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
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
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
16.
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
18.
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
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]
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