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3rd Paris Hepatitis Conference
January, 20th 2009
How to optimize the management of my
HBeAg negative patients?
Pietro Lampertico
1st Gastroenterology Unit
Fondazione Policlinico, Mangiagalli e Regina Elena
University of Milan
Milan - Italy
Case study 1

35 year old male from Italy

LB: mild chronic hepatitis B (Ishak 6+2)

HBeAg negative

ALT: 75 IU

HBV DNA 6.0 log IU/ml

No signs of liver cirrhosis, no previous anti-HBV therapy,
no concomitant medications/diseases

How would you manage this patient ?
Case study 1

PEGIFN alpha 2a, 180 ug/week for 48 weeks

HBV DNA clearance (week 24)

ALT normalization (week 30)

No significant side effects

Biochemical and virological response through week 48

PEG IFN withdrawal at week 48

HBV DNA and ALT relapse during follow-up
Peg-IFN α-2a in HBeAg-neg CHB
Sustained response after 4 years of FUP
PEGASYS +/– LAM (N=230)
30
27
Patients (%)
25
20
LAM (N=85)
24
P=0.042
18
16
17
15
P=0.021
11
10
7
5
2
0
ALT normal
<20,000 cp/mL
~4,000 IU/mL
Modified ITT analysis, missing data = non response
<400 cp/mL
<~100 IU/mL
Cleared
HBsAg
Marcellin et al, EASL 2008
Patients with
HBsAg clearance (%)
Predictive value of HBsAg reduction/level at
week 48 for HBsAg clearance at 3 years
100
90
80
70
60
50
40
30
20
10
0
HBsAg reduction
from BL to week 48
RR = 14.6 (95% CI 5.5 – 38.5)
P<0.0001
42%
3%
11/26
>2 log IU/mL
5/172
<2 log IU/mL
100
90
80
70
60
50
40
30
20
10
0
HBsAg level
at week 48
RR = 22.8 (95% CI 8 – 649)
P<0.0001
52%
2%
12/23
<10 IU/mL
4/171
>10 IU/mL
Brunetto et al. EASL 2008
Sustained response rates to PEG-IFN according to
qHBsAg at week 12 on treatment in 156 patients
HBsAg levels ≤1500 IU/mL
(n=61)
HBsAg levels >1500 IU/mL
(n=95)
An HBsAg cut-off of 1500 IU/mL at week 12 resulted in a PPV of 39%, 31% and 23% for achieving HBV
DNA levels ≤10,000 copies/mL, ≤400 copies/mL and HBsAg clearance 4 years post treatment.
The corresponding NPV were 88%, 92% and 96%, respectively
Marcellin et al, AASLD 2008
48-wk PEG alpha 2a for HBeAg-neg patients:
kinetics of HBV DNA and qHBsAg in SVR* and REL
HBV DNA levels
HBsAg levels
REL
REL
SVR
SVR (N=12): HBV DNA < 70 cp/ml at week 48 and 72
REL (n=18): HBV DNA < 70 at week 48
SVR
Moucari et al, Hepatology 2009
48-wk PEG apha 2a for HBeAg-neg patients:
serum HBsAg levels at week 12 and 24
Moucari et al, Hepatology 2009
Case study #1 - Discussion

How many HBeAg negative patients do you treat with PEG?

Do you treat only high ALT, low HBV DNA and non-D pts?

Endpoint: HBV DNA < 2000 U or PCR undetectable ?

Stopping rules for PEG on therapy?

Do you check for HBsAg titers ?

Do you rescue all patients with detectable HBV DNA ?

