1. Practical management of PI therapy in Hepatitis C Paris Februari 2012 Ola Weiland Karolinska Institutet Stockholm, Sweden

2. New major adverse events with PIs Exanthema for TVR Prolonged anemia with BOC

3. Telaprevir Illuminate study Sherman et al 2011

4. REALIZE: AEs in ≥25% of TVR-treated patients during any treatment phase* AE, n (%) Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Rash SSC93 (67)206 (53) Pruritus SSC82 (59)205 (52) Fatigue62 (45)214 (55) Headache54 (39)167 (43) Anemia SSC † 59 (42)134 (34) Nausea52 (37)129 (33) Influenza-like illness55 (40)124 (32) Insomnia39 (28)113 (29) Anorectal symptoms ‡ 33 (24)101 (26) Diarrhea33 (24)102 (26) Pyrexia34 (25)97 (25) *Grouped special search category (SSC); † Anemia reported by the investigator as an adverse event; ‡ Grouped term including several different AEs in the anorectal area; AE=adverse event Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

5. Boceprevir Respond study Bacon NEJM 2011

6. Sulkowsky et al 2011

7. Case number 1

8. HCV case male born 1947 Chronic HCV gt 1b IFN + RBV later part of 1990is relapse after Rx Liver biopsy 2004stage 1-2 Peg IFN alfa 2a + RBV in REPEAT study 72 ws Rx 2005 slow response-relapse 2005 Retinal emboli 2006 closure of atrial atrial septal defect

9. Male born 1947 gt 1 relapser on SOC

10. HCV case male born 1947 Retreat with PI + peg-IFN + RBV Wait for better DAAs

11. HCV case male born 1947 Retreatment with Telaprevir + peg-IFN alpha 2a + RBV In the realize study started Randomized to placebo – outcome response-relapse Later switched to Telaprevir + peg-IFN alpha 2a + RBV

12. Male born 1947 gt 1 relapser on SOC

13. RVR achieved but Exanthema developed

16. How to manage exanthema? Stop Rx ? Continue Rx ? Treat the exanthema and continue Rx ? Switch PI ?

17. How to manage exanthema? Initially Rx was continued Topical-steroids were given Desloratadine for pruritus

18. Outcome of exanthema? Continued to progress Week 8

20. What to do? Continue Rx with topical steroids ? Stop TVR week 8 ? Other measures ?

21. Treatment was stopped week 8 Due to exanthema and pruritus?

22. Grading of Rash (Skin Eruption) Severity  Grade 1 (Mild): localized skin eruption and/or a skin eruption with limited distribution, with or without associated pruritus  Grade 2 (Moderate): diffuse skin eruption involving up to 50% of body surface area, with or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration  Grade 3 (Severe): generalized skin eruption involving either >50% of body surface area OR rash presenting with any of the following characteristics –Rash with vesicles or bullae, superficial ulceration of mucous membranes, epidermal detachment, atypical or typical target lesions, palpable purpura/non-blanching erythema, drug reaction with eosinophilia and systemic symptoms, erythema multiforme, acute generalized exanthematous pustulosis, severe alteration of general state. A skin eruption with appearance of new significant systemic signs and symptoms related to onset and/or progression of skin eruption must be considered as grade 3  Grade 4 (life-threatening): –Toxic epidermal necrolysis, Stevens-Johnson syndrome, skin eruption with generalized bullous eruption Telaprevir French cohort ATU Protocol Available at http://www.afssaps.fr

23. Summary of Rash Data from ADVANCE Telaprevir/placebo Treatment Phase  ~90% of the rash was mild or moderate  6% of patients had a severe rash in the T12PR arm Features  Typically pruritic and eczematous, involving <30% body surface area Discontinuation (pooled telaprevir arms)  Telaprevir alone: 6%  All treatment: 0.9% Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A Patients (%) 56 6% severe 90% were mild or moderate Incidence of rashSeverity of rash T12PR: 12 weeks of telaprevir plus 24–48 weeks of PR

24. Study Drug Considerations: Grade 1 and 2 Rash Treating patients with mild or moderate rash  Use topical corticosteroids  Permitted systemic antihistaminic drugs may be tried  Regular follow up is important  Limit exposure to sun/heat  Suggest baking soda or oatmeal baths, and loose-fitting clothes Treating patients with mild or moderate rash  Use topical corticosteroids  Permitted systemic antihistaminic drugs may be tried  Regular follow up is important  Limit exposure to sun/heat  Suggest baking soda or oatmeal baths, and loose-fitting clothes Rash Grade 1 Grade 2 Telaprevir interruption generally not necessary If interruption is necessary, e.g. for progressive rash, recommend discontinue telaprevir first If no rash improvement within 7 days of stopping telaprevir (or earlier if worsening rash), consider interrupting ribavirin Telaprevir French cohort ATU Protocol Available at http://www.afssaps.fr

