yrs (N-ALT, HBeAg+)
•second stage replicating but immuneintolerant (‘immune clearance’), 5-25
yrs ( ALT, HBeAg+)
•third stage ‘nonreplicative’, generally
inactive, (N-ALT, HBeAg-)
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Natural history of chronic HBV carriage
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Disease Progression of HBV
REVEAL
REVEAL: Relationship between baseline
HBV-DNA level & cirrhosis risk
P value for log-rank test, <0.001
*From original enrolment of 3653, 69 diagnosed with cirrhosis
and 2 that died within 6 months of entry were removed.
Iloeje UH, et al. Gastroenterology 2006; 130:678–686.
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HBV and mortality from HCC and CLD:
Haimen City population-based study
• 9 of 35 townships in Haimen, China
• Original cohort from 1992-93
• 3464 HBsAg+ inception
• 701 excluded (mostly lost f/u), younger, nonpeasant men; 2763 for study
• HBV DNA from baseline; 1600cp/ml; <105; >105
• 447 total deaths; 231 HCC, 85 CLD
• 2003 survivor assessment: 1791 (3/4) agreed
Chen G et al. Am J Gastro 2006;101:1797
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Haimen City cohort: deaths due to HCC
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Chen G et al. Am J Gastro 2006;101:1797
Haimen City cohort: deaths due to CLD
Chen G et al. Am J Gastro
2006;101:1797
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Viral suppression in compensated
cirrhosis reduces HCC risk?
Disease Progression, %
25
Placebo (n = 215)
YMDDm (n = 209)
Wild-Type (n = 221)
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21%
Placebo
15
13%
YMDDm
10
WT
5
0
0
6
12
18
24
Time after Randomization (months)
Liaw et al. N Engl J Med. 2004;351:1521-1531.
30
5%
36
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HBV Natural history: conclusions
• Disease progression depends on several host and
viral factors
• Whether longterm viral suppression by Rx
decreases disease progression not proven
• Threshold levels of HBV DNA and ALT still unclear
• level of viremia is important
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Treatment
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HBV replication (see diagram)
• Virus penetrates hepatocyte
• dsDNA made in cytoplasm; cccDNA enters nucleus
• cccDNA template for RNA transcription
• pregenomic RNA + polymerase synthesizes negstrand DNA
• +strand DNA follows
• virus packaged in ER, released from hepatocytes
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Which HBeAg+ patients should be
treated with nuc analogs?
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Management considerations
• Majority of carriers do not die of liver disease
• 10-25% develop cirrhosis or HCC
• Unable to reliably predict complications
• Suppressive vs ‘curative’ Rx
• Rx: immunostimulant vs viral-suppressive
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More management considerations
•ALT levels
•Biopsy: yes or no?
•Biopsy results: inflammation, fibrosis levels
•HCV, HDV or HIV coinfected
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Algorithm for Selecting HBeAg-Positive
Patients for Treatment
HBeAg-positive
HBV DNA
< 20,000 IU/mL
ALT elevated
for 3-6 months
ALT
normal
 No treatment
 Monitor every
3 months with
ALT and HBV
DNA
 Rule out other
causes of liver
disease
HBV DNA
> 20,000 IU/mL
ALT
normal
 Monitor every
3 months
ALT
elevated
TREAT
 Consider biopsy if
> 35-40 years
 Treat if significant
disease
Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C.
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Role of Liver Biopsy
• Purpose: assess degree of liver damage and rule
out other causes of liver disease
• Most useful in persons who do not meet clear-cut
guidelines for treatment
• Decisions on liver biopsy should take into
consideration:
–
–
–
–
–
Age
Upper limits of normal for ALT
HBeAg status
HBV DNA levels
Other clinical features suggestive of chronic liver disease
Lok AS, McMahon BJ. Hepatology 2007;45:507-39.
or portal hypertension
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Monitoring on Rx
• Liver chemistry, hemogram, HBVDNA, HBeAg,
anti-HBe q-3mo
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Which nucleos/tide analog?
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Algorithm for Selection of Specific
Treatments for HBeAg-Positive Patients
HBeAg-positive
Low viral load
HBV DNA < 20 million IU/mL
High viral load
HBV DNA > 20 million IU/mL
 Standard interferon
 Entecavir
 Pegylated interferon
 Telbivudine
 Lamivudine
 Tenofovir
 Adefovir
 Entecavir
 Telbivudine
 Tenofovir
†Tenofovir
is not currently indicated for the treatment of
hepatitis B in Canada. Please consult the product
monograph for appropriate prescribing information.
Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C.
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% of patients with HBV DNA < 80 IU/mL
Relative Potency of Different Antivirals
at 48 to 52 Weeks of Therapy
100
93
91
88
90
80
70
76
73
69
71
63
60
60
49
50
38
40
30
20
13
10
0
Entecavir
Lamivudine
Telbivudine
HBeAg-positive
Lamivudine
Adefovir
Tenofovir†
HBeAg-negative
Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir† has been
compared with adefovir in two separate randomized controlled trials.
