Therapy of Chronic Hepatitis B

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Therapy ofChronic Hepatitis B

• Teresa L. Wright, M.D.

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Case presentation1

• C.F. 36 year old Burmese woman with HBV who
  presented to clinic wanting to know about
  pregnancy
• HBsAg, HBeAg positive, DNA 750 pg/mL,
  albumin 4.2, AST 90, ALT 177
• Previously refused a liver biopsy
• Other medical problems hypertension, MPGN
• BUN 19, Cr 1.6, 24 hr urinary protein 2.5 g,
  2 RBCs

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Points for discussion

• Role of liver biopsy
• Etiology of MPGN
• Need for treatment
• Risk of pregnancy
• Timing of treatment
• Risk of antiviral therapy during pregnancy
• Interferon versus lamivudine versus adefovir
• Recommendations regarding risk to infant

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Recommendations to patient

• Obtain guidance from OB/GYN and Nephrologist
  about high risk pregnancy
• If decision for pregnancy, do so ASAP
• Defer HBV treatment until after pregnancy
• If not going forward with pregnancy, treat liver
  disease, preferably with prior biopsy
• IFN - low likelihood of response
• Lam - safe, but high risk of resistance
• ADV - concern about nephrotoxicity

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Chronic Hepatitis BSerologic Profile
Chronic Infection
Inactive HBsAg Carrier
Chronic Hepatitis
HBsAg Elevated ALT HBeAg Anti-HBe - HBV DNA
HBsAg Normal ALT HBeAg Anti-HBe HBV DNA -
Antiviral Therapy
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HBV DNA AssaysSensitivity
Chronic Hepatitis
Liquid Hybridization (pg/mL)
108
106
105
HBV DNA (copies/mL)
PCR (copies/ml)
Inactive HBsAg Carrier
104
102
100
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HBV DNA AssaysSensitivity
Adapted from Lok and McMahon, 2001
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Hepatitis B TherapyTreatment End-points

• Biochemical
• Normalization of serum ALT activity
• Virological
• Decrease of serum HBV DNA (
• Loss of HBeAg (if originally positive)
• Anti-HBe seroconversion
• Histologic
• Improvement in Histologic Activity Index

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Evolution ofTherapeutic Endpoints
Loss of HBsAg
Anti-HBs
Anti-HBe
Loss of HBeAg
Loss of HBV DNA
TIME
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Therapy for HBV Sustained Response
HBeAg
Anti-HBe
Weeks
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Chronic Hepatitis BAcute Flares of ALT

• Spontaneous loss of HBeAg
• Antiviral therapy
• Interferon
• Nucleoside analogues
• Spontaneous reactivation
• Associated with immunosuppression
• HBV genotypic variation
• Precore mutant
• HBV polymerase mutant
• Superimposed hepatotropic virus infection
• HAV, HCV, HDV

Adapted from Perrillo, 2001
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Indications for Therapy

• HBsAg HBeAg
• Elevated ALT
• HBV DNA 105 copies
• HBsAg HBeAg (pre-core mutant)
• Elevated ALT
• HBV DNA 105 copies

AASLD Practice Guidelines, 2001
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Therapy For Hepatitis BTreatment Options 2002

• Interferon
• Lamivudine
• Adefovir

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Interferon for Hepatitis BEarly Virologic
Endpoints
Loss of HBeAg
Loss of HBV DNA
Anti-HBe
Loss of HBsAg
Wong et al., 1993
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Hepatitis B Replication
HBV DNA
HEPATOCYTE
3
5
3
NUCLEUS
5
SERUM
cccDNA
Hepadnaviruses RT Described
DNA
5
Pregenomic RNA
5
3
- DNA
REVERSE TRANSCRIPTASE
1980
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HBV and Lamivudine

• Negative enantiomer of 3- thiacytadine
• Terminates nascent proviral DNA chain
• Inhibits reverse-transcriptase activity of HBV
  and HIV prevents synthesis of negative DNA strand
  of HBV
• Orally administered

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Serum HBV DNA Over Time vs. Lamivudine Dose
100
LAMIVUDINE
0
-100
Time (weeks)
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HBeAg Loss Among Asians and Caucasians After One
Year of Lamivudine
HBeAg loss at W52 by baseline ALT (xULN)
ALT ALT 1.0 ALT 2.0 ALT 5.0
70
60
50
40
of Patients
30
20
10
0
Asian
Caucasian
Integrated Data Lai 1998, Schiff 1998, Dienstag
1999, Schalm 2000
Schiff et al., J Med Virol 2000
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Durability of Post-Treatment Response
HBeAg loss in different patient groups
Median follow-up 12 months
87
86
81
68
Patients
21/26
20/23
37/43
21/31
Untreated
LAM Asian
LAM Cauc.
IFN
Korenman 1991
Schiff 2000
Lok 1987
Guan 2000
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HBeAg seroconversion Effect of treatment
duration and baseline ALT
77
80
73
70
65
63
59
60
50
49
50
45
43
42
Percent of Patients
38
37
40
29
27
30
22
20
10
0
Year 1
Year 2
Year 3
Year 4
Year 5
Asian study - Lai, Leung, Liaw, Guan, from
Schiff, LaJolla 2002
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YMDD MutantClinical Course
HBeAg ve
YMDD Variant
ALT x ULN
HBV DNA
Weeks of LAM Therapy
Courtesy of Dr. N. Brown
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Lamivudine ResistanceYMDD vs Duration of Therapy
YMDD
Adapted from Schiff, 2002
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YMDD Mutations

