1. Hepatitis C virus treatment Heba Abd El-fattah Sabry Clinical pharmacist-heamatology Department Pharm D Student

2. 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.

3. 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.proteinsimmune systemvertebratesvirusesparasitestumor Interferons belong to the large class of glycoproteins known as cytokines.glycoproteinscytokines Interferons are produced by a wide variety of cells in response to the presence of double-stranded RNA, a key indicator of viral infection.RNA 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,antigen presentation 4. Inducing the resistance of host cells to viral infection

4. Mechanism of action

5. 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.

6. 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.

7. Types of interferon TYPE I interferon INFαINFβ TYPE II inteferon INFγ

8. 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)

9. 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.interferon beta-1ainterferon beta-1b multiple sclerosisautoimmune disorder 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.

10. 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.

11. 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.

12. FDA APPROVED REGULAR ALFA 2 b INTRON A ALFA-N3 ALFERON N ALFACON 1 INFERGEN 2 a ROFERON A BETA Beta-1a Avonex Beta-1b Betaseron GAMMA gamma-1b Actimmune PEGYLATED ALFA - 2a PEGASYS ALFA - 2b PEGINTRON

13. Trade nameGeneric name Roferon AInterferon alpha 2a Intron AInterferon alpha 2b MultiferonHuman leukocyte Interferon-alpha (HuIFN-alpha-Le) RebifInterferon beta 1aInterferon beta 1a, liquid form AvonexInterferon beta 1aInterferon beta 1a, lyophilized CinnovexInterferon beta 1aInterferon beta 1a, biogeneric (Iran) BetaseronBetaseron / Betaferon Interferon beta 1b PegasysPegylated interferon alpha 2a Reiferon Retard Pegylated interferon alpha 2aPegylated interferon alpha 2a (Egypt) PegIntronPegylated interferon alpha 2b PegetronPegylated interferon alpha 2bPegylated interferon alpha 2b plus ribavirin (Canada)ribavirin Types of interferon approved for use in humans

14. Pegylation : Process of covalent attachment of (polyethylene glycol) polymer chains to drug or therapeutic protein.polyethylene glycol) It produces alterations in the physiochemical properties including changes in conformation, electrostatic binding, hydrophobicity etc. propertiesconformation electrostaticbindinghydrophobicity 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.

15. Pegylated Interferon : Improved drug solubility.drug Enhanced protection from proteolytic degradation, increase biological half life. Reduced dosage frequency, without diminished efficacy with potentially reduced toxicity. toxicity Extended circulating life (reduce drug clearence). Increased drug stability.drug Lack of toxicity and immunogenicity. Altered distribution in the body.

16. 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

17. 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.

18. 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.

19. 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.

20. 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 )

21. PEGASYS and COPEGUS Dosing Recommendations DurationCOPEGUS Dose PEGASYS Dose Genotype 48 weeks 75 kg = 1200 mg 180 µgGenotype 1, 4 24 weeks800 mg180 µgGenotype 2, 3

22. 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 ).

24. 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

26. 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.

27. Dose Modifications PEGASYS Hematological Dose Modification Guidelines : Discontinue PEGASYS if: PEGASYS Dose Reduction Laboratory Values ANC <500/mm3, stop till count ↑ Reinstitute at 90 µg and monitor ANC 135 µgANC <750/mm3 Platelet count <25,000/mm3 90 µgPlatelet <50,000/mm3

28. 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.

29. 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 2 nd chamber containing sterile water for injection.

30. REBETOL ® PEG-Intron ® 800 mg/day in 2 divided doses 1.0 mcg/kg/w for one year), (180 mcg / w. for 24 to 48 weeks). (Combination) 1.5 mcg/kg/w. Dose: should not be used in patients with creatinine clearance <50 mL/min. Crcl 30-50ml/min: ↓ dose by 25%. Crcl 10-29ml/min: ↓ dose by 50%. Crcl <10ml/min: stop Dose adjustme nt.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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

36. Roferon A ®: INFalfa-2a Intron ® A INFalfa-2b 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. 3MIU tiw. For 18 to 24 months. persistently high levels of HCV RNA after 16 weeks of therapy stop treatment.RNA To inhance tolerability adminster at night. Dose Used with caution in patients with Crcl < 50 mL/min. (50% reduction) if S.E appear. Dose adj.

37. 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.

38. 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

39. 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

40. 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

41. 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.

42. 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.

43. 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.

44. 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.

45. 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

46. 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

47. 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.

48. 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.

49. 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.

50. severe cases of MPGN or rapidly progressive glomerulonephritis, initial control of the inflammatory reaction with immunosuppressive drugs may be indicated.

51. 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.

52. 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.

53. 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.

54. 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.