HCV treament with DAA Side effects: Anemia, Skin Manifestations Pr Patrice CACOUB

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1 HCV treament with DAA Side effects: Anemia, Skin Manifestations Pr Patrice CACOUB Service de Médecine Interne, CNRS UMR 7211, INSERM UMR 959 Université Pierre et Marie Curie Centre National de Référence Maladies Auto-immunes Hôpital La Pitié-Salpêtrière, Paris, FRANCE

2 Anemia and DAA during HCV treament

3 Peg-IFN/ribavirin/protease inhibitor for HCV treatment Main side effects: pooled phase III Telaprevir Rash (37%) Anemia (37% vs. 19%) Nausea (43% vs. 31%) Diarrhea (28% vs. 22%) Pruritus (50% vs. 36%) Boceprevir Anemia (49% vs. 29%) Dysgueusia (40% vs. 18%)

4 DAA & Anemia (1) Baseline characteristics : Age (years): 59 Gender: Female Body weight, 65 kg HCV genotype:1a Liver fibrosis F4 Previous response to antiviral therapy (PegIFNα/Ribavirin): relapser

5 Hg (g/dl) Week W0-W4 W4-W8 W8-W12 W12-16 W16-24 W24-48 Peg-IFNα (μg/week) Ribavirin (mg/day) Telaprevir (mg/day) 0 750x3 750x3 750x3 0 0 Epoietine beta (IU/week) ,000 30,000 30,000x2 30,000x2

6 W8, hemoglobin level 8.8 g/dl: What is your proposal? 1. Decrease the Ribavirin dose 2. Introduce Erythropoietin 3. Blood transfusion 4. Decrease PegIFN dose

7 Hg (g/dl) Week W0-W4 W4-W8 W8-W12 W12-16 W16-24 W24-48 Peg-IFNα (μg/week) Ribavirin (mg/day) Telaprevir (mg/day) 0 750x3 750x3 750x3 0 0 Epoietine beta (IU/week) ,000 30,000 30,000x2 30,000x2

8 Hg (g/dl) Week W0-W4 W4-W8 W8-W12 W12-16 W16-24 W24-48 Peg-IFNα (μg/week) Ribavirin (mg/day) Telaprevir (mg/day) 0 750x3 750x3 750x3 0 0 Epoietine beta (IU/week) ,000 30,000 30,000x2 30,000x2

9 W16, hemoglobin level 9.7 g/dl: What is your proposal? 1. Decrease the Ribavirin dose 2. Increase Erythropoietin dose 3. Blood transfusion 4. Decrease PegIFN dose

10 Hg (g/dl) Week W0-W4 W4-W8 W8-W12 W12-16 W16-24 W24-48 Peg-IFNα (μg/week) Ribavirin (mg/day) Telaprevir (mg/day) 0 750x3 750x3 750x3 0 0 Epoietine beta (IU/week) ,000 30,000 30,000x2 30,000x2

11 Hg (g/dl) Week W0-W4 W4-W8 W8-W12 W12-16 W16-24 W24-48 Peg-IFNα (μg/week) Ribavirin (mg/day) Telaprevir (mg/day) 0 750x3 750x3 750x3 0 0 Epoietine beta (IU/week) ,000 30,000 30,000x2 30,000x2

12 DAA & Anemia (2) Baseline characteristics : Age (years): 67 Gender: Female Body weight, 90 kg HCV genotype:1a Liver fibrosis : F1 Previous response to antiviral therapy (PegIFNα/Ribavirin): naive

13 Hg (g/dl) Week W0-W4 W4-W6 W6-W8 W8-W12 W12-16 W16-20 Peg-IFNα (μg/week) Ribavirin (mg/day) 1,200 1, Boceprevir (mg/day) 0 800x3 800x3 800x3 800x3 800x3 Epoietine beta (IU/wk) ,000 30,000x2 30,000x2 Red cell transfusion 3 packs at W6

14 W6, hemoglobin level 7.6 g/dl: What is your proposal? 1. Decrease the Ribavirin dose 2. Introduce Erythropoietin 3. Blood transfusion 4. Decrease PegIFN dose

