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慢性 C 型肝炎治療之現況 Current Status of Hepatitis C Treatment

慢性 C 型肝炎治療之現況 Current Status of Hepatitis C Treatment. 余 明 隆 Ming-Lung Yu Kaohsiung Municipal Ta-Tung Hospital Kaohsiung Medical University & Hospital Kaohsiung, Taiwan TSGH May 8, 2012. Outline. Introduction Evolution of Hepatitis C Treatment Standard-of-Care Personalized Therapy

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慢性 C 型肝炎治療之現況 Current Status of Hepatitis C Treatment

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  1. 慢性C型肝炎治療之現況Current Status of Hepatitis C Treatment 余 明 隆Ming-Lung Yu Kaohsiung Municipal Ta-Tung Hospital Kaohsiung Medical University & Hospital Kaohsiung, Taiwan TSGHMay 8, 2012

  2. Outline • Introduction • Evolution of Hepatitis C Treatment • Standard-of-Care • Personalized Therapy • Genotype-Guided Therapy • Response-Guided Therapy • Era of DAA for Hepatitis C Treatment

  3. Discovery of Hepatitis C Virus • The virus responsible for major transfusion-related NANB hepatitis (80%) • Identified by blind cDNA immunoscreening approach (before PCR technique), 1982-1989, Chiron Bradley DW, Et al. Gastroenterology 1985;88:773-779. Choo Q, et al. Science 1989;244:359-362.

  4. Hepatitis C Virus (HCV) Choo Q, et al. Science 1989;244:359-362.Bradley DW, Et al. Gastroenterology 1985;88:773-779. Shimizu YK, et al. Hepatology 1996;23:205-209. Kolykhalov AA, et al. Science 1997;277:570-574.

  5. Anti-HCV pos (%) 10 to 20 5 to 10 2 to 5 1 to 2 0 to 1 HCV Worldwide Prevalence 170 million carriers worldwide (3% of the general population) Heintges, T., Hepatology 1997; 26:521 WHO. Epidemiol Rec. 2000;75:18-19

  6. A-Lien 16% Byesa 23% Touyuan 35% Masagou 67% 台北縣 桃園縣 新竹縣 宜蘭縣 苗栗縣 Tzukuan 38% 台中縣 彰化縣 南投縣 花蓮縣 雲林縣 嘉義縣 台南縣 高雄縣 台東縣 屏東縣 Anti-HCV prevalence in Taiwan～4.4% in Adult Age-adjusted prevalence of anti-HCV 0 - 1% 1 - 3% 3 - 5% 5 -10% Yu ML, et al., J Med Virol, 2000. Chuang WL, Yu ML, et al., Intervirology, 2006Chen CH, et al., J Formos Med Assoc, 2007. Yang CF, ..Yu ML, et al. Kaohsiung J Med Sci, 2010

  7. HCV Genotype Distribution in Asia-Pacific Region Korea HCV-1: 68% HCV-2: 25% Else: 8% China HCV-1: 69% HCV-2: 13% Else: 18% Japan HCV-1: 67% HCV-2: 30% HCV-3: 1% Else: 2% Middle-East HCV-1: 2% HCV-4: 91% Else: 7% Taiwan HCV-1: 53% HCV-2: 40% Else: 8% India HCV-1: 14% HCV-2: 6% HCV-3: 67% HCV-4: 3% Else: 11% Macau, Vietnam, Hong Kong HCV-1: 50% HCV-2: 8% HCV-3: 7% HCV-6: 30% Else: 5% Southeast Asia HCV-1: 74% HCV-2: 4% HCV-3: 23% Australia/New Zealand HCV-1: 52% HCV-2: 9% HCV-3: 32% HCV-4: 6% HCV-6: 2% Yu ML & Chuang WL. J Gastoenterol Hepatol 2009

  8. Disease Progression in Hepatitis C (Slow) ≥30 years after infection Female sex, young age HCC (1–4% per year) Infection resolves spontaneously (20%-25%) Decompensation (~20%) (Fast) <20 years after infection Alcohol use, co-infection with HIV or HBV HCC = hepatocellular carcinoma Cirrhosis (20%) Normal liver Acute infection Chronic infection (75%-80%) Chronic hepatitis Rate of disease progression Lauer G & Walker B. N Engl J Med 2001; 345: 41.Maheshwari, A et al. Lancet 2008; 372: 321–32