• HBV DNA polymerase mutation
• Methionine to Valine or Isoleucine (M204 V/I)
• Additional mutation L180M
• Seroconversion may occur in the presence of
  mutations
• Mutations may be less fit
• Management strategies evolving
• Continued lamivudine
• Rescue agents- Adefovir
• Long-term consequences remain poorly defined

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Therapy of HBVAdefovir

• Adefovir 10mg vs 30mg vs Placebo x 48
  weeks
• N515
• Median reduction in HBV DNA 3.6 logs
• No genotypic resistance noted
• Preliminary data from other studies indicates
  activity against LAM mutants

P
p0.05
Normal ALT
Improved Histology
HBeAg Sero- conversion
Marcellin et al, AASLD, 2001
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Lamivudine for HBV Blinded ranking assessments
of baseline and W52 slides
Tassopoulos
IMPROVED
Heathcote
100
82
Dienstag
71
80
66
56
Schiff
60
46
37
Lai
36
40
30
20
0
3
8
7
10
20
13
21
26
40
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WORSENED
Lamivudine
Placebo

• Ranked assessment of changes in liver
  necroinflammation
• ITTm population patients lacking either biopsy
  excluded
• All treatment arms for 52 weeks

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Changes in Cirrhosis by Month 24 of Lamivudine
Patients failed to seroconvert on previous LAM
therapy
Progression to cirrhosis (fibrosis score of 0, 1
or 3 ? 4)
Regression of cirrhosis (fibrosis score of 4 ? 0,
1 or 3)
80
71
64
60
50
Patients
40
20
7
4
0
0
Based on Schiff et al., Hepatology 2000 (Abstr.)
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Hepatic Stellate Cell Activation
Expression of Receptors
Cellular Proliferation
TGF-? PDGF
Fibrogenic Stimulus
Synthesis of ECM proteins
Collagen
Quiescent
Loss of Retinoid Stores
Fibronectin
Expression of ?- smooth muscle actin
Activated
Adapted from Brenner
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Changes in ?SMA staining by Lamivudine Therapy
Pre-LAM
Post-LAM
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Prognosticators ofAntiviral Response
Interferon Lamivudine
Elevated ALT Low HBV DNA Necroinflammation

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Interferon vs Lamivudine vs Adefovir
Interferon Lamivudine Adefovir
/- /-
/- /- -
- - - /- /-

• Defined treatment course
• Tolerability
• HBeAg Loss
• HBV DNA Loss
• HBeAg Seroconversion
• Development of resistance
• Sustained response
• Late response
• HBsAg clearance

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Therapy for HBVCombination IFN Lamivudine
Modified ITT
p.01
of Patients HBeAg Seroconversion
(n56)
(n54)
(n70)
Schalm et al, 1999
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HBV in Special Populations

• Decompensated cirrhosis
• HBeAg pre-core mutants

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Pre-transplantation median Bilirubin and Albumin
(N36)
Lamivudine pre-transplantation improves hepatic
synthetic function
Albumin (g/dL)
Bilirubin (mg/dL)
Week
Perrillo et al, Hepatology 2000
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Lamivudine Decompensated HBV Disease

• Villeneuve et al. Hepatology 2000
• N35 HBV DNA positive patients received
  lamivudine 5 died pre-transplantation, 7
  underwent transplantation and 23 received a mean
  of 19 months of lamivudine
• Majority had improved CPT score
• Pre-treatment 10.3 vs 7.5 on treatment 7.5
  (p
• Yao et al, J Hepatol 2000
• Decrease in CPT score 3 in 9/13 (69) of
  patients receiving pre-transplantation lamivudine

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Lamivudine in HBeAg-negative HBV
Response
?
Problem Universal relapse
Hadziyannis, 2000
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Lok and McMahon, 2001
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Lamivudine

• Stage liver disease to determine urgency of
  therapy
• Recommended treatment for HBeAg HBV is 12
  months
• Stop lamivudine after HBeAg seroconversion
  documented on 2 occasions 3 months apart
• Prolonged treatment if HBeAg seroconversion not
  achieved (?)
• Lamivudine resistance
• Continue lamivudine if continued benefit
  (clinical assessment, ALT, HBV DNA)
• Consider switching to adefovir

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Adefovir

• Stage liver disease to determine urgency of
  therapy
• Recommended treatment for HBeAg HBV is 12
  months no toxicity at one year
• Stop adefovir after HBeAg seroconversion
  documented on 2 occasions 3 months apart
• Prolonged treatment if HBeAg seroconversion not
  achieved probably will be necessary in most
• Clearly indicated in treatment of lamivudine
  resistance
• Also indicated as first line therapy, although
  limited safety data after two years of treatment
• Dose reduction of renal insufficiency

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Therapy for Hepatitis B 2002Summary

• Decision about choice of antiviral agent must
  include frank discussion with patient
• Both agents have advantages and disadvantages
• Ideal treatment candidate
• Young
• High ALT
• Low HBV DNA
• Chronic hepatitis on biopsy
• Fibrosis is a dynamic process that can be
  reversed with antiviral therapy

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Therapy for Hepatitis B 2002Unanswered Questions

• Optimal treatment duration?
• What will be the role of pegylated interferon?
• What will be the role of combination therapy?
• Nucleoside nucleoside?
• Nucleoside immunomodulator?
• What will be the long-term consequences of YMDD
  mutants?
• Adefovir as first line agent?
• Therapy for pre-core mutants?