1. Hepatitis C Viruses management in Thalassemia Rifaat Safadi MD Liver Unit, Hadassah Medical Center

2. Viral Hepatitis - Overview AABBCCDDEE Source of virus fecesblood/ blood-derived body fluids blood/ blood-derived body fluids blood/ blood-derived body fluids feces Route of transmission fecal-oralpercutaneous permucosal percutaneous permucosal percutaneous permucosal fecal-oral Chronic infection noyes no Preventionpre/post- exposure immunization pre/post- exposure immunization blood donor screening; risk behavior modification pre/post- exposure immunization; risk behavior modification ensure safe drinking water Type of Hepatitis

3. Hepatitis C Virus

4. USA 4 M USA 4 M SOUTH AMERICA 10 M SOUTH AMERICA 10 M AFRICA 32 M AFRICA 32 M EASTERN MEDITERRANEAN 20M EASTERN MEDITERRANEAN 20M SOUTH EAST ASIA 30 M SOUTH EAST ASIA 30 M AUSTRALIA 0.2 M AUSTRALIA 0.2 M WHO, 1999 WESTERN EUROPE 9 M WESTERN EUROPE 9 M FAR EAST/ASIA 60 M FAR EAST/ASIA 60 M 170 Million HCV carriers 3-4 MM new cases / year 3-4 MM new cases / year 170 Million HCV carriers 3-4 MM new cases / year 3-4 MM new cases / year

5. Prevalence of infection >10%2.5–10% 1–2.5% WHO. Wkly Epidemiol Rec 2002; 77: 41

6. Genotype prevalence varies according to geographic region 75% 1a, 1b 1a, 1b, 2, 3 4 4 5 5 4 4 1a, 1b, 2, 3 1a, 1b, 2, 3 3 3 1a, 1b, 3, 6 1a, 1b, 3, 6 1a, 1b, 3 2, 1b 1. Hoofnagle J. Hepatology 2002; 36: S21 2. Zein N. Clin Microbiol Rev 2000; 13: 223 3. Alter M, et al. N Engl J Med 1999; 341: 556

7. Sources of HCV Infection Sexual 15% 1% Nosocomial; iatrogenic; perinatal Unknown 10% Injecting drug use 60% Transfusion 10% (before screening) Source: Centers for Disease Control and Prevention Occupational 4%

8. Children at Risk for HCV Infection Recurrent blood or blood product transfusion Recurrent blood or blood product transfusion –hemophilia (80-95%), thalassemia (60-75%) Blood or blood product transfusion prior to 1992 Blood or blood product transfusion prior to 1992 –ALL (4-9%), cardiac surgery (4-5%), orthopedic surgery, NICU care Adolescents with “high-risk” behaviors Adolescents with “high-risk” behaviors Children born to HCV-infected women Children born to HCV-infected women

9. Serologic Pattern of Acute HCV Infection with Recovery Symptoms +/- Time After Exposure Titer anti-HCV ALT Normal 012345 61234 Years Months HCV RNA

10. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Symptoms +/- Titer anti-HCV ALT Normal 012345 61234 Years Months HCV RNA Time After Exposure

11. Hepatic Fibrosis is the Liver’s Wound Healing Response Hepatitis Viruses Alcohol Inherited Metabolic Disorders FIBROSIS Excess Vitamin A Cholestatic Disorders Immune Disorders Drugs

12. Hepatic Stellate cells - Perisinusoidal cells of Normal Liver Friedman and Arthur, Science & Medicine,

13. Normal LiverLiver Injury Quiescent Stellate Cell Hepatic Sinusoid Hepatocytes Activated Stellate Cells Deposition of Scar Matrix Space of Disse Kupffer Cell Endothelial Cell Loss of Hepatocyte Microvilli Loss of Fenestrae Kupffer Cell Activation Sinusoidal Changes during Liver Injury

