This document discusses interferons and their role in treating viral infections. It notes that there are three main types of natural interferons - alpha, beta, and gamma - which are produced by cells in response to viral stimuli. Recombinant interferons developed for treatment include pegylated forms with longer half-lives than standard interferons. The document focuses on the use of interferons, particularly pegylated interferons, in treating hepatitis C virus infections. It reviews clinical trial results showing the superiority of combination therapy with pegylated interferon and ribavirin over monotherapy or standard interferon treatments. Common side effects are also discussed.

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2. Natural Man Made
Interferons Interferons
(Recombinant)

3.  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.  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. virus
cells
(Other stimuli:
exogenous ds RNA,
LPS, bacterial
components)

6. virus
interferon

7. No replication
virus
Inhibitor
y
proteins

10.  IFN alpha and beta
 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.  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.  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.  gamma
 Chronic granulomatous disease, Chronic Myeloid
Leukemia, Renal cell Carcinoma

14.  Actimmune
 Alferon
 Avonex
 Betaserone
 Infergen
 Intron
 Wellferon, etc

15.  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

17.  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

19.  Monotherapy
 standard interferon 3 Million units inj tiw (Low
Sustained virologic response)
 Combination therapy
 standard interferon with ribivarin
 pegylated interferon with ribivarin

20.  Limitations
 monotherapy not very effective
 cumbersome dosing (TIW)
 multiple side effects

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

22.  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.  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. 60%
56%
50% 44%
40%
29% monotherapy
30%
IFN+RBV
20% Peg+RBV
10%
0%
Pega2a IFN a2b+RBV Pega2aRBV
P=<0.001

25.  peginterferon alfa-2b
 linear molecule
 weight 12 kDa
 peginterferon alfa-2a
 larger, branched molecule
 weight 40 kDa

28. Peg alfa-2b Peg alfa-2a
Volume of 20 L 8L
distribution
Absorption half-life 4.6 50
(h)
Mean elimination 40 80
half-life (h)

29.  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.  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