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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
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Case study 1

• 35 year old male from Italy
• LB mild chronic hepatitis B (Ishak 62)
• 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 ?

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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

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Peg-IFN a-2a in HBeAg-neg CHBSustained response
after 4 years of FUP
PEGASYS / LAM (N230)
27
LAM (N85)
24
P0.042
18
Patients ()
16
17
P0.021
11
7
2
ALT normal
lt20,000 cp/mL 4,000 IU/mL
lt400 cp/mL lt100 IU/mL
Cleared HBsAg
Modified ITT analysis, missing data non response
Marcellin et al, EASL 2008
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Predictive value of HBsAg reduction/level at week
48 for HBsAg clearance at 3 years
HBsAg reduction from BL to week 48
HBsAg level at week 48
RR 22.8 (95 CI 8 649) Plt0.0001
RR 14.6 (95 CI 5.5 38.5) Plt0.0001
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Patients withHBsAg clearance ()
42
3
2
11/26
5/172
12/23
4/171
gt10 IU/mL
gt2 log IU/mL
lt2 log IU/mL
lt10 IU/mL
Brunetto et al. EASL 2008
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Sustained response rates to PEG-IFN according to
qHBsAg at week 12 on treatment in 156 patients
HBsAg levels 1500 IU/mL (n61)
HBsAg levels gt1500 IU/mL (n95)
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
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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
SVR (N12) HBV DNA lt 70 cp/ml at week 48 and
72 REL (n18) HBV DNA lt 70 at week 48
Moucari et al, Hepatology 2009
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48-wk PEG apha 2a for HBeAg-neg patients serum
HBsAg levels at week 12 and 24
Moucari et al, Hepatology 2009
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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 lt 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 ?

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55 year old, HBeAg neg (May 2003 May 2005)
ALT 206 60 25
40 426 182 40
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LAM 100 mg/day
ADV 10 mg/day
L180M and M204V
HBV-DNA (log cp/ml)
LLQ
Months
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55 year old, HBeAg neg - May 2003 May 2005
ALT 206 60 25
40 426 182 40
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LAM 100 mg/day
ADV 10 mg/day
L180M and M204V
HBV-DNA (log cp/ml)
LLQ
Months
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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 (lt10-15 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
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Partial Virological Response to NUC
Week 24
Week 48
100
87
80
68
HBeAg-positive
HBeAg-negative
60
55
Patients with detectable HBV DNA by PCR,
40
37
33
29
24
20
20
10
7
0
LAM1
LDT1
ADV2
ETV3,4
TDF2
Baseline HBV DNA
9.5
9.5
8.9
9.6
8.6
7.6
6.9
7.0
7.7
7.4
1) Lai C-L et al. NEJM 20073572576-88 2)
Marcellin P et al, NEJM 20083592442-55 3)
Chang T-T, et al. NEJM 20063541001-10 4) Lai
C-L et al. NEJM 20063541011-20.
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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
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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 ?

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Case study 342 year old male from Greece with
moderate HBeAg negative CHB
ALT
HBV DNA
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Case Study 3
ALT
HBV DNA
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Case study 3
ALT
HBV DNA
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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
ULN
Hadziyannis S. et al, AASLD 2006
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HBV-DNA levels during follow-up in sustained
biochemical responders after stopping ADV
treatment
gt10,000 copies/mL
100
90
25
30
Detectable lt10,000 copies/mL
34
43
80
50
70
HBV-DNA not detectable
79
100
31
60
70 of patients lt10,000 c/mL
14
40
33
50
17
40
30
44
43
20
33
33
30
21
10
0
0
1
2
6
12
18
22
0
FOLLOW-UP MONTH
Hadziyannis S. et al, AASLD 2006
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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 ?

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