15 Hg (g/dl) Week W0-W4 W4-W6 W6-W8 W8-W12 W12-16 W16-20 Peg-IFNα (μg/week) Ribavirin (mg/day) 1,200 1, Boceprevir (mg/day) 0 800x3 800x3 800x3 800x3 800x3 Epoietine beta (IU/wk) ,000 30,000x2 30,000x2 Red cell transfusion 3 packs at W6

16 W12, hemoglobin level 8.7 g/dl: What is your proposal? 1. Decrease the Ribavirin dose 2. Introduce Erythropoietin 3. Blood transfusion 4. Decrease PegIFN dose

17 Hg (g/dl) Week W0-W4 W4-W6 W6-W8 W8-W12 W12-16 W16-20 Peg-IFNα (μg/week) Ribavirin (mg/day) 1,200 1, Boceprevir (mg/day) 0 800x3 800x3 800x3 800x3 800x3 Epoietine beta (IU/wk) ,000 30,000x2 30,000x2 Red cell transfusion 3 packs at W6

18 Hg (g/dl) Week W0-W4 W4-W6 W6-W8 W8-W12 W12-16 W16-20 Peg-IFNα (μg/week) Ribavirin (mg/day) 1,200 1, Boceprevir (mg/day) 0 800x3 800x3 800x3 800x3 800x3 Epoietine beta (IU/wk) ,000 30,000 30,000 Red cell transfusion 3 packs at W6

19 Anemia and DAA during HCV treament Time-points? Prevalence: in phase 3 trials, in real life? Any difference Telaprevir vs. Boceprevir?

20 Peg-IFN/ribavirin/Telaprevir Trithérapie for avec HCV TVR treatment : Cinétique de l hémoglobine Hemoglobin levels: pooled phase III Hemoglobin (g/l) mean values T12/PR (750 mg q8h) Placebo/PR48 BL Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

21 Peg-IFN/ribavirin/Boceprevir Trithérapie for avec HCV BOC treatment : Cinétique de l hémoglobine Hemoglobin levels: pooled phase III Hemoglobin (g/l) mean values LI Boceprevir triple therapy or PR BOC/PR (N=1548) PR (N=547) Follow-up Weeks Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

22 Hemoglobin nadir Boceprevir & Telaprevir Boceprevir = 20 % 40 % BOC/PR PR Telaprevir Hb < 10 g/dl Hb < 8.5 g/dl % TVR12/PR PR 547/ /434 92/ / / /434 92/1048 Hb < 10 16/434 g/dl Hb < 8.5 g/dl Sprint 2, Respond 2 pooled FDA advisory committee briefing document

23 Anemia during Compassionate Use of Protease Inhibitors in viral C Cirrhosis (Cupic cohort) Anemia (%) Grade 2 ( g/dl) Grade 3/4 (<8.0 g/dl) Telaprevir (n=296) Boceprevir (n=159) Hézode C, et al. J Hepatol 2012;56 (Suppl 2):S4

24 Anemia and DAA during HCV treament Treatment options? Impact on costs, side effects, SVR?

25 Anemia during Peg-IFN/Ribavirin/Previr for HCV treatment Treatment options EPO Not reimbursed in many countries Side effects Rivarin dose reduction Impact on SVR rates? Blood transfusions Rejected by patients Risks of infection and immunisation

26 Ribavirin Dose Reduction and SVR Telaprevir, phase 3 trials Treatment naïve patients 89% 86% Patients with SVR (%) 68% 65% Sulkowski MS, et al. J Hepatol 2012;56(Suppl. 2):S459 S460

27 Ribavirin Dose Reduction and SVR Telaprevir, phase 3 trials Treatment-non naive patients Patients with SVR (%) Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459 S460

28 Ribavirin Impact Dose sur la Reduction RVS de la and réduction SVR de dose de RBV dans les essais Télaprévir de phase 3 Telaprevir, phase 3 trials Prior partial responders T12/PR48 PR Prior null responders Patients with SVR (%) n/n= Never reduced 21/ 32 4/ mg 1/ 2 0/ mg 8/ 13 0/ 5 Never reduced 18/ 59 1/ mg 2/ 3 0/ mg 2/ 8 1/ 4

29 Impact of anemia management on SVR Boceprevir SVR (%) SPRINT SVR (%) RESPOND No anemia EPO + RBV RBV EPO no EPO no RBV No anemia EPO + RBV 5 6 RBV EPO no EPO no RBV Anemia Anemia 29 Sulkowski M., EASL 2011, Abstract 476

