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3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB
WHY DO I TREAT MY PATIENTS WITH
PEGYLATED INTERFERON?
Problems Confronting Clinician with
HBeAg Negative Hepatitis B
• High rate of relapse to conventional strategies
• Diagnosis can be a bit challenging
• Patients tend to be older group than HBeAg (+)
with more severe disease
• Not much known about predictors of sustained
virologic response to IFN
Recent PEG IFN Developments that Impact
on Care of Patients with HBeAg (-) CHB
 Long-term follow up
• Durability
• HBsAg clearance
 On treatment prediction of SVR
• HBV DNA response
• HBsAg response
 Clarification of importance of genotype
 Better understanding of tolerability
Antiviral Therapy: A Matter of Choice
Case Features Should Determine Approach
Peginterferon
Nucleoside Analog
Poor tolerability in elderly and
Any age, minimal adverse
those with comorbid illness
events
Less effective for high level
Baseline viremia generally not
viremia
an issue
Chance for SVR determined by ALT elevation not required for
viral suppression
baseline ALT
Response genotype dependent Viral suppression independent
of genotype
Contraindicated with
Can be used safely in decomdecompensated disease
pensated disease
Limited usefulness in special
populations
Appropriate in certain settings
Many Other Factors Go Into a Treatment
Decision
Drug cost /cost of care
Indirect costs *
Tolerability *
Convenience *
Need for monitoring *
Finite treatment *
Diminished infectivity
Potential for long term
benefit (HBsAg loss)*
Durability off treatment
Modified from Perrillo, Hepatology, 2006
Initial and Long Term Follow Up from
PEG IFN alfa-2a Study in HBeAg-Neg CHB
70
Initial study
Follow-up study
60
6 mos after EOT
n= 356*
4years after EOT
n = 230*
60%
50
Marcellin, NEJM 2005
Marcellin, EASL, 2008
40
43%
30
27%
20
24%
19%
17%
10
0
* w/wo LAM
ALT
normal
HBV DNA
<20,000
< 400
ALT
normal
HBV DNA
< 20,000 < 400
Follow up Data in PEG IFN-Treated
HBeAg-Neg CHB
70
Initial study
Follow-up study
60
6 months after EOT
n =356
4 years after EOT
n = 230
50
40
~ 3%
increase
annually in
responders
30
20
11%
10
2% with
3%
lamivudine
0
ALT
normal
HBV DNA
< 400 copies
HBsAg
clearance
ALT
normal
HBV DNA
< 400 copies
HBsAg
clearance
Marcellin, 2005, 2008
Prolonged PCR Negativity Does not Allay
Concerns About Relapse
Virologic relapse
• 50 Chinese patients
treated with LAM
0.8
• 37 treated for 2 yrs
0.6
• 27 neg. by PCR
for ≥ 9 mos meet
criteria for treatment
withdrawal
Clinical relapse
0.4
0.2
Months to
Relapse
0-
2
4
6
8
10
12
14
16
18
Fung, 2004
Long Term Response in Adefovir-Treated
Cohort Negative for HBV DNA x 4-5 Years
• 33 patients neg for HBV DNA x 4-5 yrs on adefovir
• Followed for median duration 18 mos off treatment
• 67% continue with ALT NL
• HBV DNA becomes detectable in all (“low,” varying
from BDL to 5 x 104 copies)
• HBV DNA declines with further ollow up
Hadziyannis et al, AASLD, 2006
Worldwide Distribution of HBV Genotypes
Asia
1
Genotype A
Genotype E
Genotype B
Genotype F
Genotype C
Genotype G
Genotype D
Europe 1
46%
Mediterranean 1
35%
42%
14%
40%
USA 2
10%
35%
9%
83%
15%
1 Westland,
31%
22%
Gastroenterology 2003; 2 Chu, Gastroenterology 2003
Genotype and Virologic Response to IFN
According to HBeAg Status in 1229 Patients
Genotype Genotype Genotype Genotype
A
B
C
D
n=174
n=245
n=464
n=346
HBeAg
(+)
n=703
HBeAg
(-)
n=526
36.3%
21.1%
18.5%
14.6%
34.0%
32%
50.4%
21.4%
Standard =298l PEG = 491; with LAM 440
Erhardt , AASLD 2008, Absract 883
Frequency of Depression-Related Events
During Treatment with PEG IFN alfa-2a
25
22%
Chronic hep B studies
23%
20
Events (%)
Chronic hep C studies
15
P = 0.003
P < 0.001
9%
10
5
P = 0.027
10%
4%
2%
4/448
0
185/827
ALL PATIENTS
Depression events 4% (B) vs 22% (C)
8/346
ASIANS
4/47
9/90
180/702
CAUCASIANS
Marcellin et al, Liver International, 2007
Side Effects: HBeAg (-) CHB (n = 177) vs
CHC (n = 791)
Drug Discontinuations
B,C%
8, 17-33
Discontinuation for Safety,
B, C %
7, 7-22
1 or More
Serious
Adverse
Events
B, C%
5 (n =9),
7-16
Most Common
Serious Event
B, C%
Infection (6),
psychiatric
Patients with Cirrhosis Respond Just as
Well to IFN As Those Without
HBeAg
Response rates
Cirrhosis
Non-Cirrhosis
P Value
Niederau
+
63%
47%
ns
D Lau
+
59%
24%
0.01
van Zonneveld
+
50%
29%
0.034
Lin
+
39%
35%
ns
Cooksley Peg IFN2a +
48%
35%
ns
Buster
33%
14%
0.02*
Peg IFN2b +
Papatheodoridis
-
28%
27%
ns
Brunetto
-
26%
18%
ns
Cooksley Peg IFN2a -
40%
45%
ns
* Dose reduction, early discontinuation, and SAEs comparable for both groups (33% vs 34%,
11% vs 8%, 4% vs 5%)
modified after Chu and Liaw Sem Liver Dis 2006
Peginterferon for Delta Hepatitis
• Patients often HBeAg-negative
• Interferon only effective treatment
• Treatment required long-term
– Where possible, continue until loss of HBsAg
(Farci, J Viral Hep 2007; 14:S58-63)
3rd Paris Hepatitis Conference: Session on HBeAg-Neg CHB
HBsAg Loss, HBsAg Monitoring,
and Relationship of TreatmentInduced Changes in HBsAg
Concentration to Virologic Response
Why Is HBsAg Clearance So
Important?