25. How should exanthema be treated Lubricants Topical steroiders : betamethasone – 10 days b.i.d. – 10 days q.d. – 10 every other day Desloratadine (Aerius®) once daily for pruritus

26. What SVR rate does the shortening of Telaprevir from 12 to 8 weeks Rx offer ? 1. 50% 2.55% 3.60% 4.69%

27. ADVANCE: SVR Rates in Telaprevir-treated Patients compared with PR Alone Jacobson IM, et al. Hepatology 2010;52(Suppl.):427AT8PR: 8 weeks of telaprevir plus 24–48 weeks of PR; *p<0.0001 vs PR48 * * 6% difference (95% CI: –12.5% to +0.6%) T12PR 271/363 T8PR 250/364 PR48 158/361 n/N =

28. ADVANCE: Overall On-treatment Virologic Failure Telaprevir dosed for 12 weeks versus 8 weeks reduces subsequent failure during PR phase T12PR Virologic failure 8% 0 4 8 12 16 20 4122428364048 Weeks on treatment Patients (%) 4122428364048 Weeks on treatment T8PR Virologic failure 13% 3% 5% 3% 10% 0 4 8 12 16 20 Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A

29. The outcome of our case? The exanthema vanished rapidly Pruritus vanished rapidly SOC treatment was continued SVR was reached

31. Case number 2

32. Case no 2 57 year old lady1 2005 advanced HCV HCV gt 1b Biopsy 2003 Fibrosis stage F3, A2 Treatment with peg-IFN ribavirin prolonged to 72 weeks - response-relapse

33. 57 yr old lady2 2010 advanced cirrhosis Fibroscan mean kPa 50 No focal lesion on ultrasound No major varices Earlier Multiforme exanthem on peg-IFN alfa 2b but not on alfa-2a Desired treatment

34. 57 year old lady3 At baseline ALT /AST1,63/1,52 µkat/L Platelets51 x 10 9 /L Neutrophils2 x 10 9 /L

35. 57 year old lady Should treatment be offered ? Are low platelets a contraindication ?

36. Rx or not PI + SOC ? Rx or not PI + SOC ?

37. 57 year old lady3 Treatment was given Telaprevir + peg-IFN alfa2a + ribavirin

39. Exanthema already day 2

42. 57 year old lady Stop Rx ? Continue Rx and use exanthema plan ? Switch PI? Other option ?

43. Treatment was con-d and for the exanthema the following was given Lubricants Topical steroiders : betamethasone – 10 days b.i.d. – 10 days q.d. – 10 every other day Desloratadine (Aerius®) once daily for pruritus

44. What happened with the patient? The exanthema vanished rapidly Pruritus vanished rapidly Tripel therapy was continued RVR was achieved

45. Anemia during PI treatment Management

46. Hemoglobin Shifts on Telaprevir Treatment in the ADVANCE Trial Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A 0 Median hemoglobin (g/dL) Weeks 0 11 12 13 14 15 481216 20 24 Telaprevir T12PR (n=363) T8PR (n=364) PR (control; n=361) Telaprevir End of telaprevir treatment Peg-IFN/RBV

47. Sulkowsky et al 2011

48. 57 year old lady At week 6 during treatment ALT 0,82 µkat/L Hemoglobin93 g/L Platelets32 x 10 9 /L Neutrophils0,6 x 10 9 /L

49. ExanthemaAnemia

50. Hemoglobin G/L

51. Ribavirin dose was reduced and Rx continued

52. ExanthemaAnemiaNeutropenia

53. Nuetrophils and platelets x 10 9 /L

54. Nuetrophils and paltelets x 10 9 /L Managed by peg-IFN dose reductions but no TVR dose change

56. Effect of Anemia on Efficacy in Treatment-naïve Patients who Received Telaprevir Patients with anemiaPatients without anemia T12PR24 149/196 T12PR 267/361 T12PR48 118/165 PR 46/92 T12PR24 206/269 T12PR 384/524 T12PR48 178/255 PR 108/262 n/N= SVR (%) Pooled analysis: ADVANCE and ILLUMINATE Phase III studies Sulkowski MS, et al. J Hepatol 2011;54(Suppl.):S195

57. Sulkowsky et al 2011 Management of anemia Boceprevir studies

58. Sulkowsky et al 2011

61. Fewer patients on BOC with low ITPA activity have RBV dose reduction and/or EPO use Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 934 *Multiple stepwise regression analysis ITPA activity % (n) Normal (n=616) Low (n=292) RBV dose reduction (regardless of EPO) RBV dose reduced (alone) RBV dose reduced plus EPO used 29 (177) 7 (44) 22 (133) 21 (63) 8 (22) 14 (41) EPO used (alone)20 (125)16 (47) No RBV dose reduction and no EPO51 (314)62 (182)

