Transcript Dose

Hepatitis C virus treatment
Heba Abd El-fattah Sabry
Clinical pharmacist-heamatology Department
Pharm D Student
Agenda
Role of interferon treatment in HCV.
 Dose , dose adjustment of Interferon ,
ribavirin In HCV treatment .
 Duration of drug treatment.
 Use of interferon in HD,RT patients.
 Other uses of interferon.
 Use oh corticosteroid in HCV.

Interferon

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
Natural proteins produced by the cells of the immune system
of most vertebrates in response to challenges by foreign
agents such as viruses, parasites and tumor cells.
Interferons belong to the large class of glycoproteins known
as cytokines.
Interferons are produced by a wide variety of cells in response
to the presence of double-stranded RNA, a key indicator of
viral infection.

Interferons assist the immune response by :
1.
Inhibiting viral replication within host cells,
Activating natural killer cells and macrophages,
Increasing antigen presentation to lymphocytes,
Inducing the resistance of host cells to viral infection
2.
3.
4.
Mechanism of action
These interferons induce about 20-30 proteins,
three of the proteins that appear to play an
important role in the induction of the anti-viral
state have been intensively studied.
1)Expression of one of these proteins (2’5’ oligo A
synthase) results in activation of the second of
these proteins (a ribonuclease) which can break
down mRNA
2)Expression of the third protein (a protein
kinase) results in inhibition of the initiation step
of protein synthesis.
These activities target viral protein synthesis, but
also result in inhibition of host protein
synthesis .Thus it is important that these
proteins are only made and activated when
needed .


Double-stranded RNA is needed for activation of
these proteins.

Thus, these potentially toxic pathways are only
activated in the interferon-treated cell if doublestranded RNA is made, this will usually only
happen if virus infection actually occurs. The
activation of these proteins may sometimes
result in the death of the cell.
Types of interferon
TYPE I interferon
INFα
TYPE II inteferon
INFβ
INFγ
Types of interferon
1)TYPE I interferon:
 Interferon-alpha (leukocyte interferon) is produced
by virus-infected leukocytes.
 Interferon-beta (fibroblast interferon) is produced by
virus-infected fibroblasts, or virus-infected epithelial
cells.
2)TYPE II inteferon:
 Interferon-gamma (immune interferon) is produced
by certain activated T-cells and NK cells.
 Interferon-gamma is made in response to antigen
(including viral antigens) or mitogen stimulation of
lymphocytes. (Inflammation rather than infection)
Uses:

Antiviral, antiseptic and antioncogenic properties
when administered as drugs.

Interferons (interferon beta-1a and interferon beta-1b
) are also used in the treatment and control of
multiple sclerosis, an autoimmune disorder . By an
as-yet-unknown mechanism, interferon-beta inhibits
the production of Th1 cytokines and the activation of
monocytes.
Renal cell carcinoma (destroying kidney cancer cells ).
Since interferons have anti-proliferative effects, they
have also been used to treat certain tumors such as
melanoma and Kaposi’s sarcoma.


Side effects:



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
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
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Flu-like symptoms.
Depression and suicide.
Renal Adverse Events .
Hematologic Adverse Events.
Cardiovascular Adverse Events
Ophthalmic Adverse Events.
Endocrine Adverse Events.
Infections .
Autoimmune Adverse Events.
Injection side reaction.
Contraindication:
History of major depressive illness.
 Active alcohol use.
 Cytopenia (more than one type of blood
cell deficiency) .
 Hyperthyroidism (overactivity of the thyroid
gland) .
 Renal transplantation.
 Autoimmune disease .

