Transcript Hepatitis B - Division of Infectious Diseases

Can One Pill A Day Keep
Hepatitis B Away?
Scott K. Fung, MD, FRCPC
Toronto General Hospital
University of Toronto
November 30, 2009
TGH
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
Quiz
1
2
A.
B.
C.
D.
3
Wilson disease
Hereditary hemochromatosis
Chronic hepatitis B and HCC
Fatty liver
4
Liver Disease in Canada
HBV
Others
Alcohol
NAFLD
HCV
Age-Standardized Mortality
Cause 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
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
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
All HBV Carriers are Potential
Treatment Candidates
Stop
Slow down
Rx not indicated
Observe closely
May need Rx later
Go ahead with Rx
Stages of Chronic Hepatitis B Infection
Lok, Gastroenterology 2007
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
Disease Progression
Chronic
hepatitis
HCC
10-20%
Cirrhosis
Liver
Failure
15-40%
Death or
OLTx
20%
Age
40
EASL Consensus Guidelines. J Hepatol 2003
Lok et al, Hepatology 2004
50
60
Years
Complications of HBV
HCC
Ascites
Varices
12
Danger Signs: Time To Worry
INR
Bilirubin
Albumin
Platelets
Cirrhosis
Confusion
Jaundice
GI bleeding
Ascites
HBV DNA
New unit of measurement for HBV DNA = logs IU/ml
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
HBeAg-neg
How High Can You Go?
HBeAg-pos
1 = 100 = 1E0
10 = 101 = 1E1
Low
2
100 = 10 = 1E2
1,000 = 103 = 1E3
10,000 = 104 = 1E4
Medium
100,000 = 105 = 1E5
1,000,000 = 106 = 1E6
10,000,000 = 107 = 1E7
High
100,000,000 = 108 = 1E8
1,000,000,000 = 109 = 1E9
10,000,000,000 = 1010=1E10
REVEAL HBV
Cirrhosis
HCC
HCC in HBeAg-negative patients with normal ALT
Iloeje et al, JAMA 2006
Chen et al, Gastroenterology 2006
HBV DNA
HBV DNA Report
4.3 E+7
43,000,000
7.4 log
“Normal” ALT Levels
Upper Limit of Normal
Male 53 U/L
Female 31 U/L
Yuen et al, Gut 2005
20
ALT and Liver Mortality
Tai et al, Hepatology 2009
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 ALT
Sherman et al, Can J Gastro 2007
Histology in
HBeAg-positive CHB
Note: This study population consisted of males over the age of 30
Yang et al, Chinese J Dig Dis 2002; 3: 150
Beware ‘Normal’ ALT
Predictors of
Sig. Fibrosis:
Older Age
Fluct. ALT
Nguyen et al, Am J Gastro 2009
HBeAg-positive Patients
HBeAg-positive
HBV DNA <20,000 IU/mL
(<105,200 copies/mL)
ALT normal
No treatment.
Monitor every
3 months
with ALT and
HBV DNA
HBV DNA >20,000 IU/mL
(>105,200 copies/mL)
ALT elevated
for 3–6 months
Rule out other
causes of liver
disease
ALT normal
Monitor ALT
every 3 months.