30 Impact of anemia management on SVR Boceprevir SVR (%) SPRINT SVR (%) RESPOND No anemia EPO + RBV RBV EPO no EPO no RBV No anemia EPO + RBV 5 6 RBV EPO no EPO no RBV Anemia Anemia 30 Sulkowski M., EASL 2011, Abstract 476

31 Anemia and DAA/Boceprevir: A Prospective Randomized Trial EPO vs. Reduction of Ribavirin Dose Multicenter international (n = 687) Dose de RBV (n = 249) Après la PIB le BOC a été introduit chez tous les malades (n = 687) Hémoglobine < 10 g/dl* (n = 500) (72,8%) R EPO ( UI/Sem) (n = 251) Hémoglobine < 8,5 g/dl : seconde stratégie (EPO, dose de RBV, transfusion) * Patients might be randomized with Hb level 10 to 11 g/dl, if rapid decline Poordad F, EASL 2012, Abs. 1419

32 Anemia and DAA/Boceprevir: A Prospective Randomized Trial EPO vs. Reduction of Ribavirin Dose HCV RNA neg (%) Δ (IC 95 %) -0,7 (-8,6 ; 7,2) RBV dose EPO 203/ / / /251 19/196 19/197 Response end Rx SVR Relapse A second strategy was used in : 18 % of patients in the RBV reduction group 38 % of patients in the EPO group RBV dose decrease had no impact on SVR EPO, érythropoïétine ; RBV, ribavirin ; SVR sustained virological response. Adjusted diffference Poordad F, EASL 2012, Abs. 1419

33 Anemia and DAA/Boceprevir: EPO vs. Ribavirin Dose Reduction SVR and baseline characteristics Race, n/n (%) Gender, n/n (%) Weight, n/n (%) Fibrosis, n/n (%)* IL28B genotype, n/n (%) Catégorie RBV reduct. n = 249 EPO n = 251 Black 24/45 (53) 23/47 (49) Non-black 154/204 (75) 155/204 (76) Men 60/78 (77) 60/87 (69) Women 118/171 (69) 118/164 (72) < 75 kg 76/106 (72) 74/106 (70) 75 kg 102/143 (71) 104/145 (72) F0/1/2 156/211 (74) 147/203 (72) F3/4 19/33 (58) 26/39 (67) CC 61/78 (78) 63/77 (82) CT 86/123 (70) 89/133 (67) TT 30/46 (65) 24/37 (65) *Central pathologist. Poordad F, EASL 2012, Abs. 1419

34 Anemia and DAA/Boceprevir: EPO vs. Ribavirin Dose Reduction Side Effects Event, n (%) RBV reduct. n = 249 EPO n = 251 SE during treatment 248 (100) 248 (99) SE severe 39 (16) 33 (13) Anemia 4 (2) 2 (1) Death 1* (<1) 0 SE inducing treatment stop 27 (11) 32 (13) Stop due to anemia 5 (2) 6 (2) Blood transfusion 10 (4) 5 (2). SE: side effect; reduct reduction dose ; EPO, erythropoïétine ; *Cardiac arrest 3 weeks after the end of treatment Poordad F, et al. EASL Abstract 1419

35 Care of Anemia during Compassionate Use of Protease Inhibitors in viral C Cirrhosis (Cupic cohort) Anemia (%) Grade 2 ( g/dl) Grade 3/4 (<8.0 g/dl) EPO Transfusion RBV dose reduction Telaprevir (n=296) Boceprevir (n=159)) Hézode C, et al. J Hepatol 2012;56 (Suppl 2):S4

36 DAA and Anemia: Take Home Messages PegIFN/RBV plus BOC/TVR increase the rates of anemia (+20%) compared to PegIFN/RBV. In naive/relapser patients, non cirrhotics : First line strategy: RBV dose reduction (even when HCV RNA+) EPO: discussed on a case by case analysis In nul responders or cirrhotics : Need more data. If viremia positive, keep RBV dose and add EPO until negativation Permanent RBV stop has a negative impact on SVR V. Leroy Liver International July 2012

37 Skin eruption and DAA during HCV treatment Time-points? Prevalence: in phase 3 trials, in real life? Any difference Telaprevir vs. Boceprevir?