FDA
APPROVED
REGULAR
BETA
ALFA
PEGYLATED
GAMMA
Beta-1a
2a
Avonex
Beta-1b
ROFERON A
Betaseron
2b
INTRON A
ALFA-N3
ALFERON N
ALFACON 1
INFERGEN
ALFA - 2a
gamma-1b
Actimmune
ALFA - 2b
PEGASYS
PEGINTRON
Types of interferon approved for
use in humans
Generic name
Trade name
Interferon alpha 2a
Roferon A
Interferon alpha 2b
Intron A
Human leukocyte Interferon-alpha (HuIFN-alpha-Le)
Multiferon
Interferon beta 1a, liquid form
Rebif
Interferon beta 1a, lyophilized
Avonex
Interferon beta 1a, biogeneric (Iran)
Cinnovex
Interferon beta 1b
Betaseron /
Betaferon
Pegylated interferon alpha 2a
Pegasys
Pegylated interferon alpha 2a (Egypt)
Reiferon
Retard
Pegylated interferon alpha 2b
PegIntron
Pegylation :



Process of covalent attachment of
(polyethylene glycol) polymer chains to drug
or therapeutic protein.
It produces alterations in the physiochemical
properties including changes in conformation,
electrostatic binding, hydrophobicity etc.
These physical and chemical changes
increase systemic retention of the therapeutic
agent. Also, it can influence the binding
affinity of the therapeutic moiety to the cell
receptors and can alter the absorption and
distribution patterns.
Pegylated Interferon :







Improved drug solubility.
Enhanced protection from proteolytic
degradation, increase biological half life.
Reduced dosage frequency, without
diminished efficacy with potentially reduced
toxicity.
Extended circulating life (reduce drug
clearence).
Increased drug stability.
Lack of toxicity and immunogenicity.
Altered distribution in the body.

Alpha-interferons are totally filtered through
the glomeruli and undergo rapid proteolytic
degradation during tubular reabsorption,
rendering a negligible reappearance of intact
alfa interferon in the systemic circulation.

Pegylated IFN alpha clearance predominantly
occurs in non-renal sites with the liver being
an important site of elimination, dose of
peginterferon alfa-2a may require no or
minimal adjustment in patients with ESRD
Who Should Be Treated
Patients with:
 Anti-HCV, HCV RNA.
 Elevated serum aminotransferase levels.
 Evidence of chronic hepatitis on liver
biopsy, With no contraindications.

Patients with fibrosis or moderate to
severe degrees of inflammation and
necrosis on liver biopsy should be
treated and that patients with less
severe histological disease be
managed on an individual basis.

Patients with cirrhosis found through liver biopsy
can be offered therapy if they do not have signs of
decompensation, such as ascites, persistent
jaundice, wasting, variceal hemorrhage, or hepatic
encephalopathy.

Patients with acute hepatitis C are a major challenge
to management and therapy. Because such a high
proportion of patients with acute infection develop
chronic hepatitis C, prevention of chronicity has
become a focus of attention

In patients with clinically significant extrahepatic
manifestations, such as cryoglobulinemia and
glomerulonephritis, therapy with alpha interferon
can result in remission of the clinical symptoms and
signs. However, relapse after stopping therapy is
common.
Who Should Not Be Treated ?
Therapy is inadvisable outside of controlled
trials for patients who have :
 Clinically decompensated cirrhosis
because of hepatitis C.
 Normal aminotransferase levels .
 Kidney, liver, heart, or other solid-organ
transplant.
 Specific contraindications to either
monotherapy or combination therapy.
PEGASYS® (alfa-2a)
October 2002
PEGASYS is supplied as
 SC. injectable soln. in a vial (180mcg/1
ml )
 SC. prefilled syringes (180mcg/0.5 ml )
PEGASYS and COPEGUS Dosing
Recommendations
Genotype
PEGASYS COPEGUS Duration
Dose
Dose
Genotype
1, 4
180 µg
Genotype
2, 3
180 µg
<75 kg =
1000 mg
>75 kg =
1200 mg
48 weeks
800 mg
24 weeks
48 weeks
Renal Function:

In patients with end-stage renal disease
requiring hemodialysis:
Dose reduction to 135 µg PEGASYS is
recommended (there is a 25% to 45%
reduction in PEGASYS clearance ).
Combined (standard interferon
plus ribavirin) antiviral therapy

The elimination rate of ribavirin in
patients with impaired renal function is
reduced, and only a small fraction of
the drug is eliminated by hemodialysis.
A lack of information about appropriate
ribavirin dosing and concerns about
side-effects, i.e. severe hemolytic
anemia, have limited the use of
ribavirin in dialysis patients
Monotherapy with pegylated
interferon


