Natural Man MadeInterferons Interferons (Recombinant)
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
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
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
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
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
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
Monotherapy standard interferon 3 Million units inj tiw (Low Sustained virologic response) Combination therapy standard interferon with ribivarin pegylated interferon with ribivarin
Limitations monotherapy not very effective cumbersome dosing (TIW) multiple 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
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]
Peg alfa-2b Peg alfa-2aVolume of 20 L 8LdistributionAbsorption half-life 4.6 50(h)Mean elimination 40 80half-life (h)
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
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
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