14. Metavir Scoring System for Fibrosis F1 F3 F2 F4 Modified from Poynard

15. HCV is Asymptomatic for ~90% of its Natural History 20% Acute Variceal bleeding Liver Failure HCC F4 F3 F2 F1 F0 80% Chronic HCV Infection Modified from Poynard ~ 25 - 30 yrs ~ 1 - 5 yrs

16. Copyright ©2005 American Academy of Pediatrics Vichinsky, E. P. et al. Pediatrics 2005;116:e818-e825 AGE DISTRIBUTION OF PATIENTS WITH THALASSEMIA The age distribution of patients with thalassemia major in the present TCRN study (2002) are compared with 3 previous surveys (1973, 1985, and 1993) of similar regions

17. F METAVIR Duration (years) Rapid Intermediate Slow fibroser Poynard et al. Lancet 1997; 349: 825 N=1157 Progression of Liver Fibrosis in HCV

21. Cirrhosis is Reversible! Evidence in: HBV HBV HCV HCV Secondary biliary cirrhosis Secondary biliary cirrhosis AIH AIH PBC PBC Wilson’s disease Wilson’s disease Thalassemia after bone marrow transplantation Thalassemia after bone marrow transplantation Animal models Animal models

22. Cirrhosis Reversal post Lamivudine Rx in HBV Courtesy of Ian Wanless, MD

23. Reversibility of Cirrhosis Following Treatment of HCV Poynard et al, Gastroenterology 2002; 122:1303-1313 No. Patients

24. Time Serum Levels Old Treatment Strategies for HCV 1 Week Conventional IFN 

25. Time Serum Levels Old Treatment Strategies for HCV 1 Week Conventional IFN 

26. Time Serum Levels Higher-dose IFN  Old Treatment Strategies for HCV 1 Week Conventional IFN 

27. Time Serum Levels Higher-dose IFN  Optimized PK New Treatment Strategies for HCV 1 Week Conventional IFN 

28. WEIGHT-based dosing PEG-Intron ™ 1 PEGASYS ® 2 FIXED dose Lyophilized powder that needs to be reconstituted before each injection Dispensed as a stable solution ready for injection PEG IFNs: Dosing & Administration 1. PEG-Intron™. PDR ®. 56th ed. 2002. 2. Perry CM, Jarvis B. Drugs. 2001;61:2263-2288.

29. Patterns of virological response Sustained responder (SVR) Non-responder BaselineTreatment Time Relapser Partial responder Undetectable HCV RNA Breakthrough Detection limit 6 months 1. Strader D, et al. Hepatology 2004; 39: 1147 2. Farci P, et al. PNAS 2002; 99: 3081

30. Results of HCV Therapy: Overall SVR* 6 13 41 39 54 61 0 10 20 30 40 50 60 70 IFN 24 wk 1998 1 IFN 48 wk 1998 1 IFN + RBV 1998 1,2 PEG-IFN 2000 3,4 PEG-IFN + RBV 2002 5,6 1. McHutchison JG et al. N Engl J Med. 1998;339:1485-1492. 2. Poynard T et al. Lancet. 1998;352:1426-1432. 3. Zeuzem S et al. N Engl J Med. 2000;343:1666-1672. 4. Lindsay KL et al. Hepatology. 2001;34:395-403. 5. Manns MP et al. Lancet. 2001;358:958-965. 6. Hadziyannis SJ. EASL Annual Meeting. 2002. SVR (%) 25 *ITT analysis.