No significant differences in apparent body
clearance of peg-IFN α2a between patients
with normal kidney function and those with
significant reductions in kidney function
(creatinine clearance > 100 mL/min vs. 20-40
mL/min) have been detected .
However, the pharmacokinetics of peg-IFN
α2a during hemodialysis may vary reflecting
permeability and dialyzer pore size .
Dose Modifications

PEGASYS Hematological Dose Modification Guidelines :
Laboratory
Values
PEGASYS
Dose
Reduction
Discontinue
PEGASYS if:
ANC
<750/mm3
135 µg
ANC
Platelet
<50,000/mm3
90 µg
Platelet count
<25,000/mm3
<500/mm3,
stop till count ↑
Reinstitute at 90 µg
and monitor ANC
PEGINTRON (alfa-2b)
January 2001
Available Forms: (sub.Q)
1) Vials:
Contain PEGINTRON at strengths of either
50, 80, 120, or 150 mcg/0.5 ml.
PEGINTRON ,cont’d.
2) Redipens:


It’s the first pen delivery system
approved for administration of pegylated
interferon therapy.
Consists of a dual chamber glass
catridge containing lyophilized
PEGINTRON as a white to off-white tablet
or powder that’s whole or in pieces in the
sterile active chamber &a 2nd chamber
containing sterile water for injection.
PEG-Intron®
Dose:
REBETOL ®
1.0 mcg/kg/w for one
800 mg/day
year), (180 mcg / w. for 24 in 2 divided
to 48 weeks).
doses
(Combination)
1.5 mcg/kg/w.
Dose
Crcl 30-50ml/min:
adjustme
↓ dose by 25%.
nt.
Crcl 10-29ml/min:
↓ dose by 50%.
Crcl <10ml/min: stop
should not be
used in
patients with
creatinine
clearance <50
mL/min.


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Pegylated interferon- α2b was administered by
the patient on a day when they were not on
dialysis and when the day following the injection
was also an off dialysis day (e.g. on a Saturday
morning in patients on a Monday) .
Other benefits seen with antiviral therapy and viral
eradication prior to kidney transplant include
lower rates of hepatitis C-related
glomerulonephritis and diabetes .
It is recommended that patients receiving PEGIntron, alone or in combination with ribavirin, be
discontinued from therapy if HCV viral levels
remain high after 6 months of therapy.
INTRON A (alfa-2b)
(1988) (recombinent DNA)
Available Forms:
(IM ,IV ,Sub.Q ,Intralesional)
1- Powder for injection/reconstitution:



(doesn’t contain preservative)
10 MIU /vial +sterile water as a diluent (1ml/vial).
18 MIU /vial +sterile water as a diluent (1ml/vial(.
50 MIU /vial +sterile water as a diluent (1ml/vial).
2- Solution for injection in vials:
(vial &6 B-D safety-lok syringes)
 10 MIU multidose vial.
 18 MIU multidose vial.
 25 MIU multidose vial.
INTRON A .cont,d
3- Solution for injection in multidose pens:
6 doses of:
 3 MIU (18 MIU)
 5 MIU (30 MIU)
 10 MIU (60 MIU)
22.5 MIU/1.5 ml/pen.
37.5 MIU/1.5 ml/pen.
75 MIU/1.5 ml/pen.
 each pen contains an excess amount of solution (IFN and diluent) to
ensure delivery of the labeled dose.
INTRON A .cont,d
3- Solution for injection in multidose pens:
6 doses of:
 3 MIU (18 MIU)
 5 MIU (30 MIU)
 10 MIU (60 MIU)
22.5 MIU/1.5 ml/pen.
37.5 MIU/1.5 ml/pen.
75 MIU/1.5 ml/pen.
 each pen contains an excess amount of solution (IFN and diluent) to
ensure delivery of the labeled dose.
ROFERON A (INF α2a –Recombinant)
Available Forms (SC inj)
1. Single use injectable solution :

