Mechanism of action of interferon: priming

1
Mechanism of action of interferon priming
Choudhuri Drugs for chronic hepatitis B
2
Choudhuri Drugs for chronic hepatitis B

• Interferon Mechanism of action
• Antiviral
• Antiproliferative
• Control of apoptosis
• Immunomodulatory properties

3
Interferon effect on ALT
Choudhuri Drugs for chronic hepatitis B
Antonio Craxy J of Hepat 39 (2003) S99S105
4
Interferon long term benefits
Choudhuri Drugs for chronic hepatitis B
Probability distribution of disease
decompensation rate in HBeAg positive chronic
hepatitis B from IFN-treated (T) patients and
controls. Data from cohort studies
Probability distribution of the loss of HBsAg in
HBeAg positive chronic hepatitis B from
IFN-treated (T) patients and controls
5
Interferon long term benefits
Choudhuri Drugs for chronic hepatitis B
Probability distribution of development of HCC
rate in HBeAg positive chronic hepatitis in B
from IFN-treated (T) patients and controls
Probability distribution of liver-related
mortality in HBeAg positive chronic hepatitis in
B from IFN-treated (T) patients and controls
6
Choudhuri Drugs for chronic hepatitis B

• Interferon dosage
• 5 MU daily or 10 MU thrice weekly
• Children-6 MU / m2 thrice weekly
• Duration- 16-24 weeks in HBeAg
• - 12 months in HBeAg-
• Anna SF- Hepatology,2001341225-1241

7
Pegylated Interferon
Choudhuri Drugs for chronic hepatitis B
Cooksley WG- Br J Vir Hepatitis 2003 10298-305
8
Choudhuri Drugs for chronic hepatitis B

• Interferon Adverse effects
• Flu like illness
• Fatigue
• Anorexia, nausea, sleep disturbance
• Emotional lability, anxiety, depression
• Bone marrow suppression
• Unmasking/ exacerbation of autoimmune disorders,
  thyroid dysfunction

9
Choudhuri Drugs for chronic hepatitis B

• Predictors of IFN response in CHB
• Stage of liver disease
• ALT levels
• HAI
• HBV-DNA levels
• HIV disease
• Ethnicity
• Others

10
Quantitative HBV-DNA IFN response
Choudhuri Drugs for chronic hepatitis B
11
Choudhuri Drugs for chronic hepatitis B
Lami
IFN ?
12
Choudhuri Drugs for chronic hepatitis B
13
Choudhuri Drugs for chronic hepatitis B
14
Choudhuri Drugs for chronic hepatitis B
15
Choudhuri Drugs for chronic hepatitis B

• Nucleoside analogues
• Main target is the HBV polymerase gene product
• Reverse transcription inhibition
• Lamivudine
• Chain termination
• Deoxyadenosine monophoshate analogues
• Adefovir dipivoxil
• Deoxyguanosine analogues
• Ganciclovir, famciclovir, entecavir

16
Lamivudine
Choudhuri Drugs for chronic hepatitis B
Dienstag JL ET ALN Engl J Med 1999341125663
17
Choudhuri Drugs for chronic hepatitis B
HBeAg seroconversion after one year of
therapy (Seroconversion HBeAg-ve and
anti-HBeve)
29
30
Lai
plt0.04 compared to placebo
Patients ()
Dienstag
25
21
21
20
Schiff
20
20
17
Schalm
15
14
13
10
7
6
5
0
Placebo
Lamivudine
IFN
Lamivudine IFN
18
Choudhuri Drugs for chronic hepatitis B
HBeAg Loss Among Asians and Caucasians After One
Year of Lamivudine HBeAg Loss at W52 by baseline
ALT (xULN)
70
ALT gt5
60
Proportion of patients ()
ALT gt5
50
40
ALT 2-5
30
ALT 2-5
ALT 1-2
20
ALT 1-2
10
ALTlt1
0
Asian
Caucasian
Integrated Data Lai 1998, Schiff 1998, Dienstag
1999, Schalm 2000 Schiff et al., J Med Virol 2000
19
HBeAg seroconversion by baseline ALT after 1 year
of therapyIntegrated Phase III data Schiff 1998,
Lai 1998, Dienstag 1999, Schalm 2000 Perrillo et
al., Hepatology 1999 (Abstr.)
Choudhuri Drugs for chronic hepatitis B
50
47
Pre-treatment serum ALT
Seroconversion ()
40
gt1 x ULN
30
28
gt2 x ULN
30
24
gt5 x ULN
22
20
20
14
12
9
10
0
IFN
Placebo
Lamivudine
20
Choudhuri Drugs for chronic hepatitis B
HBeAg Seroconversion During 4 Years of
Lamivudine in Patients with Elevated
ALT Seroconversion HBeAg-ve and anti-HBeve
ALT
gt1 X ULN
Patients ()
(n41)
ALT
gt2 X ULN
(n26)
Based on Chang et al., J Gastro Hepatol 2000
(Abstr.)
21
Choudhuri Drugs for chronic hepatitis B
Durability of post-treatment response HBeAg loss
in different patient groups
87
86
81
68
Patients ()
21/26
20/23
37/43
21/31
Median follow-up gt 12 months
Lamivudine Asian
Lamivudine Caucasian
Interferon
Spontaneous
Korenman 1991
Lok 1987
Schiff 2000
Guan 2000
22
Choudhuri Drugs for chronic hepatitis B
Changes in hepatic necro-inflammation after 1
year of lamivudine or placebo
Tassopoulos
plt0.01 compared to placebo
Improved Patients () Worsened
Schalm
100

