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Quali sono i limiti dell’attuale terapia

Terapia dell’epatite C tra passato e futuro. Quali sono i limiti dell’attuale terapia. Alessandro Grasso. S.C. Medicina Interna e Gastroenterologia Osp . San Paolo Savona . SVR Rates by HCV Treatment Drug Combination and Dose. 2011 Almost 50 % of patients do not respond to treatment.

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Quali sono i limiti dell’attuale terapia

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  1. Terapia dell’epatite C tra passato e futuro Quali sono i limiti dell’attuale terapia Alessandro Grasso S.C. Medicina Interna e Gastroenterologia Osp. San Paolo Savona

  2. SVR Rates by HCV Treatment Drug Combination and Dose 2011 Almost 50% of patients do notrespond to treatment 100 Manns et al[1] Fried et al[2] 80 56† 54* 60 47 47 44 SVR (%) 40 29 20 n = 505 514 800 224 444 453 n = 0 IFN + RBV PegIFN alfa-2b 0.5 + RBV800 PegIFN alfa-2b 1.5 + RBV800 IFN + RBV PegIFN alfa-2a PegIFN alfa-2a + RBV1000-1200 *P = .01 vs both arms, †P = .001 vs both arms 1. Manns MP, et al. Lancet. 2001 2. Fried MW, et al. N Engl J Med. 2002.

  3. Factors associated with a reduction of SVR rate with PegIFN + RBV • DISEASE RELATED • Genotype 1 (1) • High viralload(1) • Cirrhosis/bridgingfibrosis(1) • Steatosis(1) • TREATMENT RELATED • Aderence(1) • Duration and schedule (6-8) • Dose reduction(9) • Controindications(7) • PATIENTS RELATED • Age > 40 years(1) • Male sex (2) • Afro-american race (1) • Increased BMI (1) • MetabolicSyndr – Diabetes(2) • Immunosuppression (3) • Alcool (4) • Geneticpolimorphysm(5) 1) Dienstag JL et al. Gastroenterology 2006; 2) Manns MP et al. Lancet 2001; 3) Bain VG et al. Aliment Pharmacol Ther 2008; 4) Hadziyannis SJ et al. Ann Intern Med 2004; 5) Hanouneh IA et al Clin Gastroenterol Hepatol 2008; 6) Backus LI et al. Hepatology. 2007; 7) Pol S et al. Expert Opin Biol Ther 2006; 8) Ge D et al. Nature 2009; 9) Falck-Y et al. Ann Intern Med 2002

  4. Outline • Impact of viral, host and geneticfactors on SVR • Adherence to antiviral treatment

  5. Outline • Impact of viral, host and geneticfactors on SVR • Adherence to antiviral treatment

  6. PegIFN alfa-2b 1.5 µg/kg/week + RBV 800 mg/day for 48 weeks[1] PegIFN alfa-2a 180 µg/week + weight-based RBV (1000 or 1200 mg/day) for 48 weeks[2] SVR With PegIFN and Ribavirin according with genotype 100 82 76 80 56 60 54 46 SVR (%) 42 40 20 n = 511 n = 348 n = 163 n = 453 n = 298 n = 140 0 Overall GT 1 GT 2/3 Overall GT 1 GT 2/3 Fried MW, et al. N Engl J Med. 2002 MannsM, et al. Lancet. 2001

  7. SVR Rates by HCV Treatment Duration Genotype, and Baseline HCV RNA 24w Low Dose 24w Standard Dose 48w Low Dose 48w Standard Dose 100 100 88 85 84 84 83 82 81 80 80 79 77 80 74 80 65 55 60 52 60 52 47 Patients (%) Patients (%) 41 42 41 36 40 40 29 26 16 20 20 0 0 51 71 60 85 N =101 118 250 271 50 47 190 186 N = 96 144 99 153 34 47 33 48 62 97 66 105 AllPatients Low HCV RNA High HCV RNA AllPatients Low HCV RNA High HCV RNA Genotype 2/3 Genotype 1 Hadziyannis SJ, et al. Ann Intern Med. 2004

  8. SVR With PegIFN and Ribavirin according with genotype and stage of Fibrosis SVR at End of Follow-up 24 wks of RBV 800 mg/day + pegIFN alfa-2a 24 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a 48 wks of RBV 800 mg/day + pegIFN alfa-2a 48 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a 100 87 84 83 81 75 80 74 73 70 57 60 46 Patients (%) 45 41 40 29 28 26 26 20 0 Genotype 1 Genotype 2/3 Genotype 1 Genotype 2/3 Advanced Fibrosis Minimal Fibrosis Hadziyannis SJ, et al. Ann Intern Med. 2004.