62. Management of Anemia observed with Telaprevir and Boceprevir in Placebo-controlled Clinical Trials Telaprevir Phase III trials 1,2 Boceprevir Phase III trials 3,4 Ribavirin dose reductions 25% (telaprevir arms)* 19–22% (boceprevir arms) vs 8–13% (control) EPO useNot permitted 41–46% (boceprevir arms) vs 21–24% (control) TransfusionsReported rarely (1.6%) ‡ 2–9% 3,4 Discontinuation Telaprevir alone: 4%** vs 0 % (control) ¥ All treatment at the same time: 1%** vs 1% (control) 0–3% (boceprevir arms) vs 0–1% (control) 1.Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A 2. Zeuzem S, et al. J Hepatol 2011;54(Suppl.):S3 3. Poordad F, et al. NEJM 2011;364:1195–1206 4. Bacon B, et al. NEJM 2011;364:1207–1217 *In the REALIZE trial; ‡ pooled placebo-controlled Phase II/III trials **T12PR in ADVANCE; ¥ discontinuation of placebo

65. REALIZE: laboratory abnormalities n (%) Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Hemoglobin ≤10g/dL ≤8.5g/dL 63 (46) 19 (14) 156 (40) 49 (13) Neutrophils Grade 3 (500 to <750/mm 3 ) Grade 4 (<500/mm 3 ) Grade 3/4 35 (25) 10 (7) 45 (32) 68 (17) 9 (2) 77 (19) Platelets Grade 3 (25,000 to <50,000/mm 3 ) Grade 4 (<25,000/mm 3 ) Grade 3/4 16 (12) 2 (1) 18 (13) 12 (3) 1 (<1) 13 (3) Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31

66. REALIZE: AEs leading to study drug discontinuation in pooled TVR arms Cirrhotics (F4) N=139 Non-cirrhotics (F0–3) N=391 Discontinuation of all study drugs during TVR treatment phase, n (%) Any AE Rash* Anemia* Pruritus* 10 (7) 3 (2) 1 (<1) 17 (4) 1 (<1) 3 (<1) 0 Discontinuation of TVR during TVR treatment phase, n (%) Any AE Rash* Anemia* Pruritus* 21 (15) 8 (6) 4 (3) 2 (1) 46 (12) 14 (4) 11 (3) 2 (<1) Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31 *Grouped SSC

67. REALIZE: hemoglobin levels in TVR-treated patients Median hemoglobin levels over time Mean change from baseline in hemoglobin Cirrhotics, n12413513112812011495931241351311281201149593 Non-cirrhotics, n341367360344339333306297340366359343338332306297 Total, n465502491472459447401390464501490471458446401390 36 Number of patients with data at each stated time point Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31 Cirrhotics (N=139)Non-cirrhotics (N=391)

68. REALIZE: platelet levels in TVR-treated patients Median platelet levels over time Mean change from baseline in platelets Cirrhotics, n12113112812511611293901211311281251161129390 Non-cirrhotics, n339364357342336331302292337362355340334328301291 Total, n460495485467452443395382458493483465450440394381 36 Number of patients with data at each stated time point Pol S, et al. Hepatology 2011;54(Suppl. S1): Abstract 31 Cirrhotics (N=139)Non-cirrhotics (N=391)

69. Case no 3

71. Stopping rules during boceprevir dosing period 0 48 Weeks 28 48 24 36 12 If ≥100 IU/mL at Week 12 If detectable at Week 24 Stop all drugs Boceprevir EU SmPC

72. Response-guided therapy criteria for TVR and BOC TVR SmPC: Detectable HCV RNA below the lower LOQ should not be used as a substitute for ‘undetectable’ for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates RT-PCR assay used in Phase III studies Limit of quantification (LOQ)25 IU/mL Limit of detection (LOD)9.3–15 IU/mL RGT criteria used in Phase III studies TVR: Undetectable HCV RNA at Week 4 and 12 (<LOD) BOC (naives): Undetectable HCV RNA at Week 8 and 24 (<LOD) RT-PCR: real-time PCR; RGT: response-guided therapyTelaprevir EU SmPC; Boceprevir EU SmPC

73. New on-treatment response-guided criteria with TVR and BOC Telaprevir EU SmPC; Boceprevir EU SmPC TVR + PR 048 Weeks 2848243612 BOC + PR PR +/- BOC PR Extension depending on on-treatment response, fibrosis stage and/or treatment experience HCV RNA undetectable at:

74. Telaprevir (ILLUMINATE): no RGT in treatment-naïve patients with cirrhosis 22% n=118 T12PR48 115/127 T12PR24 119/124 No fibrosis, minimal fibrosis, or portal fibrosis Bridging fibrosis Cirrhosis T12PR24 19/20 T12PR48 18/21 T12PR24 11/18 T12PR48 11/12 Telaprevir EU SmPC SVR: HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV-RNA data point from Week 12 of follow-up onwards was used

