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Can One Pill A Day Keep Hepatitis B Away?
Scott K. Fung, MD, FRCPCToronto General Hospital
University of Toronto
November 30, 2009 TGH
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Learning Objectives
• To discuss new ‘normal’ values for ALT and define significant HBV DNA levels
• To briefly review antiviral treatment options for chronic HBV infection in 2009
• To illustrate indications for treatment of chronic hepatitis B and monitoring strategies using case studies
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Quiz
1 2 3 4
A. Wilson diseaseB. Hereditary hemochromatosisC. Chronic hepatitis B and HCCD. Fatty liver
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Liver Disease in Canada
HBV
HCVNAFLD
Alcohol
Others
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Age-Standardized MortalityCause of Death 2001* 2003* 2005*
Chronic liver disease/ cirrhosis 6.5 6.4 6.1
Renal failure 8.3 8.5 8.3
Diabetes mellitus 19.3 20.5 19.1
Heart disease 143.1 133.3 121.5
Malignant neoplasm 178.7 175.6 170.3
*Rate per 100,000 population, both sexes
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Hepatitis B and HCC in Canada• Rate of HCC is rising in Canada and
most Western countries• Related to immigration from HBV
endemic parts of the world• No accurate data on overall prevalence
of HBV and HCC in Canada• Estimated 1981-2005 using 2006
National census
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Hepatitis B and HCC in Canada• Between 1981-2005, Canada accepted • 4 million new immigrants• 90% from HBV endemic areas (>3-7%)• HBsAg+ immigrants = 209,401 individuals• HBsAg+ nonimmigrants = 182,000 indiv.• Overall prevalance in Canadian pop =1.3 %• Limited impact of HBV vaccine • ~500 immigrants will develop HCC per yr (0.22/100,000/yr)
Leber et al, Can J Gastro 2009
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All HBV Carriers are Potential Treatment Candidates
Slow down
Observe closely
May need Rx later
Stop
Rx not indicated
Go ahead with Rx
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Stages of Chronic Hepatitis B Infection
Lok, Gastroenterology 2007
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HBeAg-negative CHB
• Viral Load >3–4 log IU/mL
• HBeAg-negative– pre-core / core promoter
mutant
• ALT intermittently abnormal
• Biopsy– inflammation intermittent– fibrosis progression
• Risk of complications (cirrhosis/ HCC) higher
Adapted from Yim & Lok, Hepatology 2006; 43: S173
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Disease Progression
Chronic hepatitis
Cirrhosis
Liver Failure
Death or OLTx20%
15-40%
HCC
10-20%
EASL Consensus Guidelines. J Hepatol 2003 Lok et al, Hepatology 2004
Age 40 50 60 Years
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12
Complications of HBV
Ascites
Varices
HCC
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Danger Signs: Time To Worry
CirrhosisINR
Bilirubin
Albumin
Platelets
Confusion
Jaundice
GI bleeding
Ascites
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HBV DNA
New unit of measurement for HBV DNA = logs IU/ml
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HBV Viral load in Log Scale
• Log scales simplify large numeric differences in HBV DNA values
• Error of the test = 0.5 log IU • Tripling of viral load = within the error of
the test• Following trends in HBV DNA important• If in doubt, repeat testing to confirm
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How High Can You Go?