3 MIU (11.1 mcg/mL) Roferon-A per vial

6 MIU (22.2 mcg/mL) Roferon-A per vial

9 MIU (33.3 mcg/0.9 mL) Roferon-A per vial
2. Multidose vial:

36 MIU (133.3 mcg/mL) Roferon-A per vial
3.



Single use prefilled syringes:
3 MIU (11.1 mcg/0.5 mL) Roferon-A per syringe
6 MIU (22.2 mcg/0.5 mL) Roferon-A per syringe
9 MIU (33.3 mcg/0.5 mL) Roferon-A per syringe
Intron® A
INFalfa-2b
Roferon A®:
INFalfa-2a
Dose
3MIU tiw. For 18 to 24
months.
persistently high levels of
HCV RNA after 16 weeks of
therapy stop treatment.
To inhance tolerability
adminster at night.
1)3 MIU tiw for 12
months .
2)6 MIU tiw for the
first 3 months
followed by 3 MIU tiw
for 9 months.
If no response within
the first 3 months
stop treatment.
Dose
adj.
(50% reduction) if S.E
appear.
Used with caution in
patients with Crcl <
50 mL/min.
Infergen
®:
(Interferon Alfacon-1)
 Dose:
9 mcg 3 times weekly. Allow at least 48 hours to elapse
between doses for 24 weeks.
Individuals who tolerated previous interferon therapy
and did not respond to the initial regimen or
relapsed after discontinuance may receive 15 mcg 3
times weekly for up to 48 weeks .

Renal Impairment. Interferon alfacon-1: Increases in
Scr reported; renal failure reported rarely. Monitor
patients with impaired renal function; use with
caution in patients with renal insufficiency.
Robetrol® : (Ribavirin)
Ribavirin is an nucleoside analogue
antiviral drug. It is used in combination
with interferon for the treatment of chronic
hepatitis C.
 It is thought to interfere with the
production and/or action of viral DNA and
RNA which are critical to the survival and
multiplication of the virus.
 Decreased renal clearance of ribavirin can
worsen hematologic toxicity

Effect of Food on Absorption of
Ribavirin

Bioavailability of a single oral dose of
Ribavirin was increased by
coadministration with a high-fat meal.
The absorption was slowed (Tmax was
doubled) and the AUC0-192h and Cmax
increased by 42% and 66%,
respectively, when Ribavirin was taken
with a high-fat meal compared with
fasting conditions
Renal Dysfunction:
Administration of Ribavirin in patients
with creatinine clearance < 50 mL/min.
 Therefore, patients with creatinine
clearance < 50 mL/min should not be
treated with Ribavirin

Therapy of chronic HCV in CKD
population (renal transplant
recipients(
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No safe and effective therapy exists for the treatment
of chronic HCV post-RT due to ↓ SVR and drop-out
rate .
The most frequent side-effect requiring interruption
was graft dysfunction, typically acute rejection
refractory to corticosteroid therapy.
Antiviral therapy with interferon needs to be
considered only in patients [i.e., fibrosing cholestatic
hepatitis (FCH)] in whom the risk of not treating
justifies the possible loss of the allograft .
Alternative regimens based on drugs other than
interferon have been described but no proof of their
efficacy has been provided. Amantadine , ribavirin
monotherapy or their combination had no impact
on viral levels or liver histology.
Therapy of chronic HCV in CKD
population (renal transplant
candidates(:
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There is increasing interest in treating HCV infection
in RT candidates, At 22.5 months after renal
transplantation, HCV viremia was absent in all
patients, and no patient developed PTDM.
Pre-transplant interferon may also reduce the
occurrence of post-transplant de novo or recurrent
glomerulonephritis, post-transplant diabetes mellitus .
An additional benefit of pre-transplant antiviral
therapy may be a reduced incidence of chronic
allograft nephropathy (CAN) as HCV infection has
been implicated in its pathogenesis.

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IFN-a treatment was effective in both HCV-positive
HD patients and renal transplant recipients. IFN-a
treatment prior to renal transplantation (HD
patients) seemed to be better than posttransplant
treatment, since the total dose of IFN-a is almost
half in HD patients compared to transplant
patients and IFN-a may induce a rejection crisis in
renal transplant recipients.
The use of immunosuppressive medications
following renal transplantation usually leads to an
elevation in HCV RNA circulating titers by an
average of 1 log.

