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Terapia dell’epatite virale C tra passato e futuro

Terapia dell’epatite virale C tra passato e futuro. Edoardo G. Giannini, MD, PhD Cattedra di Gastroenterologia Dipartimento di Medicina Interna Università di Genova Genova. L’attesa dei nuovi farmaci antivirali.

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Terapia dell’epatite virale C tra passato e futuro

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  1. Terapia dell’epatite virale C tra passato e futuro Edoardo G. Giannini, MD, PhD Cattedra di GastroenterologiaDipartimento di Medicina InternaUniversità di Genova Genova L’attesadeinuovifarmaciantivirali XI Congresso Trisocietario Ligure di Gastroenterologia. Genova, 26 novembre 2011

  2. 1. Where we were in 2011 2. New drugs: for many but not for everyone 3. Therapeutic gain with DAAs 4. How to use DAAs 5. Conclusions Agenda HCV management in 2012

  3. Where we were in 2011 Beckett S. En Attendant Godot. 1952 Editions de Minuit, Paris, France.

  4. 1991 1998 2001 2002 2012 The Evolution of Initial HCV Treatment Smith RET. Nature Rev Drug Disc. 2006; 5: 715-716.

  5. The Evolution of HCV Therapy 2002 2012 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor Host targeting agent

  6. New Drugs:For Many But Not For Everyone

  7. Bad BugsNeed More Drugs

  8. HCV Standard of Care in 2011 Genotype 1: • Least responsive to PegIFN/RBV • Comonly associated with older age and advanced disease PegIFN alfa-2b 1.5 µg/kg/wk + RBV for 48 Wks PegIFN alfa-2a 180 µg/wk + Weight-Based RBV for 48 Wks 100 100 82 76 80 80 56 60 60 54 SVR (%) 46 42 40 40 20 20 n = 511 348 147 n = 453 298 140 0 0 Overall GT1 GT2/3 Overall GT1 GT2/3 Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982.

  9. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating ER lumen Virionassembly (+) RNA LD LD LD Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen Translation andpolyprotein processing Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  10. HCV NS3/4A Serine Protease:The “Master Switch” for Replication PKR regulator RdRp capsid envelope un 3' A B A B 5' core E1 E2 p7 NS2 NS3 NS5 NS4 Helicase domain Protease domain NS3: 70 kDa NS4A: 54aa Lindenbach BD, et al. Nature. 2005;436:933-938. Kim JL, et al. Cell. 1996;87:343-355. Love RA, et al. Cell. 1996;87:331-342. Yao N, et al. Structure. 1999;7:1353-1363. Kim JL, et al. Structure. 1998;6:89-100.

  11. HCV NS5B RNA Polymerase:Nucleoside and Nonnucleoside Inhibition Allosteric GTP-Binding Sites Flap Thumb Fingers Non-nucleoside Inhibitors Thumb Inhibitors Catalytic Site Nucleoside Analogues (potentially active across all genotypes) Non-nucleoside Inhibitors (gradient activity across HCV 1 subtypes) Palm Butcher SJ, et al. Nature. 2001;410:235-240.

  12. Each Drug Class Has Unique Features

  13. Therapeutic Gain With DAAs

  14. On-Treatment Viral Kinetics PEG-Interferon Ribavirin First phase Second phase HCV RNA HCV RNA negative in blood 0 4 12 24 36 48 Weeks

  15. On-Treatment Viral Kinetics Improve both first and second phase kinetics • Increase efficacy First phase Boceprevir / Telaprevir HCV RNA HCV RNA negative in blood 0 4 12 24 36 48 Weeks

  16. On-Treatment Viral Kinetics Improve both first and second phase kinetics • Increase efficacy • Shorten treatment duration First phase Boceprevir / Telaprevir HCV RNA HCV RNA negative in blood Secondphase 0 4 12 24 36 48 Weeks

  17. 2 Protease Inhibitors Approved for Genotype 1 HCV Infection For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV remains the standard of care Ghany MG, et al. Hepatology. 2011;54:1433-1444.