75. ADVANCE and ILLUMINATE (telaprevir): eligibility for shorter treatment duration Patients with undetectable HCV RNA (%) Week 4 (RVR) Weeks 4 and 12 (eRVR) Patients eligible to receive 24 weeks of treatment in total PR48 34/361 T12PR 635/903 T12PR 565/903 PR48 29/361 n/N= Adapted from Sherman KE, et al. CROI 2011. Abstract 957

76. Telaprevir regimen in G1 HCV-infected patients: treatment-NAÏVE without cirrhosis *In Phase III studies, a sensitive real-time PCR assay with a limit of quantification of 25 IU/mL and a limit of detection of 10–15 IU/mL was used to determine whether HCV RNA levels were undetectable. Detectable HCV RNA below the lower limit of assay quantification should not be used as a substitute for ‘undetectable’ for making decisions on treatment duration, as this may lead to an insufficient duration of therapy and higher relapse rates Telaprevir EU SmPC Peg-IFN alfa + ribavirin if detectable at Week 4 or 12* Peg-IFN alfa + ribavirin Stop at Week 24 if undetectable at Week 4 and 12 Telaprevir + PR If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR HCV RNA: 048 Weeks 4 24 36 12

77. Boceprevir (SPRINT-2): RGT in treatment naïve patients SVR (%) BOC44/ PR48 Undetectable HCV RNA between Weeks 8–24* Detectable HCV RNA ≥1 time between Weeks 8–24* BOC44/ PR48 BOC RGT *Not including 256/734 (35%) BOC-treated patients discontinuing prior to Week 28 due to a stopping rule, adverse events or non-medical reasons; SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward Boceprevir EU SmPC BOC 24 PR 28 Overall SVR 156/162 BOC RGT 155/16145/6855/73 BOC 24W PR 48W BOC 44 PR 48 BOC 44 PR 48 BOC44/ PR48 BOC RGT PR48 137/363 233/368242/366

78. Boceprevir (SPRINT-2): no RGT for patients with cirrhosis SVR (%) PR48 123/328 BOC44/ PR48 211/313 n/N= No, minimal or portal fibrosis (F0–F2) BOC RGT 213/319 Poordad F, et al. N Engl J Med 2011;364:1195–206 Cirrhosis (F4)Bridging fibrosis (F3) PR48 3/11 BOC44/ PR48 12/18 BOC RGT 9/18 PR48 6/13 BOC44/ PR48 10/24 BOC RGT 5/16 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward

79. Boceprevir regimen in G1 HCV-infected patients: treatment-NAÏVE without cirrhosis PR lead-in BOC + PR 048 Weeks 28 48 24 BOC + PR 36 PR* If detectable at Week 8 but undetectable at Week 24: 12 HCV RNA *This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC Assess for RGT criterion If ≥100 IU/mL discontinue all drugs If detectable discontinue all drugs Stop treatment at Week 28 if undetectable at Week 8 and 24

80. SPRINT-2 (boceprevir): eligibility for shorter treatment duration Patients with undetectable HCV RNA (%) PR48 60/363 BOC44/PR48 204/366 n/N= Week 8 1 Weeks 8 to 24 2 BOC RGT 208/368 BOC44/PR48 161/366 BOC RGT 162/368 Patients eligible to receive 28 weeks of total treatment 1. Boceprevir EU SmPC 2. Poordad F, et al. N Engl J Med 2011;364:1195–206 PR48 43/363

81. 48 4 012 36 24 Dosing duration in all patients with compensated cirrhosis BOC+ Peg-IFN + RBV Peg-IFN + RBV ≥100 IU/mL: Stop 3 drugs Detectable: Stop 3 drugs TVR + Peg-IFN + RBV Peg-IFN + RBV >1000 IU/mL: Stop 3 drugs >1000 IU/mL: Stop 3 drugs Detectable: Stop PR Detectable: Stop PR Telaprevir EU SmPC; Boceprevir EU SmPC

82. HCV RNA levels in patients who met the >1000 IU/mL HCV RNA Week 4 futility rule Treatment-naïve patients (n=15) Treatment-experienced patients (n=11) 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10 0468 12 102 Weeks on treatment HCV RNA (IU/mL) 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10 0468 12 102 Weeks on treatment HCV RNA (IU/mL) Adda N, et al. HepDART 2011; Abstract 45

83. This year has brought a paradigm shift to gt 1 treatment Addition of a 1 st gen protease inhibitor to SOC -Achieves 30 % higher SVR in naïve HCV genotype 1 patients -Offers shorter treatment for a majority

85. Thanks

86. Good Luck with the treatment of your HCV patients 2012