1. Pharmacology of Interferon

2. Interferon
Natural
Interferons
Man Made
Interferons
(Recombinant)

3. Interferon Basics
Interferons play an important role in the first line of defense against viral infections
Interferons are part of the non-specific immune system
Interferons are made by cells in response to an appropriate stimulus

4. Types on Interferon alpha (leukocyte interferon)
produced by virus infected leukocytes
beta (fibroblast interferon)
produced by virus infected fibroblasts or epithelial cells
gamma (immune interferon)
produced by certain activated T cells & NK cells

5. How Does It Prevent Viral Replication?
virus
cells
(Other stimuli:
exogenous ds RNA,
LPS, bacterial
components)

6. How Does It Prevent Viral Replication?
virus
interferon

7. How Does it Prevent Viral Replication?
No replication
virus
Inhibitory
proteins

8. Interferon Response to Acute Viral Infection

9. Effects of Interferon Treatment

10. Mechanisms of Action IFN alpha and beta IFN gamma All IFN
induction of inhibitory protein synthesis
IFN gamma
inc class II MHC molecules of APC
Inc ability of macrophages to resist viral infx and kill other cells if infected
All IFN
inc class I MHC molecules
inc activity of NK cells

11. Viral Defense Against Interferon
block interferon binding to cells
inhibit action of interferon-induced protein kinase
inhibit NK function
interfere with cell surface expression MHC
block complement activation
prevent apoptosis in host cell

12. Indications for Interferon
alpha
Hepatitis B & C, Hairy cell leukemia, Chronic myeloid leukemia, multiple myeloma, low grade lymphomas, Kaposi’s Sarcoma, Melanoma
beta
Multiple Sclerosis, (Ulcerative colitis)

13. Indications for Interferon
gamma
Chronic granulomatous disease, Chronic Myeloid Leukemia, Renal cell Carcinoma

14. Incomplete List of Interferons
Actimmune
Alferon
Avonex
Betaserone
Infergen
Intron
Wellferon, etc

15. HCV Epidemiology HCV is leading cause of liver disease
4 million Americans have been exposed
approx 3 million are infected
HCV infection leads to decompensated cirrhosis and hepatocellular carcinoma
HCV-related cirrhosis is the most common reason for OLT in the US
NIH Consensus Development Conference Statement 2002

16. Distribution of HCV

17. Management of Hepatitis C
Consensus Statement in 2002
treatment eligible patients
IVD users, consume alcohol, comorbidities (depression, HIV coinfections)
pegylated interferon with ribiviran better than peginterferon monotherapy or standard interferon-ribivarin

18. HCV Infection

19. Interferon in Hepatitis C
Monotherapy
standard interferon 3 Million units inj tiw (Low Sustained virologic response)
Combination therapy
standard interferon with ribivarin
pegylated interferon with ribivarin

20. Interferon in HCV Limitations monotherapy not very effective
cumbersome dosing (TIW)
multiple side effects

21. Interferon Side Effects
(Hepatitis C Data)
Flu-like symptoms
Headache
Nausea, vomiting, diarrhea
Depression, irritability, anxiety
Injection site reactions, partial alopecia
Hematologic abnormalities
Autoimmune disorders

22. Management of Side Effects
Depression (77% Manns et al, Lancet 2001)
NIH consensus - “monitor patients for depression and prescribe antidepressants when necessary”
Hematologic abnormalities
neutropenia and thrombocytopenia
treatment options include decreasing dose or giving hematopoietic growth factors

23. Pegylated Interferon HCV is an ideal setting for peginterferon
polyethylene glycol (PEG):interferon
Pegylation was developed to overcome disadvantages of standard interferon
shields IFN from enzymatic degradation thus lowers systemic clearance
allows less frequent dosing
achieve higher/sustained serum [interferon]

24. Fried et al: Peginterferon Alfa-2a Plus Ribavirin
56%
44%
29%
P=<0.001

25. Differences in PEG peginterferon alfa-2b peginterferon alfa-2a
linear molecule
weight 12 kDa
peginterferon alfa-2a
larger, branched molecule
weight 40 kDa

26. Peginterferon

28. Pharmacologic Parameters of Peginterferons

29. Weight-Based Dosing and Peginterferon Therapy
Once weekly dosing
alfa 2b
weight based dosing (1-1.5 mcg/kg/week)
high volume of distribution
kidney, heart, liver and throughout the bloodstream
alfa 2a
fixed dose at 180 mcg/week
low volume of distribution

30. Conclusions
Interferons are important in the nonspecific immune response
Interferons are effective in the treatment of patients with chronic hepatitis
Pegylated interferons are superior therapies for patients with HCV
Side effects should be monitored closely