82
Dienstag

80

71
66
Schiff
56
60
46
Lai
37
36
40
30
20
0
3
8
7
10
20
13
21
26
40
38
Lamivudine 100mg
Placebo

• Ranked assessment of changes in liver
  necro-inflammation
• ITTm population patients lacking either biopsy
  excluded

Leung, J Med Virol 2000
23
Choudhuri Drugs for chronic hepatitis B
Changes in liver fibrosis after 1 year of
lamivudine or placebo
Tassopoulos
50
Improved Patients () Worsened
47
Schalm
39
40
34
Dienstag
30
Schiff
19
20
Lai
15
11
10
2
0
0
2
3
4
6
10
7
15
20
17
plt0.01 compared to placebo
30
27
Lamivudine 100mg
Placebo

• Ranked assessment of changes in liver fibrosis
• ITTm population patients lacking either biopsy
  excluded

Leung, J Med Virol 2000
24
Choudhuri Drugs for chronic hepatitis B

• Adverse events during 1 year of
  lamivudine/placebo
• Adverse event
  Incidence ( ) Placebo (n200) Lamivudine
  (n416)
• Malaise and fatigue 28 26Headache 21 22Viral
  respiratory infection 17 19Nausea and
  vomiting 17 16Abdominal discomfort/pain 17 15ENT
  infections 12 14Diarrhoea 12 14Viral ENT
  infections 11 11Throat tonsil
  discomfort/pain 8 11Cough 9 10Musculoskeletal
  pain 10 8
• Lai 1998, Dienstag 1999, Schalm 2000, Schiff 1998

25
Choudhuri Drugs for chronic hepatitis B
Actuarial survival in end-stage liver disease
Historical Comparisons
100
Lamivudine in decompensated CHB1
80
70
Patients surviving ()
60
Cirrhosis2
55
40
Decompensated cirrhosis3
20
14
1
3
2
4
5
0
Years
Perrillo et al., 20011, Weissberg et al., 19842,
and De Jongh et al., 19923
26
Choudhuri Drugs for chronic hepatitis B
Actuarial Survival Post Transplant Historical
Comparison
100
Lamivudine (N47)1
80
Long-term HBIg (N209)2
60
Patients surviving ()
No HBIg (N67)2
40
20
1
3
2
4
5
0
Years
Perrillo et al., Hepatology 20011 and Samuel et
al., N Engl J Med, 19932
27
Literature comparison
Choudhuri Drugs for chronic hepatitis B
28
Literature comparison
Choudhuri Drugs for chronic hepatitis B
29
Choudhuri Drugs for chronic hepatitis B

• Lamivudine resistance
• In phase III trials for 12 months, incidence of
  mutations in the YMDD motif of the viral
  polymerase-
• 14- Asian study
• Lai et al N Engl J Med 19983396168
• 31- European study
• Schalm SW, Gut 200046562568.
• 32- American study
• Dienstag JL N Engl J Med 199934112561263.

30
Adefovir
Choudhuri Drugs for chronic hepatitis B
Marcellin P, N Engl J Med 2003348808816
31
Adefovir
Choudhuri Drugs for chronic hepatitis B
Marcellin P, N Engl J Med 2003348808816
32
Adefovir
Choudhuri Drugs for chronic hepatitis B
Marcellin P, N Engl J Med 2003348808816
33
Interferon Lamivudine
Choudhuri Drugs for chronic hepatitis B
Schalm SW Gut 200046562568.
34
Choudhuri Drugs for chronic hepatitis B
HbeAg seroconversion after one year of
therapy Seroconversion HBeAg-ve and anti-HBeve
29
30
Lai
plt0.04 compared to placebo
Patients ()
Dienstag
25
21
21
Schiff
20
20
20
17
Schalm
15
14
13
10
7
6
5
0
Placebo
Lamivudine
IFN
Lamivudine IFN
35
Combination treatment
Choudhuri Drugs for chronic hepatitis B
Barbaro G et al- J Hepatol 200135406411
36
Choudhuri Drugs for chronic hepatitis B

• Thymosin alpha 1 mechanism
• 28 amino acid peptide- Dual mechanism
• Immunomodulatory
• Increases NK, CD4, CD8
• Shifts immune response towards Th1
• 2. Direct anti-viral
• Decreases MHC 1 on infected cells
• Inhibits viral replication

37
Combination treatment
Choudhuri Drugs for chronic hepatitis B