Do you treat with PEG patients with compensated cirrhosis ?
55 year old, HBeAg neg – (May 2003 – May 2005)
ALT
206
60
25
40
HBV-DNA (log cp/ml)
LAM 100 mg/day
426
182
40
41
ADV 10 mg/day
L180M and M204V
LLQ
0
2
4
6
8
10 12 14 16 18 20 22 24
Months
55 year old, HBeAg neg - May 2003 – May 2005
ALT
206
60
25
40
HBV-DNA (log cp/ml)
LAM 100 mg/day
426
182
40
41
ADV 10 mg/day
L180M and M204V
LLQ
0
2
4
6
8
10 12 14 16 18 20 22 24
Months
Responses on NUC Therapy
Primary non-response
Less than 1 log10 IU/mL decrease in HBV DNA
level from baseline at 3 months of therapy
Virological response
Undetectable HBV DNA by real-time PCR assay
(<10-15 IU/mL) within 48 weeks of therapy
Partial virological response
Decrease of HBV DNA of more than 1 log10 IU/mL
but detectable HBV DNA by real-time PCR at 24 or
48 weeks of therapy (according to drug potency
and genetic barrier to resistance)
Virological breakthrough
Confirmed increase in HBV DNA level of more
than 1 log10 IU/mL compared to the nadir
HBV resistance to NUCs
Selection of HBV variants with amino acid
substitutions that confer reduced susceptibility
to the administered NUC(s)
EASL CPG HBV, J Hepatol 2009, in press
Patients with detectable HBV DNA by PCR, %
Partial Virological Response to NUC
Week 24
100%
Week 48
87%
80%
68%
HBeAg-positive
60%
HBeAg-negative
55%
40%
37%
29%
33%
24%
20%
20%
10%
7%
0%
Baseline
HBV DNA
LAM1
9.5
7.4
LDT1
9.5
7.7
ADV2
8.9
7.0
ETV3,4
9.6
7.6
TDF2
8.6
6.9
1) Lai C-L et al. NEJM 2007;357:2576-88; 2) Marcellin P et al, NEJM 2008;359:2442-55;
3) Chang T-T, et al. NEJM 2006;354:1001-10; 4) Lai C-L et al. NEJM 2006;354:1011-20.
Partial Virological Response

Check for compliance

Patients receiving LAM, ADV or LDT with a partial
virological response at week 24:


Either change to a more potent drug (TDF or ETV)

Or add a more potent drug that does not share cross-resistance
Patients receiving TDF or ETV with a partial virological
response at week 48:

Add the other drug in order to prevent resistance in the long term
EASL CPG HBV, J Hepatol 2009, in press
Case study #2 - Discussion

How do you manage Partial Virological Responders (PVR) ?

Do you follow EASL guidelines ?

Do you rescue PVR with LAM, LDT at week 24 ?

Do you rescue PVR with ADV, ETV, TDF at week 48 ?

How do you rescue: switch vs add on ?
Case study #3
42 year old male from Greece with moderate HBeAg negative CHB
ADV 10mg/day
200
1,E+08
12,545,500
1,E+07
160
120
1,E+05
265,500
1,E+04
80
1,E+03
40
1,E+02
0
1,E+01
Months
ALT
HBV DNA
Logs HBV-DNA
ALT/AST (IU/L)
1,E+06
Case Study #3
ADV 10mg/day
200
1,E+08
12,545,500
1,E+07
160
120
1,E+05
265,500
1,E+04
80
1,E+03
40
1,E+02
0
1,E+01
Months
ALT
HBV DNA
Logs HBV-DNA
ALT/AST (IU/L)
1,E+06
Case study #3
ADV 10mg/day
200
1,E+08
12,545,500
1,E+07
160
120
1,E+05
265,500
1,E+04
80
1,E+03
40
1,E+02
0
1,E+01
Months
ALT
HBV DNA
Logs HBV-DNA
ALT/AST (IU/L)
1,E+06
Median ALT levels (IU/L) during 22 months of follow-up
after stopping 4 or 5 yrs of ADV therapy. Results
among patients in sustained biochemical remission
100
Median ALT
80
60
ULN
40
20
0
2
4
6
12
18
22
Months Follow-up
Hadziyannis S. et al, AASLD 2006
HBV-DNA levels during follow-up in
sustained biochemical responders after
stopping ADV treatment
>10,000 copies/mL
100%
90%
25%
34%
30%
43%
80%
50%
70%
60%
100%
79%
HBV-DNA
not detectable
31%
14%
50%
33%
40%
70%
17%
40%
30%
43%
20%
44%
33%
33%
30%
18
22
21%
10%
0%
0%
0
1
2
Detectable
<10,000 copies/mL
6
12
of
patients
<10,000
c/mL
FOLLOW-UP MONTH
Hadziyannis S. et al, AASLD 2006
Case study #3 - Discussion

Stopping rules for HBeAg negative CHB on NUCs ?

Do you follow EASL guidelines ?

Would you stop a NUC in a 5 year long-term responder ?

How frequent do you monitor HBV DNA on therapy ?

Side effects on long term NUC therapy ?