1 = 100 = 1E0
10 = 101 = 1E1
100 = 102 = 1E2
1,000 = 103 = 1E3
10,000 = 104 = 1E4
100,000 = 105 = 1E5
1,000,000 = 106 = 1E6
10,000,000 = 107 = 1E7
100,000,000 = 108 = 1E8
1,000,000,000 = 109 = 1E9
10,000,000,000 = 1010=1E10
Low
Medium
High
HB
eAg
-neg
HB
eAg
-po
s
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REVEAL HBV
Iloeje et al, JAMA 2006 Chen et al, Gastroenterology 2006
Cirrhosis
HCC
HCC in HBeAg-negative patients with normal ALT
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HBV DNA
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HBV DNA Report
4.3 E+7
43,000,000
7.4 log
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20
“Normal” ALT Levels
Yuen et al, Gut 2005
Upper Limit of Normal
Male 53 U/L
Female 31 U/L
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ALT and Liver Mortality
Tai et al, Hepatology 2009
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ALT Normal Values
• Current upper limit of normal too high
• New standard for ALT
– Male <30 U/L
– Female <19 U/L
• Normal ALT does not exclude significant liver disease
• Patients should not be denied antiviral treatment based on normal ALTSherman et al, Can J Gastro 2007
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Histology in HBeAg-positive CHB
Yang et al, Chinese J Dig Dis 2002; 3: 150
Note: This study population consisted of males over the age of 30
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Beware ‘Normal’ ALT
Nguyen et al, Am J Gastro 2009
Predictors of Sig. Fibrosis:
Older Age
Fluct. ALT
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HBeAg-positive Patients
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
HBeAg-positive
No treatment. Monitor every
3 months with ALT and
HBV DNA
Rule out other causes of liver
disease
Monitor ALT every 3 months. Consider biopsy
if age >35–40 years, and treat
if significant disease
Treat
ALT normalALT normalALT elevated
for 3–6 monthsALT elevated
for 3–6 months
HBV DNA >20,000 IU/mL(>105,200 copies/mL)
HBV DNA <20,000 IU/mL(<105,200 copies/mL)
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
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Selection of Specific Agents for HBeAg-positive CHB
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Standard interferon
Pegylated interferon
Adefovir
Entecavir*
Tenofovir*†
Entecavir*
Tenofovir*†
HBV DNA <20 million IU/mL(<105.2 million copies/mL)
HBV DNA >20 million IU/mL(>105.2 million copies/mL)
HBeAg-positive
*If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine†Approved since publication of the guidelines
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
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HBeAg-negative Patients
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
HBeAg-negative
No treatment. Monitor every 3 months for 1–2 years with ALT and HBV DNA
Rule out other causes of liver
disease
Monitor ALT every 3 months, or consider
biopsy, since ALT often fluctuates. Treat if
significant disease. Long-term treatment required (oral agents)
Treat. Long-term treatment required
(oral agents)
ALT normalALT normal ALT elevated ALT elevated
HBV DNA >2,000 IU/mL(>10,520 copies/mL)
HBV DNA <2,000 IU/mL(<10,520 copies/mL)
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Selection of Specific Agents for HBeAg-negative CHB
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Pegylated interferon
Adefovir
Entecavir*
Tenofovir*†
Entecavir*
Tenofovir*†
HBV DNA <20 million IU/mL(<105.2 million copies/mL)
HBV DNA >20 million IU/mL(>105.2 million copies/mL)
HBeAg-negative
*If Entecavir or Tenofovir not available, use Telbivudine or Lamivudine†Approved since publication of the guidelines
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
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Comparison of Oral Therapy for Chronic Hepatitis B
Lamivudine Adefovir Entecavir* Telbivudine Tenofovir*
RelativeAntiviralPotency
++ ++ ++++ +++ ++++
Resistance High Low Very low Intermediate Very low
* Recommended as first-line therapy for HBV
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HBV Treatment in Ontario in 2009Public Formulary Private Formulary
Treatment-Naive(1st Line)
Tenofovir*Entecavir*LamivudineStandard IFN-α
AdefovirTenofovirTenofovir + FTCTelbivudinePEG-IFNStandard IFNLamivudine
Treatment-Experienced(2nd Line)
Adefovir**Tenofovir**├
EntecavirTenofovirTenofovir + FTCTelbivudinePEG-IFNStandard IFNLamivudine
* Cirrhosis with DNA > 6 log IU/ml** LAM virologic breakthrough and F3/F4 fibrosis or LAM-resistant HBV├ Suboptimal response to LAM after 6 months
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On Treatment Monitoring*
•Frequency can be decreased once stable on treatment (HBV DNA undetectable)
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Patterns of Response
Lok et al. Hepatology. 2007;45:507-539.