Consider biopsy
if age >35–40
years, and treat
if significant
disease
ALT elevated
for 3–6 months
Treat
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Selection of Specific
Agents for HBeAg-positive CHB
HBeAg-positive
HBV DNA <20 million IU/mL
(<105.2 million copies/mL)
HBV DNA >20 million IU/mL
(>105.2 million copies/mL)
Standard interferon
Entecavir*
Pegylated interferon
Tenofovir*†
Adefovir
Entecavir*
Tenofovir*†
*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
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
HBeAg-negative Patients
HBeAg-negative
HBV DNA <2,000 IU/mL
(<10,520 copies/mL)
HBV DNA >2,000 IU/mL
(>10,520 copies/mL)
ALT normal
ALT elevated
ALT normal
ALT elevated
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)
Based on a conversion factor of 1 IU/mL = 5.26 copies/mL
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Selection of Specific
Agents for HBeAg-negative CHB
HBeAg-negative
HBV DNA <20 million IU/mL
(<105.2 million copies/mL)
HBV DNA >20 million IU/mL
(>105.2 million copies/mL)
Pegylated interferon
Entecavir*
Adefovir
Tenofovir*†
Entecavir*
Tenofovir*†
*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
Sherman et al, Can J Gastroenterol 2007; 21(Suppl. C): 5C–24C
Comparison of Oral Therapy for
Chronic Hepatitis B
Relative
Antiviral
Potency
Lamivudine
Adefovir
Entecavir*
Telbivudine Tenofovir*
++
++
++++
+++
Low
Very low
Intermediate Very low
Resistance High
* Recommended as first-line therapy for HBV
++++
HBV Treatment in Ontario in 2009
Public Formulary
Treatment-Naive
(1st Line)
Treatment-Experienced
(2nd Line)
Tenofovir*
Entecavir*
Lamivudine
Standard IFN-α
Adefovir**
Tenofovir**├
Private Formulary
Adefovir
Tenofovir
Tenofovir + FTC
Telbivudine
PEG-IFN
Standard IFN
Lamivudine
Entecavir
Tenofovir
Tenofovir + FTC
Telbivudine
PEG-IFN
Standard IFN
Lamivudine
* 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
On Treatment Monitoring*
ALT/AST/Bilirubin
Every 3 months
CBC/ INR/ Ca-MgPhos/ CK/ Creat
HBeAg/Anti-HBe
Every 3 months
Every 3-6 months
HBsAg/ Anti-HBs
Every 6 months
HBV DNA
Every 3 months
Resistance Testing
As needed
•Frequency can be decreased once stable on treatment
(HBV DNA undetectable)
Patterns of Response
Antiviral Drug
Change in HBV DNA
(log10 IU/mL)
1.0
0
Primary
nonresponse
Virologic
breakthrough
-1.0
Suboptimal
response
-2.0
-3.0
1 log
Nadir
-4.0
0
6
12
Mos
Lok et al. Hepatology. 2007;45:507-539.
18
HBV Resistance Pathways
184/202/250 Pathway
S
Pre-existing
ETV-R
resistant mutants
R
180/204
Pathway
R
236 Pathway
181 Pathway
LAM-R
LdT-R
ADV-R
Endpoints of Therapy
HBsAg
Clearance
HBV DNA
Suppression
HBeAg
Loss
Regression of Fibrosis
Pre-Tx
Adefovir
Post-Tx
Antiviral Therapy for
Advanced Liver Disease
Liaw et al, NEJM 2004
True Goals of Therapy
Lower
Mortality
Prevent
HCC and
Cirrhosis
Decrease
Liver
Transplant
New Kid on the Block:
Tenofovir
Tenofovir for Chronic Hepatitis B
8 Years
RANDOMIZATION 2:1
Double Blind
Open-label
Tenofovir 300 mg
Tenofovir 300 mg
Study 102 N=250
Study 103 N=176
Adefovir 10 mg
Tenofovir 300 mg
Study 102 N=125
Study 103 N=90
Pre-treatment
Liver Biopsy
Marcellin P et al., NEJM 2008
Week 48
Liver Biopsy
Week 72
Week 240
Liver Biopsy
HBeAg (-) Study 102
% Patients with HBV DNA <400 c/mL
Randomized Double Blind
Open Label
100
91% [P=0.672]
89%
90
Percentage (%)
80
70
On-Treatment Analysis
60
99% [P=0.166]
100%
50
40
30
20
~ 89%
Patient Retention
10
0
0
8
16
24
32
40
48
56
64
72
80
88
96
W eeks on Study
TDF-TDF
ADV-TDF
N=
N=
250
125
245
125
243
124
248
120
247
123
242
123
243
122
234
122
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)
Marcellin P, et al., AASLD 2009; Oral # 146.
HBeAg (+) Study 103
% Patients with HBV DNA <400 c/mL
100
Open Label
Randomized Double Blind
90
78% [P=0.801]
78%
Percentage (%)
80
70
60
50
On-Treatment Analysis
40
89% [P=0.374]
85%
30
20
10
~ 86%
Patient Retention
0
0
16
8
24
40
32
48
56
64
72
80
88
96
W eeks on Study
TDF-TDF
ADV-TDF
N=
N=
176
90
174
89
170
88
172
88
171
90
168
89
164
87
166
86
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.)
