Hepatitis%20B:%20predictors%20and%20endpoints%20revisited?

1
Hepatitis B predictors and endpoints revisited?

• Rami MOUCARI, MD
• Hôpital Beaujon, France

2
Rational

• Durable virological remission
• Finite period of treatment
• HBsAg clearance (closest to cure)

3
History

• A 52-year-old white female
• HBsAg positive test ordered by her internist
• Multiple risk factors including multiple sexual
  partners and multiple tattoos and piercings.
• She has no history of injection drug use, or of
  excessive alcohol intake.

4
Current Presentation

• She is referred to you for workup and
• management of her hepatitis B.
• You order laboratory testing that reveals
• Hepatitis B antigen HBeAgnegative disease
• HBV DNA 107 IU/mL
• Alanine aminotransferase (ALT) 95 IU/L
• Aspartate aminotransferase (AST) 75 IU/L
• Alpha-fetoprotein (AFP) 22 µg/L
• Platelet count 152,000/mm3
• Albumin 3.8 g/dL
• Bilirubin 1.0 mg/dL
• International normalized ratio (INR) 1.1

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How would you manage the patient at this time?

• A. HBV Genotype
• B. Abdominal Ultrasound
• C. Perform a Liver Biospy
• D. Start Antiviral Therapy

6
Investigations

• HBV Genotype D
• Abdominal Ultrasound no evidence of cancer or
  liver mass.
• Liver Biopsy A2F2 (METAVIR). No steatosis

7
Which of the following agents would be preferable
for this patient?

• A. Pegylated Interferon Alfa-2a
• B. Telbivudine
• C. Tenofovir
• D. Entecavir

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Pegylated Interferon Therapy
HBsAg Positive
HBV DNA (Log IU/Ml)
9
What is Your Preferred Strategy

• A. Add Entecavir
• B. Add Telbivudine
• C. Add Tenofovir
• D. Prolong Treatment Duration with Pegylated
  Interferon Alfa-2a

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HBsAg Quantification
HBsAg Log IU/mL
11
Prolongation of Pegylated Interferon Therapy
HBsAg Log IU/mL
12
IFN-Long-Term Results HBsAg
Moucari et al. J Hepatol 2009
13
IFN-Long-Term Results HBsAg
Moucari et al. J Hepatol 2009
14
IFN-Long-Term Results HBsAg
Moucari et al. J Hepatol 2009
15
HBsAg Peginterferon Alfa 2a
38

23
19
17
11
3
HBV DNA lt 10 000 copies/mL
HBV DNA lt 400 copies/mL
HBsAg Loss
Marcellin et al. NEJM 2004 Marcellin et al. EASL
2008
16
Baseline Predictors Of ResponseMultivariate
Analysis

• Significant predictors of sustained response
• Age Gender
• High baseline ALT
• Low baseline HBV DNA
• HBV Genotype

Bonino et al. GUT 2007

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Early Serum HBsAg Drop

A Strong Predictor of
Sustained Virological Response
to Pegylated Interferon Alfa-2a in
HBeAg-Negative Patients

• Moucari et al. Hepatology 2009

18
Patients

• 48 consecutive HBeAg-negative patients
• Pegylated Interferon alfa-2a /180 micrograms per
  week / 48 weeks.
• End of treatment (EOT) response undetectable
  serum HBV DNA at the EOT
• SVR undetectable serum HBV DNA 24 weeks after
  treatment cessation
• Follow-up 48 weeks after treatment cessation

Moucari et al. Hepatology 2009
19
Methods

• HBV genotype TRUGENE HBV genotyping kit
• Baseline, Treatment weeks 12, 24 and 48
• and Follow-up weeks 72 and 96
• Serum HBV DNA TaqMan polymerase chain reaction
  assay (COBAS TaqMan, Roche Molecular System
  lower limit of detection 70 copies/mL)
• Serum HBsAg Abbott Architect HBsAg QT assay
  (limits of detection 0.05 125 000 IU/mL)