  9. Extrahepatic Disorders Associated with Chronic HCV Infection Hematologic Essential mixed cryoglobulinemia Non-Hodgkin’s lymphoma RenalMembranoproliferative glomerulonephritis Membranous nephropathy Dermatologic Porphyria cutaneatarda Leukocytoclasticvasculitis Lichen planus Autoimmune Diabetes mellitus Idiopathic thrombocytopenic purpura Metaboilc Diabetes mellitus Altering lipid profile Cardiovascular? Huang JF, Yu ML, Chuang WL, et al. Am J Gastroenterol 2008; 103: 1933-40. Dai CY, Chuang WL, Yu ML, et al. J Hepatol 2008; ; 49: 9-16. Gumber SC and Chopra S., Ann Intern Med 1995;126 Cacoub P, et al., Medicine 2000; 79:47

  10. HCV - Cryoglobulinemia HCV RNA positive All Patients with EMC HCV RNA negative Anti-HCV antibodies can be demonstrated in the vessel walls of skin biopsies of patients with cryoglobulinemia and cutaneous vasculitis Agnello V, et al., N Engl J Med 1992; 327(21):1490 Agnello V. et al., Springer Semin Immunopathol 1997; 19:111; Monti G, et al., QJM 1995; 88:115

  11. HCV - Renal Manifestations- Proteinuria - P=0.03 P=0.02 P=0.04 P=0.02 P=0.004 P=0.004 P=0.002 P=0.001 Huang JF, Yu ML, et al. J Intern Med 2006

  12. HCV - Renal Manifestations • Most common lesion is membranoproliferative glomerulonephritis (MPGN) Univariate and Multivariate Logistic Regression Analyses of CKD Johnson RJ, et al., N Engl J Med 1993; 328:465 Fornasieri A, et al., Am J Kidney Dis 1996; 27:476 Tsui JI, et al. Arch Intern Med 2007;167:1271-6 Lee JJ, et al., Am J Kidney Dis. 2010 Jul;56(1):23-31.

  13. Prevalence of Overt T2DM among subjects with different etiologies of viral hepatitis Community survey of 10536 subjects P<0.001 P<0.001 P<0.01 Huang JF, Yu ML, Chuang WJ, et al. Am J Gastroenterol 2007; 102: 1237-43.

  14. P<0.001 P<0.001 P<0.001 86 478 997 8004 258 683 285 1412 86 478 3624 10536 199 478 6868 10536 3 3 1 2 Profound Influence of HCV ViremiaonMetabolic Profiles Prevalence % P<0.001 • Huang JF, Yu ML, Chuang WJ, et al. Am J Gastroenterol 2007; 102: 1237-43. • Huang JF, Yu ML, Chuang WL, et al. Am J Gastroenterol 2008; 103: 1933-40. • Dai CY, Chuang WL, Yu ML, et al. J Hepatol 2008; ; 49: 9-16.

  15. HCV – Cerebrovascular Disease Death A community-based prospective cohort study of 23 665 residents hazard ratio: 2.18 (1.5-3.2) Lee M et al. Stroke 2010;41:2894-2900.

  16. Chronic Hepatitis C: A Systemic Disease (Slow) ≥30 years after infection Female sex, young age HCC (1–4% per year) Infection resolves spontaneously (20%-25%) Decompensation (~20%) (Fast) <20 years after infection Alcohol use, co-infection with HIV or HBV HCC = hepatocellular carcinoma X X X X Cirrhosis (20%) Normal liver Acute infection Chronic infection (75%-80%) Chronic hepatitis X Rate of disease progression X Lauer G & Walker B. N Engl J Med 2001; 345: 41.Maheshwari, A et al. Lancet 2008; 372: 321–32

  17. Prevention of Hepatitis C Progression (Slow) ≥30 years after infection Female sex, young age (Fast) <20 years after infection Alcohol use, co-infection with HIV or HBV (Slow) Primary Prevention X Normal liver Acute infection Rate of disease progression Vaccine XEducation (Fast) Lauer G & Walker B. N Engl J Med 2001; 345: 41Maheshwari, A et al. Lancet 2008; 372: 321–32