Adapted from: 1. CASL Consensus Guidelines.. Can J Gastroenterol 2007;21(Suppl C):5C-24C; 2. Chang TT, et al. N Engl J Med 2006;354:1001-10;
3. Lai CL, et al. N Engl J Med 2006;354:1011-20; 4. Lai CL, et al. Gastroenterology 2005;129:528-36; 5. Marcellin P, et al. Presented at the 58th AASLD; Boston, MA,
November 2-6, 2007; 6. Heathcote J, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007.
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Relative Potency of Different Antivirals
at 48 to 52 Weeks of Therapy
Entecavir
Lamivudine
Telbivudine Lamivudine
Adefovir
Tenofovir
Mean log10 decline in HBV DNA
0
-1
-2
-3
-3.3
-4
3.7-
3.8-
-5
4.4-
-4.66
5.2-
5.2-
-6
-7
4.5†
-5.5
-5.9
-6.5
-6.98
-8
HBeAg-positive
anti-HBe-positive
Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir† has been
compared with adefovir in two separate randomized controlled trials.
Adapted from: 1. CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C; 2. Chang TT, et al. N Engl J Med 2006;354:1001-10;
3. Lai CL, et al. N Engl J Med 2006;354:1011-20; 4. Lai CL, et al. Gastroenterology 2005;129:528-36; 5. Marcellin P, et al. Presented at the 58th AASLD; Boston, MA,
November 2-6, 2007; 6. Heathcote J, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007.
HBeAg Seroconversion Rates with
Hepatitis B Antiviral Therapy*
Duration of
treatment
HBe seroconversion
rate
Standard interferon
16-24 weeks
33% (HBeAg loss)1
Pegylated interferon
24-48 weeks
29-32%2-4
Lamivudine
1 year
3 years
17-20%5-8
40%9
Adefovir
1 year
3 years
12%10
43%11
Entecavir
1 year
3 years
21%8
39%12
Telbivudine
1 year
2 years
22%13
33%14
48 weeks
21%15
Tenofovir
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Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir† has been
compared with adefovir in two separate randomized controlled trials.
Adapted from CASL Consensus Guidelines. Sherman M, et al. Can J Gastroenterol 2007;21(Suppl C):5C-24C. 1. Wong DK, et al. Ann Intern Med 1993;119:312-23; 2. Lok AS, et al.
Gastroenterology 1987;92:1839-43; 3. Cooksley WG, et al. J Viral Hepat 2003;10:298-305; 4. Lau GK, et al. N Engl J Med 2005;352:2682-95.; 5. Lai CL, et al. N Engl J Med 1998;339:618.; 6. Dienstag JL, et al. N Engl J Med 1999;341:1256-63; 7. Schalm SW, et al. Gut 2000;46:562-8; 8. Chang TT, et al; BEHoLD AI463022 Study Group. N Engl J Med 2006;354:1001-10;
9. Chang TT, et al. J Gastroenterol Hepatol 2004;19:1276-82; 10. Marcellin P, et al; N Engl J Med 2003;348:808-16; 11. Hadziyannis SJ, et al; Adefovir Dipivoxil 438 Study Group.
Gastroenterology 2006;131:1743-51; 12. Chang TT, et al. Hepatology 2006;44(Suppl 1):66A. (Abst); 13. DiBisceglie A, et al; Study Group The GLOBE. Hepatology 2006;44(Suppl
1):230A. (Abst) 14. van Bommel F, et al. Hepatology 2006;44:318-25;
15. Heathcote J, et al. 58th AASLD; Boston, MA, November 2-6, 2007.
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Algorithm for the Management of
Hepatitis B Cirrhosis
HBV DNA
(PCR)
HBV DNA
≥ 2000 IU/mL
HBV DNA
< 2000 IU/mL
 Treat with entecavir,
telbivudine or tenofovir
 Consider combination
therapy
 May choose to treat or
observe
 Treat with entecavir,
telbivudine, adefovir,
tenofovir
 Consider combination
therapy
Patients with cirrhosis who are on therapy
should not have therapy withdrawn due to
concerns of a hepatitis flare and decompensation
Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C.
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CASL Consensus recommendations
• Resistance linked to insufficient early viral
suppression; check HBVDNA at 6 mos, consider
switch if detectable
• Naïve: LAM only for cost, and LVL. ADV <200,000
IU/ml. ETV, Telbivudine, TDF for HVL
• 6-12 months consolidation Rx after anti-HBe+
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My preferences
• HBeAg+: PEG-IFN x 1 yr in younger, low viral load
(106 IU), and increased ALT
• Start NA if PEG-IFN unsuccessful
• NA for older, HVL, cirrhosis, longterm suppression
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Conclusions
• Selection of pts for Rx based on viral load, ALT,
biopsy, age and other factors
• Cirrhosis: once you start, do not stop (unless
HBsAg loss)
• Both IFN and NA have roles in Rx
• NA choice tailored according to cost/benefit and
viral load