1 log
Ch
ang
e in
HB
V D
NA
(lo
g10
IU
/mL
)
0
-1.0
-2.0
-3.0
-4.0
1.0
Nadir
Virologic breakthrough
Antiviral Drug
Mos
60 12 18
Primary nonresponse
Suboptimal response
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HBV Resistance Pathways
R
LAM-R
180/204 Pathway
S
LdT-R
236 Pathway
ADV-R
R
ETV-R
Pre-existing
resistant mutants
LAM ADV
184/202/250 Pathway
181 Pathway
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Endpoints of Therapy
HBsAgClearance
HBV DNASuppression
HBeAgLoss
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Regression of Fibrosis
Pre-Tx
Post-Tx
Adefovir
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Antiviral Therapy for Advanced Liver Disease
Liaw et al, NEJM 2004
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True Goals of Therapy
Lower Mortality
PreventHCC and Cirrhosis Decrease
Liver Transplant
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New Kid on the Block:
Tenofovir
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RA
ND
OM
IZA
TIO
N 2
:1 Tenofovir 300 mg
Adefovir 10 mg
Open-label8 Years
Week 240Liver Biopsy
Week 48
Liver BiopsyPre-treatment Liver Biopsy
Double Blind
Week 72
Tenofovir 300 mg
Tenofovir 300 mg
Marcellin P et al., NEJM 2008
Study 102 N=250Study 103 N=176
Study 102 N=125Study 103 N=90
Tenofovir for Chronic Hepatitis B
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Per
cent
age
(%)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
250TDF-TDF N= 250250 245245245 243243243 248248248 247247247 242242242 243243243 234234234125ADV-TDF N= 125125 125125125 124124124 120120120 123123123 123123123 122122122 122122122
% Patients with HBV DNA <400 c/mL
89%
91%[P=0.672]
One patient was <400 copies/mL on FTC + TDF at Week 96.Long Term Evaluation ITT Analysis: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL excluded (N= 7)
Randomized Double Blind Open Label
Marcellin P, et al., AASLD 2009; Oral # 146.
HBeAg (-) Study 102
99%100%
[P=0.166]
On-Treatment Analysis
~ 89%Patient Retention
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Per
cen
tage
(%)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 8 16 24 32 40 48 56 64 72 80 88 96
176TDF-TDF N= 176176 174174174 170170170 172172172 171171171 168168168 164164164 16616616690ADV-TDF N= 9090 898989 888888 888888 909090 898989 878787 868686
78%78%
[P=0.801]
Five patients were <400 copies/mL at Week 96 on FTC + TDF.Long Term Evaluation: Patients who discontinued for administrative reasons with HBV DNA <400 copies/mL had their data excluded for visits after discontinuation (N = 8.)
% Patients with HBV DNA <400 c/mL
Randomized Double Blind Open Label
HBeAg (+) Study 103
Heathcote J, et al., AASLD 2009; Oral # 153.
89%85%
[P=0.374]
On-Treatment Analysis
~ 86%Patient Retention
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77%
61%
P= 0.014
Per
cent
age
(%)
0
10
20
30
40
50
60
70
80
90
100
Weeks on Study
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76
176TDF N= 176176 165165165 160160160 146146146 90ADV N= 90 90 85 85 85 84 84 84 82 82 82
Randomized Double Blind Open Label TDF
ALT Normalization
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HBeAg Loss & Seroconversion
HBeAg Loss HBeAg Seroconversion
TDF (Wk 48); TDF-TDF (Wk 64)
ADV (Wk 48); ADV-TDF (Wk 64)
0
5
10
5
20
25
30
22%
18%
P=NS
27%
21%
P=NS
Week 48 Week 64
% P
atie
nts
0
5
10
15
20
25
30
26%
21%
P=NS
21%
18%
P=NS
Week 48 Week 64
% P
atie
nts
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Cumulative Probability* of HBsAg Loss in HBeAg (+) Patients
Cum
ula
tive
Pro
babi
lity
Fun
ctio
n E
stim
ate
0.00
0.05
0.10
Weeks on Study
0 12 24 36 48 64 80 96
*Kaplan-Meier
6% TDF-TDF6% ADV-TDF
Switch to Open label TDF
Heathcote, et al., EASL 2009; Poster #909.
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Resistance Surveillance
• Loss of viral response in 2 patients between Weeks 48 and 72 related to non-adherence documented in both patients
• Viremic patients received combo TDF + FTC
• Neither patient developed genotypic changes associated with AVR
• No genotypic changes associated with AVR were detected up to 72 weeks
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Case 1: To Be or Not To Be
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Mr. W.