  18. Education decreased anti-HCV prevalencein HCV-hyperendemic areas Adult population1,2 5 5 4.5% 4 4 2.8% 3 3 2 2 anti-HCV (+) (%) 1.0% 1 1 0.7% n= n= 4/394 4/89 32/616 25/887 0 0 1997-2005 2005 1993-4 1995 Teenage population3,4 1, Lu SN, Huang JF, et al. Kaohsiung J Med Sci 1997 2. Tsai PS, et al. Liver Int 2010 3. Huang JF, Yu ML, et al. Epidemiol Infect 2001 4. Huang CF, Yu ML, et al. Trans R Soc Trop Med Hyg 2008

  19. Prevention of Hepatitis C Progression (Slow) ≥30 years after infection Female sex, young age (Fast) <20 years after infection Alcohol use, co-infection with HIV or HBV Secondary Prevention X Normal liver Acute infection Chronic infection (75%-80%) Rate of disease progression Vaccine XEducation Infection resolves spontaneously (20%-25%) 1. IL28B CC genotype2. Younger age3. Symptomatic4. Transmission mode Lauer G & Walker B. N Engl J Med 2001;Maheshwari et al. Lancet 2008; Thomas et al. Nature 2009.

  20. Treatment of Acute Hepatitis C • Chronicity < 20% after 24-week Interferon-based therapy • Only 10-15% AHC patients are symptomatic Maheshwari et al. Lancet 2008; 372: 321–32

  21. Prevention of Hepatitis C Progression (Slow) ≥30 years after infection Female sex, young age (Fast) <20 years after infection Alcohol use, co-infection with HIV or HBV Tertiary Prevention X X HCC (1–4% per year) Cirrhosis (20%) Normal liver Acute infection Chronic infection (75%-80%) Chronic hepatitis Rate of disease progression X Vaccine XEducation X Infection resolves spontaneously (20%-25%) Decompensation (~20%) 1. IL28B CC2. Younger age3. Symptomatic4. Transmission mode Lauer G & Walker B. N Engl J Med 2001;Maheshwari et al. Lancet 2008; Thomas et al. Nature 2009.

  22. Objectives ofChronic Hepatitis C Treatment • Viral eradication • Sustained virological response (SVR) • serum HCV-RNA persistently undetectable (<50 IU/ml)for 24 weeks after end-of-treatment • Durable ( > 97% in 10-year FU) • SVR associated with improved outcome • Leads to improved histology • Leads to clinical benefits • Decrease risk of cirrhosis • Decreases decompensation • Prevents de novo esophageal varices • Decreases risk of hepatocellular carcinoma • Decreases mortality Bruno S, et al. Hepatology. 2010;51:2069. Veldt BJ, et al. Ann Intern Med. 2007;147:677. Maylin S, et al. Gastroenterology. 2008;135:821. Huang JF, Yu ML, et al., Aliment Pharmacol Ther. 2007;25:1029.Yu ML, et al., Antiviral Therapy, 2006;11:985.Yu ML, et al., Hepatology, 2006;44:1086.

  23. Reducing Risk of LC in non-cirrhotic CHC Patients with IFN-based Therapy Benefit only in patients with SVR • 1386 pts from LK-CGMH, KCGMH, KMUH • IFN-based therapy, 896; untreated, 494 • mean FU, 5.16 y (1-16 y) 22% 5% Huang JF, Yu ML, et al., Aliment Pharmacol Ther. 2007;25:1029-37.

  24. Reducing Risk of HCC Development and Mortality in CHC Patients with SVR to IFN-based Therapy • 1619 pts from LK-CGMH, KCGMH, KMUH • IFN-based therapy, 1057; untreated, 562 • mean FU, 5.16 y (1-16 y) 36% 35% RR, 0.245 3% Yu ML, et al., Antiviral Therapy, 2006;11:985-94.Yu ML, et al., Hepatology, 2006;44:1086-97.