31. PEGASYS ® (Peginterferon Alfa-2a [40KD]) Plus RBV: SVR by HCV Genotype & Viral Load  2 x 10 6 copies/mL >2 x 10 6 copies/mL  2 x 10 6 copies/mL >2 x 10 6 copies/mL IFN  -2b + RBV PEG-IFN  -2a (40KD) + RBV Genotype 1Genotype 2/3 Fried MW et al. N Engl J Med. 2002;347(13):975-82. SVR (%)

32. 0 10 20 30 40 50 60 70 80 90 43 30 68 79 82 29 SVR (%) PEG-Intron ™ (Peginterferon Alfa-2b [12KD]) Plus RBV: SVR by HCV Genotype and Viral Load IFN  -2b + RBV PEG-IFN  -2b (12KD) 1.5  g/kg + RBV PEG-Intron™. PDR ®. 56th ed. 2002. n = 92n = 247n = 96n = 345n = 351n = 256  2 x 10 6 copies/mL >2 x 10 6 copies/mL Genotype 1 Genotype 2,3

33. Prognosis & response to IFN-based treatment vary with baseline factors Viral factors Viral factors –Genotype (1 and 4 versus 2 and 3) –Viral load (high versus low viral load) Patient-specific factors Patient-specific factors –Age –Liver histology (cirrhosis versus no cirrhosis) –Race –Body weight –Alcohol/drug use –Gender –Iron 1. Trepo C. J Viral Hepat 2000; 7: 250 2. Davis G & Lau G. Hepatology 1997; 26: 122S 3. Lee S, et al. Hepatology 2000; 32(4, pt 2): 370A 4. Poynard T, et al. Lancet 1998; 352: 1426 5. Schalm S, et al. Hepatology 1997; 26: 128S

34. Side effects of anti HCV treatment Interferon alpha2 Flu-like symptoms Flu-like symptoms –Fever, chills, Myalgia, arthralgia –Headache/ Fatigue or asthenia/ arthralgia Nausea/Anorexia/Diarrhea Nausea/Anorexia/Diarrhea Psychiatric symptoms Psychiatric symptoms –Depression/ Insomnia Alopecia Alopecia Injection-site reaction Injection-site reaction Leukopenia/ Thrombocytopenia Leukopenia/ Thrombocytopenia Thyroiditis/ Autoimmunity Thyroiditis/ Autoimmunity 1. INTRON ® A. PDR ® 2. ROFERON ® -A. PDR ® Ribavirin: Haemolytic anaemia Haemolytic anaemia Teratogenicity Teratogenicity Cough and dyspnoea Cough and dyspnoea Rash and pruritus Rash and pruritus Insomnia Insomnia Anorexia Anorexia 1. REBETOL ®. PDR ® 2. Chutaputti A. J Gastroenterol Hepatol 2000; 15(suppl): E156

35. Special At-Risk Patient Groups RBV-related risks RBV-related risks –Significant cardiovascular disease –Hemoglobin level <12 g/dL in women, <13 g/dL in men –Noncompliance with contraception –Renal failure –Thalassemia IFN-related risk IFN-related risk –Autoimmune diseases –Significant psychiatric disease

36. Safety & efficacy of pegylated interferon {alpha}-2a & ribavirin for HCV in thalassemia Haematologica. 2008 Jun 12 Median transfusions increased by 44%. Median transfusions increased by 44%. Overall liver iron remained stable. Overall liver iron remained stable. 1 of 4 patients with genotype 2 or 3 demonstrated SVR, compared with 50% with genotype 1 (6/12). SVR: 1 of 4 patients with genotype 2 or 3 demonstrated SVR, compared with 50% with genotype 1 (6/12). No patient developed cardiac, liver or endocrine toxicities, No patient developed cardiac, liver or endocrine toxicities, Neutropenia occurred in 52%. Neutropenia occurred in 52%.

37. New Therapeutic Approaches Serine Protease Inhibitors: Serine Protease Inhibitors: Anti HCV antibodies Anti HCV antibodies

38. New Therapeutic Approaches Growth Factors Growth Factors –Erythropoitin analogues –GCSF Viramidine vs. Ribavirin Viramidine vs. Ribavirin –Less Hemolysis –Less dose adjusment –More anti viral effect Patients with thalassemia should not be treated with RBV, and RBV should be avoided in patients with renal failure.

39. Thank You