• 48 year old Chinese male patient
• Known to be HBV ‘carrier’
• Otherwise healthy
• History of liver CA in older brother
• On no prescription medications or herbals
• Routine diagnosis of HBV in China
• No previous ‘Western’ medication for HBV
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Labs
ALT
Total bilirubin
AST
INR
Albumin
ALPHb
WBC Platelets
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Baseline Bloodwork
35
12
40
0.89
42
97148
9.7 138
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HBV Testing
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3 Months Later
75
11
55
1.07
35
99133
4.0 132
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Assessment of Fibrosis
Liver Biopsy:
A1F4
Abdominal U/S:
Coarse liver
Spleen sl. enlarged
FibroScan:
16 kPa
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Clinical Course on TDF Month ALT AST ALP Total BR Albumin INR
0 75 55 99 11 35 1.07
3 103 86 90 15 38 1.06
6 68 43 95 10 40 0.96
9 45 31 87 11 39 0.9
12 19 21 85 12 43 0.9
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Clinical Course
0
1
2
3
4
5
6
7
0 3 6
HBV
DN
A l
og I
U/m
l
HBV DNA
HBsAg+ HBsAg+
HBeAg- HBeAg-
Tenofovir 300 mg po od
Months on treatment
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Case 2:To Treat Now or Later?
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Miss L.
• 27 year old teacher born in Canada
• Family history of HBV (mother)
• Healthy, seasonal allergies
• Meds: Claritin tabs occasionally
• Married but no children
• Contemplating pregnancy in 1-2 years
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Baseline Bloodwork
25
5
20
0.91
40
68122
8.7 267
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HBV TestingHBsAg +
HBeAg +
Anti-HBe -
HBV DNA 3.5 E+9 IU/ml
3,500,000,000 IU/ml
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3 Months Later
20
7
18
0.89
39
68119
7.6 253
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Assessment of Fibrosis
Liver Biopsy:
A1F0
Abdominal U/S:
Hemangioma segment 6
FibroTest:
0.35
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6 Months Later
78
7
16
0.91
40
65126
6.5 237
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Question
She is wondering about treatment prior to
starting a family. What would you suggest?
1. Standard IFN-alpha x 20 weeks
2. Long-term lamivudine monotherapy
3. Entecavir x 1 year
4. Pegylated IFN-alpha x 6-12 months
5. Adefovir 10 mg po od
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Course on PEG-IFN
PEG-IFN
0
1
2
3
4
5
6
7
8
9
10
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
HB
VD
NA
(lo
g c
/ml)
0
10
20
30
40
50
60
70
80
90
100
AL
T (
IU/L
)
HBVDNA
ALT
HBeAg + +
Anti-HBe - -
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Question
HBeAg seroconversion was not achieved.
What would you suggest now?1. Observe off therapy for the next 6 months
2. Start oral antiviral therapy before pregnancy
3. Repeat a liver biopsy to assess response
4. Retreat with a different PEG-IFN
5. Start combination oral agents
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10 Months Post PEG
22
9
16
0.91
35
100120
6.5 226
Miss L is pregnant, 12 weeks GA
HBeAg + HBV DNA 8.6 E+8 IU/ml
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Question
How can you manage HBV infection
during pregnancy?1. Consult high-risk obstetrician
2. Start entecavir in 1st trimester
3. Start adefovir in 2nd trimester
4. Treat if HBV DNA > 7 logs in 3rd trimester
5. Check HBV DNA only post-partum
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Question
Which of the agents can be considered
for use during pregnancy?1. Entecavir
2. Tenofovir
3. Clevudine
4. Telbivudine
5. Lamivudine
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Summary
• HBV DNA quantitation is the new standard of care for chronic hepatitis B• Disease progression
• Risk of cirrhosis and HCC
• Beware ‘normal’ ALT • Does not exclude progressive liver damage• Low platelet count is a clue
• Antiviral treatment reduces complications– Use potent agents with low rates of resistance
– Long term therapy is required
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Questions?
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Can One Pill A Day Keep Hepatitis B Away?
Scott K. Fung, MD, FRCPCToronto General Hospital
University of Toronto
November 30, 2009 TGH