Heathcote J, et al., AASLD 2009; Oral # 153.
ALT Normalization
100
Open Label TDF
Randomized Double Blind
90
Percentage (%)
80
77%
P= 0.014
70
61%
60
50
40
30
20
10
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
Weeks on Study
ADV N= 90
TDF N= 176
85
165
84
160
82
146
76
HBeAg Loss & Seroconversion
TDF (Wk 48); TDF-TDF (Wk 64)
ADV (Wk 48); ADV-TDF (Wk 64)
P=NS
P=NS
P=NS
P=NS
27%
30
30
25
20
21%
22%
18%
5
25
% Patients
% Patients
26%
20
10
5
5
0
0
Week 64
HBeAg Loss
18%
15
10
Week 48
21%
21%
Week 48
Week 64
HBeAg Seroconversion
Cumulative Probability* of HBsAg Loss
in HBeAg (+) Patients
Cumulative Probability Function Estimate
0.10
Switch to
Open label TDF
6% TDF-TDF
6% ADV-TDF
0.05
0.00
0
12
24
36
48
64
80
96
Weeks on Study
Heathcote, et al., EASL 2009; Poster #909.
*Kaplan-Meier
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
Case 1:
To Be or Not To Be
Mr. W.
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•
•
•
•
•
•
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
Labs
AST
Hb
ALP
ALT
INR
Albumin
Total bilirubin
WBC
Platelets
Baseline Bloodwork
40
148
97
35
0.89
42
12
9.7
138
HBV Testing
3 Months Later
55
133
99
75
1.07
35
11
4.0
132
Assessment of Fibrosis
Abdominal U/S:
Liver Biopsy:
Coarse liver
A1F4
Spleen sl. enlarged
FibroScan:
16 kPa
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
Clinical Course
HBeAg-
HBeAg-
HBsAg+
HBsAg+
7
Tenofovir 300 mg po od
6
HBV DNA log IU/ml
5
4
3
HBV DNA
2
1
0
0
3
Months on treatment
6
Case 2:
To Treat Now or Later?
Miss L.
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•
•
•
•
•
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
Baseline Bloodwork
20
122
68
25
0.91
40
5
8.7
267
HBV Testing
HBsAg
+
HBeAg
+
Anti-HBe
-
HBV DNA
3.5 E+9 IU/ml
3,500,000,000 IU/ml
3 Months Later
18
119
68
20
0.89
39
7
7.6
253
Assessment of Fibrosis
Abdominal U/S:
Liver Biopsy:
Hemangioma
segment 6
A1F0
FibroTest:
0.35
6 Months Later
16
126
65
78
0.91
40
7
6.5
237
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
Course on PEG-IFN
HBeAg
+
+
-
-
HBVDNA (log c/ml)
Anti-HBe
10
100
9
90
8
80
7
70
6
60
5
50
4
40
3
30
HBVDNA
ALT
2
1
20
10
0
0
0
1
2
3
4
5
6
7
Time (months)
8
9
10
11
12
ALT (IU/L)
PEG-IFN
Question
HBeAg seroconversion was not achieved.
What would you suggest now?
1.
2.
3.
4.
5.
Observe off therapy for the next 6 months
Start oral antiviral therapy before pregnancy
Repeat a liver biopsy to assess response
Retreat with a different PEG-IFN
Start combination oral agents
10 Months Post PEG
Miss L is pregnant, 12 weeks GA
16
120
100
22
0.91
35
6.5
226
9
HBeAg +
HBV DNA 8.6 E+8 IU/ml
Question
How can you manage HBV infection
during pregnancy?
1.
2.
3.
4.
5.
Consult high-risk obstetrician
Start entecavir in 1st trimester
Start adefovir in 2nd trimester
Treat if HBV DNA > 7 logs in 3rd trimester
Check HBV DNA only post-partum
Question
Which of the agents can be considered
for use during pregnancy?
1.
2.
3.
4.
5.
Entecavir
Tenofovir
Clevudine
Telbivudine
Lamivudine
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
Questions?
Can One Pill A Day Keep
Hepatitis B Away?
Scott K. Fung, MD, FRCPC
Toronto General Hospital
University of Toronto
November 30, 2009
TGH