  9. On-treatment Viral Response and Outcome • PPV for SVR in genotype 1 HCV • RVR 75-90% • EVR 50% • Slow responders 20-30% PegIFN alfa and RBV 7 Null Response* 6 5 Partial Response* 4 HCV RNA (log10 IU/mL) 3 Slow Response Relapse 2 1 Undetectable RVR EVR ETR SVR DVR 0 -8 -4 -2 0 4 8 12 16 20 24 32 40 48 52 60 72 Wks After Start of Therapy *Subset of Nonresponse Ghany MG, et al. Hepatology. 2009 on behalf of American Association for the Study of Liver Diseases

  10. Comparing Treatment Durations in GT 2/3 Patients Achieving RVR Von Wagner et al[1] Shiffman et al[2] 16 wks total 16 wks total PegIFN α-2a 180 µg/wk + WB RBV PegIFN α-2a 180 µg/wk + RBV 800 mg/day RVR RVR 24 wks total 24 wks total 100 100 85* 82 80 79 80 80 60 60 SVR (%) SVR (%) 40 40 20 20 0 0 24 Wks (n = 732) 16 Wks (n = 733) 16 Wks (n = 71) 24 Wks (n = 71) 1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Shiffman M, et al. N Engl J Med. 2007;357:124-134. *P = .002 vs 16 wks.

  11. Extending Therapy in Treatment-Naive Genotype 1 HCV Pts With Slow Response • Higher SVR rate with 72 vs 48 wks of treatment in slow responders*[1] • Dose reductions, discontinuations similar 48 wks total PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day Slow responders 72 wks total • p=0.004 100 • p=0.03 SVR 80 59 Relapse 60 38 Patients (%) 40 20 18 20 0 48 Wks(n = 165) 72 Wks(n = 161) • SUCCESS study had same study design and showed no overall benefit[2] 1. Pearlman BL, et al. Hepatology. 20007 2. Buti M, et al. EASL 2010

  12. Response-guided therapy in patients with genotype 1 (applies also to genotype 4 at a B2 grade of evidence) J Hepatol 2011 *LVL Y<400,000-800,000 IU/ml

  13. Response-guided therapy in patients with genotype 2 and 3 J Hepatol 2011

  14. Retreatment of PegIFN/RBV Relapsers McHutchison et al[1] EPIC3[2] 100 100 80 80 60 60 SVR (%) SVR (%) 40 40 33 20 20 20 0 0 PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV Relapsers PegIFN alfa-2a/RBV for 48 Wks in PegIFN/RBV Relapsers 1. McHutchison JG, et al. N Engl J Med. 2010 2. Poynard T, et al. Gastroenterology. 2009

  15. Retreatment of PegIFN/RBV Nonresponders Yields Low SVR Rates REPEAT[1] EPIC3[2] DIRECT[3] 100 100 100 80 80 80 60 60 60 SVR (%) SVR (%) SVR (%) 40 40 40 20 20 20 10.7 6.3 8.0 0 0 0 PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV Nonresponders PegIFN alfa-2a/RBV for 48 Wks in PegIFN alfa-2b/RBV Nonresponders cIFN for 48 Wksin PegIFN/RBV Nonresponders 1. Jensen D, et al. Ann Intern Med. 2009 2. Poynard T, et al. Gastroenterology. 2009 3. Bacon BR, et al. Hepatology. 2009

  16. REPEAT: 72-Week Treatment Duration Associated With Higher SVR Rate Patients with chronic HCV infection not responsive to pegIFNalfa-2b/ RBV therapy Modified ITT* 40 Pooled 72 weeks (n = 473) vs 48 weeks (n = 469) SVR (%) P = .0006 20 16 8 0 72 Weeks(360/180 µg and 180 µg) 48 Weeks(360/180 µg and 180 µg) n=469 n=417 Jensen D, et al. Ann Intern Med. 2009.