Moucari et al. Hepatology 2009
20
Baseline Characteristics
Characteristic All Patients (N48)
Age (years) 44 (38 - 53)
Sex ( male) 83
Ethnicity ( Caucasian) 67
Serum ALT (IU/L) 98 (60 - 240)
HBV Genotype ( A, B, C, D, E) 27, 17, 12, 29, 14
Serum HBV DNA (Log copies/mL) 7.0 (5.5-8.0)
Serum HBsAg (Log IU/mL) 3.8 (3.2 - 4.2)
Liver necroinflammation ( A2-A3) 50
Liver Fibrosis ( F3-F4) 50
Moucari et al. Hepatology 2009
21
Virological Response
62
25
30/48
12/48
Moucari et al. Hepatology 2009
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HBV DNA LevelSVRs vs. Non Responders
NRs (n18)
Log copies/mL
SVRs (n12)
Treatment
FUP
Moucari et al. Hepatology 2009
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HBV DNA Level SVRs vs. Relapsers
Relapsers (n18)
Log copies/mL
SVRs (n12)
Treatment
FUP
Moucari et al. Hepatology 2009
24
HBsAg LevelSVRs vs. Non Responders
NRs (n18)
Log IU/mL
SVRs (n12)
FUP
Treatment
Moucari et al. Hepatology 2009
25
HBsAg Level SVRs vs. Relapsers
Relapsers (n18)
Log copies/mL
SVRs (n12)
Treatment
FUP
Moucari et al. Hepatology 2009
26
HBsAg Predictive Value of Week 12 Drop
(0.5 log IU/mL)
SVR ()
N 8
PPV 89
Week 12 ? HBsAg 0.5 LogIU/mL
N 9
N1
SVR (-)
48 Patients
SVR ()
N 4
N39
Week 12 ? HBsAg lt 0.5 LogIU/mL
N 35
NPV 90
SVR (-)
Moucari et al. Hepatology 2009
27
HBsAg Predictive Value of Week 24 Drop
(1 log IU/mL)
SVR ()
N 11
PPV 92
Week 24 ? HBsAg 1 LogIU/mL
N 12
N 1
SVR (-)
48 Patients
SVR ()
N 1
N 36
Week 24 ? HBsAg lt 1 LogIU/mL
N 35
NPV 97
SVR (-)
Moucari et al. Hepatology 2009
28
HBsAg Level in SVRsHBsAg (-) vs. HBsAg ()
Log IU/mL
HBsAg () (n9)
HBsAg (-) (n3)
Treatment
FUP
Moucari et al. Hepatology 2009
29
Conclusion (1)

• HBsAg clearance closest to cure in chronic HBV
  infection
• Reduced rate of cirrhosis and HCC
• Improved survival
• HBsAg clearance is achievable in a high steady
  rate in CHB patients responding to IFN therapy

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Conclusion (2)

• Serum quantitative HBsAg seems to be an excellent
  on-treatment marker predicting sustained
  off-treatment response, and identifying in the
  early phase of PEG-IFN therapy the patients who
  are most likely to benefit from this treatment.

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Virologic Response in HBeAg- Patients
(Undetectable HBV DNA at Year 1)
Not head-to-head trials different patient
populations and trial designs
100
93
90
87
88
80
70
63
60
51
Patients With Undetectable HBV DNA ()
40
20
0
LAM
ADV
ETV
LdT
TDF
Peg-IFN
Peg-IFN LAM
HBsAg loss 0
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Early viral kinetic (day 10) is predictive of
long term virological response
69 HBe patients
Predictive value of early kinetic (D10) on
virological response (lt300 cp/ml) at W24 et
W48 - HBV DNA lt 6log 76 and 82 - 7log lt HBV
DNA lt 8log 14 and 29
Leung N, Hepatology 2009
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HBsAg Loss in HBeAg-Negative Patients Following
Long-term Adefovir Treatment

• 33 HBeAg-negative CHB patients
• Adefovir for 4-5 years with undetectable HBV DNA
• 4 years of follow-up after Adefovir
  discontinuation
• 18 of 33 patients (55) SVR
• 9/18 (50) HBsAg Clearance

Hadziyannis SJ et al. AASLD 2008 (Abstract 874)