38 Patient with toxic skin eruption Baseline characteristics : Age (years): 52 Gender: Female Body weight, 72 kg HCV genotype: 1b Liver fibrosis: F2 Previous response to antiviral therapy (PegIFNα/Ribavirin): non-responder

39 W12 Toxic skin eruption Treatment, Day 0: PegIFNα (180μg/week) + Ribavirin (800mg/day) W4 to W8 : PegIFNα (180μg/week) + Ribavirin (1.000mg/day) + Telaprevir (750mgx3/day) Week 12 (i.e. W8 of triple HCV therapy) : HCV RNA negative, skin eruption

40 W8 of PegIFN/RBV/Telaprevir

41 W8 of PegIFN/RBV/Telaprevir

42 W8 of PegIFN/RBV/Telaprevir, skin eruption: What is your proposal? 1. Stop Telaprevir 2. Stop Ribavirin 3. Topic steroids plus skin hydratation 4. Decrease PegIFN dose

43 W12 Toxic skin eruption W12 to W16 : PegIFNα (180μg/week) + Ribavirin (1.000mg/day) + Telaprevir (750mgx3/day) + H2 blocker (Atarax 25mgx3/day) + Dexeryl cream Week 16 : regression of toxic skin eruption : -> toxidermia grade 1 W16 to W24 : PegIFNα (180μg/week) + Ribavirin (1.000mg/day) + Dexeryl cream, complete resolution of toxic skin eruption Week 72 : SVR, no more skin symptom

44 Cacoub P et al. J Hepatol 2012

45 Rash / Skin reactions, Boceprevir SPRINT 1, SPRINT 2, RESPOND 2 BOC/PR N = 1548 n (%) PR N = 547 n (%) Rash/ skin reaction 32% (490) 27% (150) Rash 17% (262) 17% (95) No Stevens-Johnson syndrome/ no DRESS syndrome

46 Skin Eruption with Telaprevir (pooled phase 2 & 3 studies) Incidence of rash (%) Telaprevir arms 33 Control arms Incidence of rash (%) Aspect > 90% mild or moderate Pruritus or eczema-like lesion <30% body surface Grade increase, rare (<10%) Starting point 50% within the first month

47 Skin Eruption with Telaprevir: time relationship, pooled phases 2 & 3 studies

48 Classification of Skin Lesion Grades Type Grade 1 (mild) Localized, w/wo pruritus Grade 2 (moderate) Diffuse 50 % BSA Grade 3 (severe) Grade 4 (SCAR) > 50% BSA or Mucous superficial ulcerations DRESS signs Drug Reaction with Hypereosinophilia Sd (DRESS) Stevens Johnson Syndrome (SJS) Toxic epiderrmic necrolysis (TEN, Lyell) BSA = body surface area; SCAR = severe cutaneous adverse reaction

49 Body surface evaluation Skin Eruption: Body Surface Evaluation 9 % 1 hand palm = 1 % 9 % 1 % Ant. 18 % Post 18 % 18 % 18 % 9 % Adult Surface Arm 9 % Head 9 % Neck 1 % Leg 18 % Trunk (anterior) 18 % Trunk (posterior) 18 % Hettiaratchy S, et al. BMJ 2004;329:101 3

50 Classification of Skin Lesion Grades Type Grade 1 (mild) Localized, w/wo pruritus Grade 2 (moderate) Diffuse 50 % BSA Grade 3 (severe) Grade 4 (SCAR) > 50% BSA or Mucous superficial ulcerations DRESS signs Drug Reaction with Hypereosinophilia Sd (DRESS) Stevens Johnson Syndrome (SJS) Toxic epiderrmic necrolysis (TEN, Lyell) BSA = body surface area

51 Grade 2 Skin Eruption with Telaprevir

52 Courtesy, N. Dupin Grade 2 eruption W5 telaprevir

53 Courtesy N. Dupin Week 2 of PegIFN/ribavirin/Telaprevir

54 Skin Quand Eruption adresser with Telaprevir au dermatologue? Grade 1 Local treatment Rash Grade 2 Local treatment Plus dermatology advise within 7 days GRADE 1 & 2 : management by the hepatologist or the HCV-physician Do not stop HCV treatment, including PI Anti-histaminics (H2-blockers) Topic steroids No sun exposure Follow-up of skin manifestations