  17. Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV) • ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n = 1604) plus 67 patients from another trial Thompson AJ, et al. Gastroenterology 2010.

  18. A genome-wide associationstudy of more than 1,600 individualsidentifiedthat a polymorphism • on chromosome 19, rs12979860, is strongly associated with SVR The polymorphism resides 3 kilobases (kb) upstream of the IL28B gene encoding IFN-λ-3

  19. Interleukin-28B polymorphism is associated with rapid virological response in genotype 1 HCV patients Neumann AU, et al. J Hepatol 2010 Thompson AJ, et al. Gastroenterology 2010.

  20. High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitisC • Retrospectiveanalysis of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000 • A total of 253 patients were treated with either IFN monotherapy(either standard or pegylated) or IFN-2b in combination with ribavirin. BresslerBL,et al. Hepatology 2003

  21. Insulin-resistance and SVR in HCV G1 patients • 159 patients with chronichepatitis C (113 G1; 46 non-G1) treated with PegIFN + RBV 100 P = .007 80 61 60 SVR (%) 40 33 20 0 HOMA-IR > 2 HOMA-IR<2 Genotype , HOMA-IR and fibrosiswereindependentlyassociated with SVR Romero-Gomez M, et al. Gastroenterology. 2005

  22. Impact of insulin resistance on sustained response in HCV patients treated with pegylatedinterferon and ribavirin: A meta-analysis Deltenre P. et al. J Hepatol 2011

  23. Outline • Impact of viral, host and geneticfactors on SVR • Adherence to antiviral treatment

  24. Manyfactorsassociated with poor Adherence to PegIFN and Ribavirin

  25. Controls Impact of HCV Infection on Quality of Life HCV positive P < .01 for all comparisons between control and HCV positive SF36 Score 93 100 91 91 86 86 79 79 75 73 80 64 66 60 59 57 53 60 48 40 20 0 Pain RL: Physical Mental Health RL: Emotional Energy/Fatigue Health Perception Social Functioning Physical Functioning Foster G, et al. Hepatology. 1998.

  26. Common Adverse Events Associated With PegIFN/RBV Therapy • Influenza like (fatigue, headache, fever, and rigors): > 50% • Psychiatric (depression, irritability, and insomnia): 22% to 31% • Neutropenia (ANC < 1500/mm3): 18% to 20%[1,2] • Severe neutropenia* (ANC < 500/mm3): 4% • Serious infections are uncommon and G-CSF is rarely necessary[3] • Anemia (Hb < 12 g/dL): ~ 30%[1,2] • Nadir within 6-8 wks • Severe anemia† (Hb < 10 g/dL): 9% to 15% • Laboratory abnormalities are the most common reasons for HCV therapy dose reduction *And treatment discontinuation.†And dose modification. Manns MP, et al. Lancet. 2001 Fried MW, et al. N Engl J Med. 2002. Soza A, et al. Hepatology. 2002.

  27. Time Course of Treatment-Associated Psychiatric Adverse Effects 100 80 Anxiety Depression 60 Incidence/Severity Fatigue 40 20 Influenza-like symptoms 0 0 1 2 3 4 Months Dan A, et al. J Hepatol. 2006 Constant A, et al. J Clin Psychiatry 2005

  28. SVR according with Adherence to combination therapy in G1 chronic hepatitisC Analysis in a subgroup of 511 patientstreated with Peginterferon alfa 2b plus ribavirin 0-011 0-034 SVR % McHutchison JC, et al. Gastroenterology 2002

  29. The new waves of HCV therapy • Wave 3 (2016-2020): the holygrail • Oral cocktails of DAAs, hostcofactorinhibitor, RBV • Manyroads to the samedestination! > 90% cure of G1 with oralpills with no side effects • Wave 2 (2014-2016): the bettermousetrap • Substitution of 2° generation DAAs, nucs • Substitution of bettertoleratedIFNs • 4 drugregimen for P/R/DAA failure • Wave 1 (2011-2014): add-onTx • 1° generation DDAs + SOC: naive and experienced • -Naives: considerempiricTx • -Experienced: offerTx(particularlyrelapser) • -Nulls: stratify by stage 2001-2011 PegInterferon plus Ribavirin

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