  25. Outline • Introduction • Evolution of Hepatitis C Treatment • Standard-of-Care • Personalized Therapy • Genotype-Guided Therapy • Response-Guided Therapy • Era of DAA for Hepatitis C Treatment

  26. Interferon (IFN) has a dual MOA: Viral inhibition and Immune modulation 7 Lymphocyte 1. Inhibition of viral replication log HCV RNA 2. Immune system elimination of infected cells Induction phase Maintenance phase Detection limit 0 14–28 days 24–48 weeks 1stdose Adapted from Ferenci P, et al. Viral Hep Rev 1999; 5: 229

  27. Evolution of Hepatitis C Treatment IFN, interferonRBV, ribavirinPegIFN, pegylated IFN SVR rate Elucidation of HCV Genome IFN 6%-12% 1990 1995 2000 2005 Davis et al., NEJM 1989; Di Bisceglie et al., Ann Intern Med 1995; Boucher et al., Hepatology 1995;Lai et al., Gastroenterology 2000; McHutchison et al., NEJM 1998; Poynard et al., Lancet 1998; Sherman et al., Hepatology 1998; Zeuzem et al., Hepatology 1999; Zeuzem et al., Hepatology 2000; Nelson et al., Gastroenterology 2000; Zeuzem et al., NEJM 2000; Hadziyannis S, et al. Ann Intern Med 2004

  28. Ribavirin (RBV): exact MOA not fully understood • Potential mechanisms for antiviral activity of ribavirin • Direct inhibition of HCV replication • Inhibition of the enzyme inosine-monophosphate-dehydrogenase (IMPDH) • Immunomodulation (Th2 -> Th1) • Mutagenesis Dixit N & Perleson A, Cell Mol Life Sci 2006; 63: 832

  29. Evolution of Hepatitis C Treatment IFN, interferonRBV, ribavirinPegIFN, pegylated IFN IFN+Thymosin SVR rate IFN+UDCA IFN +Amantadin IL-12 IL-10 Elucidation of HCV Genome 40%-45% 0% IFN+RBV 6%-12% RBV IFN 1990 1995 2000 1998 2005 Davis et al., NEJM 1989; Di Bisceglie et al., Ann Intern Med 1995; Boucher et al., Hepatology 1995; Lai et al., Gastroenterology 2000;McHutchison et al., NEJM 1998; Poynard et al., Lancet 1998;Sherman et al., Hepatology 1998; Zeuzem et al., Hepatology 1999; Zeuzem et al., Hepatology 2000; Nelson et al., Gastroenterology 2000; Zeuzem et al., NEJM 2000; Manns M, et al. Lancet 2001;Fried M, et al. N Engl J Med 2002; Hadziyannis S, et al. Ann Intern Med 2004

  30. Optimised PK Pegylated IFN Optimising IFN-Alfa Pharmacokinetics Higher dose conventional IFN- Serum IFN- Levels (U/mL) Conventional IFN- One week Time Kozlowski et al. BioDrugs 2001; Perry & Jarvis. Drugs. 2001; Glue et al. Clin Pharmacol Ther. 2000.

  31. 48 wks’ treatment with PEG-IFN plus ribavirin is the standard of care 80 Peg-IFN-2a (40KD) + RBV 70 Peg-IFN-2b (12KD) + RBV 56% 60 54% 50 All HCV genotypes SVR (%) 40 30 20 10 n= 511 453 0 2001 2002 Fried2 Manns1 1. Manns M, et al. Lancet 2001; 358: 958 2. Fried M, et al. N Engl J Med 2002; 347: 975

  32. Evolution of Hepatitis C Treatment IFN, interferonRBV, ribavirinPegIFN, pegylated IFN IFN+Thymosin SVR rate IFN+UDCA IFN +Amantadin IL-12 IL-10 Elucidation of HCV Genome 55% - 60% PegIFN/RBV 40%-45% PegIFN IFN+RBV 6%-12% RBV IFN 2001 1990 1995 2000 1998 2005 Davis et al., NEJM 1989; Di Bisceglie et al., Ann Intern Med 1995; Boucher et al., Hepatology 1995; Lai et al., Gastroenterology 2000;McHutchison et al., NEJM 1998; Poynard et al., Lancet 1998;Sherman et al., Hepatology 1998; Zeuzem et al., Hepatology 1999; Zeuzem et al., Hepatology 2000; Nelson et al., Gastroenterology 2000; Zeuzem et al., NEJM 2000; Manns M, et al. Lancet 2001;Fried M, et al. N Engl J Med 2002; Hadziyannis S, et al. Ann Intern Med 2004