  18. SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced Patients 100 100 Current Standard of Care SOC + Protease Inhibitors 80 80 63-75 59-66 + 30% 60 60 SVR (%) SVR (%) 38-44 40 40 + 40% 17-21 20 20 0 0 Treatment-Naive Pts Treatment-Experienced Treatment-Naive Pts Treatment-Experienced Asselah T, et al. Liver Int 2011; 31 Suppl 1: 69-77.

  19. Telaprevir and Boceprevir SVR by Patient Type 100 75-83 80 68-75 53-62 60 52-59 SVR (%) 29-38 40 20 14* 0 Relapser Naive White/ Nonblack Naive Black Partial Responder Null Responder Cirrhotic Null Responder *Pooled TVR arms of REALIZE trial. Asselah T, et al. Liver Int 2011; 31 Suppl 1: 69-77.

  20. How to Use DAAs(Treatment-Naïve Patients)

  21. 0 4 8 12 24 28 36 48 New Standard of Care for Genotype 1Treatment-Naive Patients • Recommendation: Optimal treatment for all genotype 1 treatment-naive patients is BOC or TVR + pegIFN/RBV • BOC and TVR should not be used without pegIFN/RBV Boceprevir Early response*; stop at Wk 28; f/u 24 wks PegIFN + RBV BOC + PegIFN +RBV PegIFN + RBV F/u 24 wks BOC + PegIFN +RBV Telaprevir eRVR†; stop at Wk 24, f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV No eRVR; PegIFN+ RBV F/u 24 wks 0 4 12 24 48 *Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy).†Undetectable HCV RNA at Wks 4 and 12 of triple therapy. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

  22. SVR Rates With BOC + PegIFN/RBV in Genotype 1 Treatment-Naive Patients SPRINT-2 P < .001 P = .004 P < .001 P = .04 100 100 80 80 68 67 60 60 53 Patients (%) Patients (%) 40 42 40 40 23 20 20 125/311 211/316 213/311 n/N= 12/52 22/52 29/55 n/N= 0 0 PR 48 PR 48 BOC/PR48 BOC/PR48 BOC RGT BOC RGT Nonblack Patients Black Patients Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

  23. SVR Rates With TVR + PegIFN/RBV in Genotype 1 Treatment-Naive Patients ADVANCE Pooled Analysis From ADVANCE and ILLUMINATE Nonblack P < .001 Black 100 100 75 75 80 80 61 60 60 45 SVR (%) SVR (%) 44 40 40 25 20 20 n/N = 158/361 271/363 151/333 60/99 n/N = 7/28 599/804 0 0 PR T12PR PR T12PR Dusheiko GM, et al. EASL 2011. Abstract 1788. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

  24. Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive Patients • Recommendation: All therapy should be discontinued in patients with the following: Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

  25. How to Use DAAs(Treatment-Experienced Patients)

  26. Suboptimal Virologic Responses PegIFN/RBV 8 7 Relapse Null response 6 5 2 log10 decline Breakthrough HCV RNA (log10 IU/mL) 4 3 Partial response 2 Limit of detection 1 Incomplete treatment 0 0 4 8 12 18 24 30 36 42 48 54 60 66 72 78 Wks McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

  27. Retreatment of PegIFN/RBV Nonresponders Yields Low SVR Rates REPEAT EPIC3 DIRECT 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 Poynard T, et al. Gastroenterology. 2009;136:1618-1628. Bacon BR, et al. Hepatology. 2009;49:1838-1846. Jensen D, et al. Ann Intern Med. 2009;150:528-540.

  28. Retreatment of PegIFN/RBV Relapsers McHutchison et al. EPIC3 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 Poynard T, et al. Gastroenterology. 2009;136:1618-1628. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.