Qualitative Differences Between HBsAg
and Prolonged Viral Suppression
• Durability of virologic response
• Significantly lower levels of intracellular genomic
template (cccDNA)
• Better long-term prognosis
– Lower rate of HCC
– Lower rate of progression to cirrhosis
• Less chance of viral reactivation
– Spontaneous
– Immune suppression
HBsAg Levels with Peg IFN Alfa -2a and
Lamivudine in HBeAg (-) CHB
• 63 patients (42 IFN, 21 LAM) analyzed for HBsAg by ADVIA
Centaur [Bayer]; (92% geno D)
• Low BSL HBsAg level predictive of HBsAg clearance
• HBsAg decreased in both treatment groups
- Sharp drop in most IFN treated patients; sustained in VR
- More gradual slope for LAM: ETU of HBsAg is median of 10.6
yrs of treatment vs 5.4 yrs with IFN
Manensis et al, Anitiviral Ther, 2007
Measuring HBsAg in HBeAg (-) CHB:
with 60 Week Extended Course of Peg IFN Alfa -2a
HBsAg
ng/mL
Baseline Treatment
Week 12
Treatment
Week 60
Follow up Follow up
Week 12 Week 24
Resp 1*
6,515
7,257
19
77
0
Resp 2
>7692
>7692
273
446
205
Resp 3
1,619
566
9
20
61
Resp 4
NR 1
>7,692
196
38
27
19
1,212
1,056
NA
1,910
1,473
NR 2
6,881
>7,692
6,088
6,823
5,219
NR 3
368
392
304
NA
189
NR 4
5,019
6,030
7,584
6,161
7,715
* Response = PCR negative at FU week 24
Gish, Lau, Schmid, Perrillo Am J Gastro 2007
HBV DNA
SVRs vs Non-responders
8
7
Log copies/mL
6
NRs (n=18)
5
4
3
SVRs (n=12)
2
1
0
BL
W12
W24
Treatment
W48
W72
W96
FUP
Moucari et al, Hepatology, in press
HBsAg Level
SVRs vs Non-Responders
4
3.5
NRs (n=18)
Log IU/mL
3
2.5
2
1.5
1
SVRs (n=12)
0.5
0
BL
W12
W24
Treatment
W48
W72
W96
FUP
Moucari et al, Hepatology, in press
HBsAg: Predictive Value for SVR by Wk 24
Decline (1 Log IU/mL)
Week 24
↓ HBsAg ≥ 1 Log IU/mL
SVR (+)
n = 11
PPV = 92 %
n = 12
n=1
SVR (-)
48 Patients
SVR (+)
n=1
n = 36
Week 24
↓ HBsAg < 1 Log IU/mL
n = 35
SVR (-)
NPV = 97 %
HBsAg Decline at Wk 48 Predicts
Outcomes at Year 3 After End of Rx*
Predictive Value of qHBsAg
at Wk 48 for Outcome:
NPV PPV Spec Sens
Sustained HBsAg Clearance at Yr 3
HBsAg < 380 IU/mL at wk 48
100
25
100
74
HBsAg reduction > 1.9 log10 at wk 48
98
44
92
75
HBsAg < 19 IU/mL at wk 48
98
44
75
92
HBsAg reduction > 0.46 log10 IU/mL at
wk 48
95
30
66
81
HBV DNA ≤ 400 copies at 3 Yrs
* Based on subset of 198 patients
In initial treatment cohort; HBsAg (-) in 16 (8%)
Brunettto et al, Hepatology, in press
SUMMARY
Why PEG IFN First for HBeAg-Negative CHB?
• Useful as first line therapy in selected patients:
• Age, comorbid illnesses, compensated liver disease
Test for genotype (non geno D)
• Better tolerated than in hepatitis C
• Patients with stable cirrhosis can be treated safely
• Specific advantages:
–
–
–
–
Discrete interval of treatment
Responses can be durable
HBsAg loss
Possibility of response directed therapy
Summary:
Why PEG IFN FIrst? (2)
• Responses can be durable
• If treatment fails, no impact on success with NA or
requirement for more complex therapy
Managing Patients with Limited Access to Care
Potential Problem
Addressment
Identify those chronically infected
Government or privately sponsored
screening programs
Determine ease of, and need for
Liver biopsy may be optional:
•High likelihood of response
•Obvious features of cirrhosis
•Treatment to prevent HCC?****
treatment
Investigate treatment possibilities
Government health care programs
Pharmaceutical free/discounted drug
Only monitor what and when it is
•More dependence on ALT
•Minimize HBV DNA testing intervals
•Monitor compliance
•Annual HBeAg assessment
necessary
Manage patient education
Native language; encourage family
participation; reasonable insight
Survey for confounding factors
Social circumstances, HIV/HCV/delta,
Compliance history