  33. Peg/RBV vs. IFN/RBV 24-wk PegIFN/RBV vs. IFN/RBV for CHC- A RCT of 5 Centers in Taiwan - PegIFN- 2b 1.5 g/kg/w + RBV 1000-1200 mg/dfor 24 w IFN- 2b 3 MU tiw + RBV 1000-1200 mg/dfor 24 w ITT 100 87% P=0.019 80 68% 67% 66% 64% 60 SVR (%) 41% 40 20 38 39 76 n= 38 38 77 0 All HCV-non-1 HCV-1 Early termination, Peg_18% vs. IFN_7%, P= 0.029 Lee SD, Yu ML, et al, J Viral Hepatitis 2005

  34. 全民健康保險加強慢性B型及C型肝炎治療試辦計畫 2002 • □ Anti-HCV (+) • □ ALT  2X 以上（半年兩次，間隔三個月） • □ 肝組織切片中等纖維化(  F2) • □ 無肝功能代償不全者 • 治療期限：6個月 □ -干擾素+ Ribavirin 800-1200mg /day

  35. Common AEs associated with HCV therapy Flu-like symptoms Fatigue, headache, fever,myalgia & rigors1–3 Hematological AEs4 Anemia, neutropenia & thrombocytopenia Dermatological AEs4 Skin rash, itching, injection site reactions, hair loss & eye problems HCV treatment-associated AEs Neuropsychiatric symptoms4 Cognitive impairment, anxiety, depression, irritability, insomnia & psychosis (rare) Gastrointestinal AEs4 Nausea, diarrhea, weight loss, dehydration, taste changes & mouth sores 1. Fried M, et al. NEJM 2002; 347: 975; 2.Hadziyannis S, et al. Ann Intern Med 2004; 140: 346; 3. Russo and Fried. Gastroenterol 2003; 124: 1711;4. Hepatitis C Support Project 2008. A guide to Hepatitis C treatment side-effect management. Available at: www.hcvadvocate.org (accessed June 2011) Yu-35

  36. Rare adverse effects of IFN-a -Arrhythmia -Myocardial infarction -Angina pectoris -TIA -Stroke -Acute psychosis -Major depression -Suicidal attempt -Importance -Retinal hemorrhage -Visual loss -Neuropathy -Seizures -Photosensitivity -Severe skin rashes -Local abscess -Interstitial pneumonitis -Type I DM Documented in clinical trial, manufactures’ data and isolated case reports

  37. Personalized HCV Therapy Maximize efficacyMinimize side effects and cost Issues with IFN-based Therapyfor Hepatitis C • Highcost • Moderate efficacy • Frequent side effects Efficacy is mainly determined by: Viral Factors, Host Factors & Treatment Regimens

  38. Baseline On-treatment Antivirals/Regimens • Virological factors • HCV genotype • HCV viral loads • Quasispecies • Host factors • Gender • Age • Ethnicity • Host genetics: IL28B polymorphisms • Insulin resistance • Obesity • Hepatic steatosis, fibrosis/cirrhosis • Coinfection with HIV • Nonresponse to previous antiviral therapy • Viral kinetics • RVR at week 4 • EVR at week 12, cEVR vs pEVR • Medical adherence • Preparation (PI, NNPI), dose, duration Factors associated withofSVR Changeable Yu ML & Chuang WL. J Gastoenterol Hepatol 2009 Ge D, et al. Nature. 2009;461:399-401.

  39. 84% 81% 80% 79% 52% 42% 41% 29% 96 144 99 153 n= 101118 250 271 Genotype 1 Genotype 2/3 Optimal treatment regimen-- Genotype-guided therapy Peg-IFN-2a 180 mcg/w + RBV 24-LD AASLD 2004 recommendation • 48 weeks of PegIFN plus SD of RBV for HCV-1/4 • 24 weeks of PegIFN plus LD of RBV for HCV-2/3 100 24-SD 48-LD 80 48-SD 60 RBVLD = 800 mg/d SD = 1000–1200 mg/d SVR (%) 40 20 0 Hadziyannis S, et al. Ann Intern Med 2004; 140: 346 Strader et al. Hepatology 2004

  40. Evolution of Hepatitis C Treatment IFN, interferonRBV, ribavirinPegIFN, pegylated IFN IFN+Thymosin SVR rate IFN+UDCA IFN +Amantadin IL-12 IL-10 Genotype-Guided Therapy Elucidation of HCV Genome 55% - 60% PegIFN/RBV 40%-45% PegIFN IFN+RBV 6%-12% RBV IFN 2004 2001 1990 1995 2000 1998 Davis et al., NEJM 1989; Di Bisceglie et al., Ann Intern Med 1995; Boucher et al., Hepatology 1995; Lai et al., Gastroenterology 2000;McHutchison et al., NEJM 1998; Poynard et al., Lancet 1998;Sherman et al., Hepatology 1998; Zeuzem et al., Hepatology 1999; Zeuzem et al., Hepatology 2000; Nelson et al., Gastroenterology 2000; Zeuzem et al., NEJM 2000; Manns M, et al. Lancet 2001;Fried M, et al. N Engl J Med 2002; Hadziyannis S, et al. Ann Intern Med 2004