  29. 0 4 8 12 24 28 36 48 Retreatment With BOC + PegIFN/RBV in Treatment-Experienced Patients • Recommendation: BOC approved for previous relapsers, partial, and null responders. • AASLD guidelines say BOC “recommended” for previous relapsers and partial responders; advise caution in null responders given lack of definitive information from phase III studies Early response; stop at Wk 36; f/u 24 wks BOC + PegIFN + RBV PegIFN + RBV F/u 24 wks BOC + PegIFN + RBV PegIFN + RBV 0 4 8 12 24 28 36 48 100 Previous partial response Previous relapse 75 80 69 60 52 SVR (%) 40 40 29 20 7 n/N = 2/29 15/51 23/57 72/105 30/58 77/103 0 PR48 BOC RGT BOC/PR48 Ghany MG, et al. Hepatology. 2011;54:1433-1444. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.

  30. Retreatment With TVR + PegIFN/RBV in Treatment-Experienced Patients • Recommendation: TVR approved for previous relapsers, partial, and null responders • AASLD guidelines say TVR “recommended” for previous relapsers and partial responders; “may be considered” for previous null responders Previous relapsers* (same as naives) eRVR; stop at Wk 24, f/u 24 wks TVR + PegIFN + RBV PegIFN + RBV No eRVR; PegIFN + RBV F/u 24 wks 0 4 12 24 48 Previous partial responders† and null responders TVR + PegIFN + RBV PegIFN + RBV F/u 24 wks 0 4 12 24 48 *Response-guided therapy not studied in relapsers in registration trials.†AASLD guidelines say RGT “may be considered” for prior partial responders but package insert recommends 48 weeks of therapy Telaprevir [package insert]. 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

  31. SVR in Previous Relapsers, Partial Responders, Null Responders REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders Lead-in examined but found not to influence response and not included in TVR label PR48 T12/PR48 LI T12/PR48 Previous Relapsers Previous Partial Responders Previous Null Responders 100 88* 83* 80 59* 60 54* SVR (%) 40 33* 29* 24 15 20 5 n/N= 16/68 121/145 124/141 4/27 29/49 26/48 21/72 25/75 2/37 0 *P < .001 vs PR48. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

  32. Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Exp Patients • Recommendation: All therapy should be discontinued in patients with the following: Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

  33. Challenges as HCV Therapy Evolves to Incorporate DAAs Resistance issues • Impact of baseline variants • Persistence of resistant variants • Cross-resistance within classes • Impact of dosing/adherence Baseline predictors of response • Who to treat • Tailored therapies • Tailored duration New viral kinetic rules with new therapies • Positive predictive values • Negative predictive values • Tailored duration Markers of complete viral eradication Toxicities

  34. Success DoesNot Come Alone • Increasedincidenceofadverseevents • Increaseduseofgrowthfactors • Interactionwithdrugsmetabolisedby CYP-450 • Selectionofdrug-resistance • Increasedcosts

  35. The Reality of Current 48-Wk Standard-of-Care HCV Therapy Treatment-Naive G1 Patients SVR (40-50%) Discontinue (10-20%) SOC Tx Relapse (10-20%) NR (15-20%) Initial Treatment Present

  36. Evolving Therapies: Where Will We Be Soon? Treatment-Naive G1 Patients SVR SVR (60-70%) Discontinue Standard of Care Tx Discontinue (10-20%) Relapse Relapse (5-10%) NR NR (10-20%) Near Future Initial Treatment

  37. Conclusions The advent of DAAs has drmatically modified our approach to antiviral therapy in HCV genotype 1 patients. Boceprevir and Telaprevir provide a definite opportunity of cure especially to treatment-experienced patients. Evaluation of viral kinetics is the key and should be used to shorten duration of therapy in rapid responders, and terminate early treatment in patients who are unlikely to respond Use of DAAs may be associated with difficult treatment schedules and burdened with side effects. This “first wave” of drugs undoubtedly represents a useful paradigm for HCV treatment, and will open new avenues for new drugs.

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