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

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,2. Activating natural killer cells and macrophages, 3. Increasing antigen presentation to lymphocytes, 4. Inducing the resistance of host cells to viral infection

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 double-stranded 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 TYPE II inteferon

INFα 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: 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

FDA APPROVED

REGULARREGULAR PEGYLATEDPEGYLATED

ALFAALFA BETABETA GAMMAGAMMA ALFA - 2aALFA - 2a ALFA - 2bALFA - 2b

2 a2 a

2 b2 b

ROFERON AROFERON A

INTRON AINTRON A

PEGASYS

PEGASYS PEGINTRONPEGINTRONgamma-1b

Actimmune

gamma-1b Actimmune

Beta-1a

AvonexBeta-1a

Avonex

Beta-1bBetaseron

Beta-1bBetaseron

ALFA-N3ALFA-N3

ALFACON 1ALFACON 1

ALFERON N ALFERON N

INFERGENINFERGEN

Generic nameTrade name

Interferon alpha 2aRoferon A

Interferon alpha 2bIntron A

Human leukocyte Interferon-alpha (HuIFN-alpha-Le)Multiferon

Interferon beta 1a, liquid formRebif

Interferon beta 1a, lyophilizedAvonex

Interferon beta 1a, biogeneric (Iran)Cinnovex

Interferon beta 1bBetaseron / Betaferon

Pegylated interferon alpha 2aPegasys

Pegylated interferon alpha 2a (Egypt)Reiferon Retard

Pegylated interferon alpha 2bPegIntron

Pegylated interferon alpha 2b plus ribavirin (Canada)Pegetron

Types of interferon approved for use in humans

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 Dose

COPEGUS Dose

Duration

Genotype 1, 4

180 µg <75 kg = 1000 mg <75 kg = 1200 mg

48 weeks 48 weeks

Genotype 2, 3

180 µg800 mg24 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 µgANC <500/mm3, stop till count ↑Reinstitute at 90 µg and monitor ANC

Platelet <50,000/mm3

90 µgPlatelet count <25,000/mm3

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®REBETOL ®

Dose:1.0 mcg/kg/w for one year), (180 mcg / w. for 24 to 48 weeks).

(Combination)

1.5 mcg/kg/w.

800 mg/day in 2 divided doses

Dose adjustment.

Crcl 30-50ml/min:

↓ dose by 25%.

Crcl 10-29ml/min:

↓ dose by 50%.

Crcl <10ml/min: stop

should not be used in patients with creatinine clearance <50 mL/min.

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 PEG-Intron, 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) 22.5 MIU/1.5 ml/pen. 5 MIU (30 MIU) 37.5 MIU/1.5 ml/pen. 10 MIU (60 MIU) 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) 22.5 MIU/1.5 ml/pen. 5 MIU (30 MIU) 37.5 MIU/1.5 ml/pen. 10 MIU (60 MIU) 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

Dose3MIU 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( 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(:

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.

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 false-negative 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

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.

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

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 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:

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.