  41. Data from International or Western Trials SVR Rate with Recommended Regimens 100 83% HCV-1/4, 48 weeks 95% HCV-2/3: 24 weeks 90 84% 80% 80 96 71 50% 70 60% 60 52% 52% 90 SVR (%) 50 46% 271 95 298 40 30 20 10 19 0 20021 20042 20063 20054 20042 20045 20054 1. Fried M, et al. N Engl J Med. 2002;347:975; 2. Hadziyannis S, et al. Ann Intern Med. 2004;140:346; 3. Ferenci P, et al. J Hepatol. 2006;44:275; 4. Zeuzem S, et al. J Hepatol. 2005;43:250; 5. Von Wagner M, et al. Gastroenterology. 2005;129:522;7.

  42. HCV G1 RVR Efficacy to 24w PegIFN/RBV for CHC in Taiwan 95% 84% 83% 100 83% 78% 50 64 29 45 CMUH5 KMUH6 Ninecenter7 TP-VGH3 KL-CGMH4 HCV non-1 PegIFNα-2a + RBV for 24w PegIFNα-2b + RBV fo 24w 87% PegIFNα-2a or 2b + RBV for 24w 100 90 57% 80 70 59% 58% 56% 60 56% 56% 100 36 SVR (%) 72 62 154 50 40 30 20 10 n= 0 CMUH5 KMUH1 NTUH2 TP-VGH3 KL-CGMH4 HCV-1 • Yu ML, et al., Hepatology 2008;47:1884-93. • Liu CH, et al. Clin Infet Diseas 2008; 47:1260-9. • Chu CJ, et al. Hepatogastroenterology 2007; 54:866-70. • Chen LW, et al.. J Gastroenterol Hepatol 2010; 25:259-63. • Su WP, et al. Hepatogastroenterology 2009; 56:798-801. • Yu ML, et al. Gut, 2007;56:553-9. • Liu CJ,.. Yu ML, et al. Gastroenterol 2009. 136:496-504

  43. HCV-1b Better efficacy with 48-wk PegIFN/RBVfor HCV-1 in Taiwan 3 RCTs in Taiwan, ITT Peg-IFN-2b + RBV 100 77% Peg-IFN-2a + RBV 90 80% 79% 76% 80 56% 70 59% 60 56% 49% 50 SVR rate (%) 40 30 20 10 15 154 n = 45 154 100 100 0 3NTUH 1KMUH 2KMUH 3NTUH 1KMUH 2KMUH 24 weeks 48 weeks • Yu ML, et al., Liver International, 2006, 26: 73-81. • Yu ML, et al., Hepatology 2008;47:1884-93. • Liu CH, et al. Clin Infet Diseas 2008; 47:1260-9.

  44. Higher SVR rate with SOC in Asian HCV pts PegIFNα-2a + RBV Western Countries or International Trials Korea Taiwan 95% 100 93% 87% 100 90 28 84% 79% 77% 80 100 110 65% 70 60 50% SVR (%) 50 40 30 20 10 0 11 6-8 12 10 1-5 9 6-8 Reference 1-5 HCV-1/4: 48 weeks HCV-2/3: 24 weeks 1. Fried M, et al. N Engl J Med 2002; 347: 975; 2. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346; 3. Ferenci P, et al. J Hepatol 2006; 44: 275; 4. Zeuzem S, et al. J Hepatol2005; 43: 250; 5 . Von Wagner M, et al.. Gastroenterology 2005; 129: 522; 6. Lee H, et al. Korean J Hepatol 2006;12:31- 40. 7. Kim KT, et al. Korean J Hepatol 2008;14:36-453. 8. Lee HJ, et al. Korean J Hepatol 2008;14:46- 57. 9. Yu ML, Hepatology 2008. 10. Liu CJ et al. Gastroenterol, in press. 11. Yu ML et al. Gut 2007;56:553.12. Lee SD, Yu ML et al, J Viral Hepatitis 2005