Patients who contract HCV while on
hemodialysis may be too
immunosuppressed to develop anti-HCV
antibodies, and testing may yield a falsenegative result. Therefore, patients who have
a history of hemodialysis should be
considered for an HCV RNA assay rather
than an EIA. Measurement of ALT will not be
useful because ALT levels are lower in
patients with ESRD .
Other uses of interferon therapy


Alpha-interferon is another biological agent
that has been used in the treatment of
Kidney Cancer since 1983.
Interferon appears to work by altering the
surface proteins of the cancer cells as well
as by directly slowing their growth.
Responses to treatment with interferon alone
do occur, but are rarely complete or long
lasting
Treatment of Extrahepatic manfistation


There is association of chronic HCV infection
with a heterogeneous group of non-hepatic
conditions ,such as pulmonary fibrosis,
cutaneous vasculitis, glomerulonephritis ,
which were regarded as extrahepatic
manifestations of chronic HCV infection .
There is relationship between chronic HCV
infection and systemic autoimmune diseases
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Adequate management of HCV-related
extrahepatic features should be targeted at
two independent goals:
1)Eradication, of the circulating viral load
with antiviral therapy.
2) Treatment of autoimmune features using
corticosteroids, cytotoxic agents and/or
plasmapheresis, in order to control the
formation, tissue deposition and
inflammatory effects of immune complexes.
IFN-α is effective in HCV-associated
cryoglobulinaemia.
Ribavirin monotherapy may be effective in
IFN- -intolerant patients with symptomatic
HCV cryoglobulinaemia .


Thiele et al .found a favourable response to
corticosteroid therapy in patients with
chronic HCV infection .Another study
showed neither an apparent increase in HCV
RNA nor worsened liver function when
steroids were combined with IFN -to treat
HCV-associated MC .
Recent studies have demonstrated that
antiviral therapy, as well as corticosteroids,
may be effective in managing extrahepatic
HCV manifestations, although
discontinuation often produces relapses .
Membranoprolifirative glomerunephritis.
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Association between chronic HCV infection, mixed
cryoglobulinaemia and glomerular disease has
prompted the use of antiviral agents in these
patients in monotherapy or combined regimens .
IFN- monotherapy IFN has been proved to decrease
proteinuria and stabilize renal function, suppress
viremia .
It appears that, in mild renal disease, IFN with or
without low-dose steroids, is currently the best
option.
In patients with more severe disease, such as rapidly
progressive glomerulonephritis or nephrotic
syndrome with a rising creatinine level, a
combination of antiviral agents, steroids,
cyclophosphamide and/or plasmapheresis may be
needed.

severe cases of MPGN or rapidly
progressive glomerulonephritis ,initial
control of the inflammatory reaction with
immunosuppressive drugs may be
indicated .
Different therapeutic regimens used
for treating HCV-related
glomerulonephritis
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Antiviral therapy.
IFN -monotherapy.
Ribavirin monotherapy.
Combined IFN+ -ribavirin.
Immunosuppressive
therapy Cyclophosphamide
Cyclophosphamide+plasmapheresis.
Combined therapy IFN+ -corticosteroids.
Role of Corticosteroids in the
Hepatitis C


Prednisone priming prior to interferon
therapy in patients with chronic HCV
infection did not improve the sustained
response rate and, furthermore, that this
therapy was associated with significant
morbidity as well an increase in viral burden .
If corticosteroids are used in this setting, we
are careful to taper the dosage very slowly to
below 10 mg/day in order to minimize the
possible rebound effect of serum ALT.
Corticosteroid and
immunosuppressive therapies

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The poor disease course of patients with hepatitis B
virus treated with corticosteroids led to the
suggestion hypothesis that HCV viraemia would be
increased in patients treated with these drugs.
Some studies have described a rapid progression of
liver disease in immunosuppressed patients with
chronic HCV infection, i.e. patients coinfected with
HIV and HCV and transplanted patients .
Other studies found that corticosteroids increased
HCV viraemia when given for a short time (1–6
months) and that when corticosteroids were
withdrawn the viraemia reverted to previous levels .
References:

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AHFS Drug information 2007.
Uptodate 2004.
New york state department of health (Guide line
for management of HCV) .
Pl Martin and F Fabrizi. Hepatitis C virus and
kidney disease. Journal of Hepatology 49(4):
613-624. October 2008
Oxford journal –medicine –Rheumatology
volume 42.