55 Prescription in case of Grade 1 or 2 Skin Eruption with Telaprevir Miss Skin Hydratation with Dermachronic bid If pruritus or eczema : on involved skin areas Betamethasone (Diprosone ) topic bid for 2 wks, then thrice a week for one month Desloratadine (Aerius ) 2 pills/d Hydroxyzine (Atarax ) if insomnia Dr.. 55

56 Quand adresser au dermatologue? Skin Eruption with Telaprevir Grade 3 Dermatology advise : urgent (24.00 hrs.) Rash SCARs Hospitalization in a dermatology unit, urgent GRADE 3 & 4 : management by a dermatologist

57 Classification of Skin Lesion Grades Type Grade 1 (mild) Localized, w/wo pruritus Grade 2 (moderate) Diffuse 50 % BSA Grade 3 (severe) Grade 4 (SCAR) > 50% BSA or Mucous superficial ulcerations DRESS signs Drug Reaction with Hypereosinophilia Sd (DRESS) Stevens Johnson Syndrome (SJS) Toxic epiderrmic necrolysis (TEN, Lyell) BSA = body surface area

58 Skin Eruption with Telaprevir grade 3 (severe)

59 Skin Eruption with Telaprevir grade 3 (severe)

60 Skin Eruption with Telaprevir grade 3 (severe)

61 Skin Eruption with Telaprevir grade 3 (severe)

62 Courtesy N. Dupin Grade 2/3 skin eruption Moderate pruritus, Fever, 39 C PegIFN/ribavirin/Telaprevir - Stop Telaprevir

63 Courtesy N. Dupin Grade 3 skin eruption PegIFN/ribavirin/Telaprevir - Stop Telaprevir

64 SCAR: Severe Cutaneous Adverse Reaction 3 SJS 1 cas 11 S après l arrêt du TT) DRESS 11 cases of suspected (0.4%), 3 cas confirmation histologique DRESS also called drug-induced hypersensitivity syndrome (DIHS); SJS and TEN may be considered as variants of single disorder Roujeau JC, Stern RS. N Eng J Med 1994;331: ; Roujeau JC, et al. Dermatol Sinica 2009;27:203 9

65 Courtesy N. Dupin Week 9 of PegIFN/ribavirin/Telaprevir

66 Courtsey N. Dupin Week 9 of PegIFN/ribavirin/Telaprevir

67 Week 9 of PegIFN/ribavirin/Telaprevir Week 9 Telaprevir Body surface >40% Facial edema T > 38 7 C Eosinophilia = 913/mL DRESS possible Stop all treatments Courtesy N. Dupin S9

68 Cacoub P et al. J Hepatol 2012 Cacoub P et al. Am J Med, 2010 Grade 4 («risque vital») Évaluation générale du patient

69 Skin Eruption with Telaprevir Take Home Messages Quand arrêter le Télaprévir Grade 1 Do NOT stop Telaprevir Rash

70 Quand arrêter le Télaprévir Skin Eruption with Telaprevir Take Home Messages Grade 1 Do NOT stop Telaprevir Rash Grade 2 Do NOT stop Telaprevir Stop only if progression of skin lesions Stop ribavirin if not better 7 days after stopping Telaprévir

71 Skin Eruption with Telaprevir Take Home Messages Quand arrêter le Télaprévir Grade 1 Do NOT stop Telaprevir Rash Grade 2 Grade 3 Do NOT stop Telaprevir Stop only if progression of skin lesions Stop ribavirin if not better 7 days after stopping Telaprevir Stop Telaprevir Stop ribavirin if not better 7 days after stopping Telaprevir

72 Skin Eruption with Telaprevir Take Home Messages Quand arrêter le Télaprévir Grade 1 Do NOT stop Telaprevir Rash Grade 2 Grade 3 Do NOT stop Telaprevir Stop only if progression of skin lesions Stop ribavirin if not better 7 days after stopping Telaprevir Stop Telaprevir Stop ribavirin if not better 7 days after stopping Telaprevir Grade 4 Grade 4 Stop ALL treatments