  45. HCV-2, IFN + RBV for 24 Wks HCV-1, IFN + RBV for 24 Wks HCV-1, LVL, PegIFN + RBV for 24 Wks A fixed treatment duration is not always appropriate The probability of SVR increases with the speed of viral clearance 100 93% 89% 94 78% 110 80 72% 45 22 60 SVR rate (%) 40 29% 25% 35 17% 61 20 24 0 Week 4 Week 24 Week 12 Time to First PCR HCV-Negativity RVR = HCV RNA <50 IU/mL at week 4 Zeuzem S, et al. J Hepatol 2006; 44: 97 Yu ML, et al., Translational Research 2006;148:120.

  46. Patterns of On-Treatment Virological Responses HCV Treatment 8 7 6 No EVR 5 2 log decline HCV RNA (log10 IU/mL) 4 EVR p 3 Slow responder 2 Limit of detection EOT 1 EVR c SVR RVR 0 -6 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Weeks RVR = rapid virologicalresponse EVR = early virological response; cEVR, complete EVR; pEVR, partial EVR SVR = sustained virological response Yu ML & Chuang WL. J Gastoenterol Hepatol 2009

  47. HCV-1 patients with an RVR and LVLEqual Efficacy with 24-week PegIFN/RBV HCV G1 RVR 100% 100% 96% 95% 93% 57 24 89% 27 85% 13 85% 27 110 13 19 Jens.3 Zeuz.4 Yu1 Liu2 Jens.3 Zeuz.4 Berg5 Berg5 Asian Caucasian Caucasian PegIFNα-2a + RBV PegIFNα-2b + RBV 96% 100 94% 28 69 90 80 70 60 SVR (%) 50 40 30 20 10 n= 0 Yu1 Liu2 Asian 48 weeks 24 weeks RVR = HCV RNA <50 IU/mL at wk 4; LVL (low viral load) = 1≤400,000; 4 ≤600,000; 2,3 ≤800,000 IU/mL 1. Yu ML, et al., Hepatology 2008;47:1884-93. 3. PEGASYS EU SPC, revised 2007. (based on: Jensen D, et al. Hepatology 2006; 43: 954)2. Liu CH, et al. Clin Infet Diseas 2008; 47:1260-9. 4. Zeuzem S, et al. J Hepatol 2006; 44: 97. 5. Berg A, et al. Hepatology. 2009;50:369-77.

  48. Treatment-naive CHC HCV Genotype1 or 4 HCV Genotype2 or 3 LVL andRVR (+) HVL or RVR (-) EVR (+) EVR (-) PegIFN/SD RBV for 24 weeks PegIFN/SD RBV for 48 weeks Stop treatment Roadmap for Individualized HCV Therapy SD: 1000-1200 mg/dLVL: HCV RNA < 400,000 IU/ml at wk 0RVR: HCV RNA < 50 IU/ml at wk 4 BL W4 W12 Cost saving: 11.8%/SVR Yu ML & Chuang WL. J Gastoenterol Hepatol 2009

  49. Extended Therapy in non-RVR HCV-1 PatientscEVR vs. pEVR (slow responders) Meta-analysis 42 (149) / 62 (142) 7 (7) /10 (11) 56 (87) / 68 (93) cEVR 8 (21) / 33 (52) 5 (7) / 11 (14) 17 (100) / 31 (106) 37 (86) / 35 (73) 9 (49) / 20 (52) 0 (21) / 4 (53) 1 (11) / 7 (9) 15 (52) / 20 (57) 12.6% (95% CI, 5.7 to 19.5%, p = 0.004) pEVR 14.7% (95% CI, 4 to 25.5%, p = 0.0072) Risk difference (SVR) Farnik H, et al. Clin Gastroenterol Hepatol 2010;8:884-90

  50. Non-EVR in HCV-1:12-week stopping rule PegIFN-2a 180 g/wk plus RBV1000–1200 mg/day EVR = HCV RNA negative or drop of ³2 log10 NPV = negative predictive value *PegIFN alfa-2a dosage reduced to 135 µg/wk after Wk 48 1. Yu ML, et al., Hepatology, 2008;47:1884-93.2. Ferenci P, et al. Gastrenterology. 2010;138:503-12.

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