Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy. Side effects of new and old HCV medications

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1 Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Milan, Italy Side effects of new and old HCV medications

2 The O.pe.r.a. Study Safety of PEG IFN and Ribavirin in 1523 HIV/HCV patients treated in Italy from 2004 to 2008 Others 10% Infections 5% Drop Out 12% Gastro 9% AE (16%) Skin 9% No withdrawal 71% Subjective Intol. 21% Psychiatric 21%

3 Telaprevir in Genotype 1 Patients 750 mg (two 375-mg tablets) q8hr with food (not low fat; standard fat meal is 21 g) Treatment Naive and Previous Relapsers TVR + PR PR ervr non cirrhosis; stop at Wk 24: 63% No ervr or cirrhosis; PR Previous Partial or Null Responders TVR + PR PR ervr: HCVRNA undetectable at 4 & 12 weeks Time Point Criterion Stopping Rule Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy Wk 24 Detectable HCV RNA Discontinue PR Any Discontinuation of PR for any reason Discontinue TVR Telaprevir [package insert]. May EMA. Telaprevir [package insert] 2011.

4 Boceprevir in Genotype 1 Patients 800 mg (four 200-mg capsules) q8hr with meal or light snack Treatment Naïve w/o cirrhosis PR BOC + PR BOC + PR Previous Relapsers or Partial Responders w/o cirrhosis PR Pts with cirrhosis or Null Responders PR BOC + PR BOC + PR Early response stop at Wk 28: 59% PR PR Wks Early response: HCVRNA undetectable at 8 & 24 weeks 48 All cirrhotic patients should receive lead-in followed by PR + BOC for 44 wks If considered for treatment, null responders should receive lead-in then PR + BOC for 44 wks EMA label recommends fixed-duration therapy for all trt-expd patients: LI + 32 wks triple + 12 wks PR Time Point Criterion Stopping Rule Wk 12 HCV RNA 100 IU/mL Discontinue all therapy Wk 24 Detectable HCV RNA Discontinue all therapy Any Discontinuation of PR for any reason Discontinue BOC Boceprevir [package insert]. May EMA. Boceprevir [package insert] 2011.

5 Boceprevir-Related Adverse Events in Clinical Trials Most notable adverse events occurring more frequently with boceprevir-based therapy vs pegifn/rbv ( mg/d) alone Anemia, neutropenia, and dysgeusia Adverse Event, % Boceprevir + PegIFN/RBV PegIFN/RBV Treatment-naive patients Anemia Neutropenia Dysgeusia Treatment-experienced patients Anemia Dysgeusia (n = 1225) (n = 323) (n = 467) (n = 80) Boceprevir [package insert]. May 2011.

6 Telaprevir-Related Adverse Events in Clinical Trials Most notable adverse events occurring more frequently with telaprevir-based therapy vs pegifn/rbv ( mg/d) alone Rash, anemia, and anorectal symptoms Adverse Event, % Telaprevir + PegIFN/RBV (n = 1797) PegIFN/RBV (n = 493) Rash Anemia Anorectal symptoms 29 7 Telaprevir [package insert]. May 2011.

7 Safety and tolerability with DAAs Common AEs with PR include: 1 3 Fatigue, headache, nausea, pyrexia and myalgia Anemia and neutropenia Depression, irritability and insomnia Rash Additional management considerations with DAAs Telaprevir: 4 6 Rash, Anorectal symptoms, Anemia Boceprevir: 7,8 Anemia and Dysgeusia AE: adverse event 1. Pegintron EMA Summary of Product Characteristics; 2. Pegasys EMA Summary of Product Characteristics 3. Rebetol EMA Summary of Product Characteristics; 4. Jacobson IM, et al. Hepatology 2010;52(Suppl.):427A 5. Sherman KE, et al. Hepatology 2010;52(Suppl.):401A; 6. Foster GR, et al. Hepatol Int 2011;5(Suppl. 1):14 7. Poordad F, et al. NEJM 2011;364: ; 8. Bacon BR, et al. N Engl J Med 2011;364:

8 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 8

9 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 9

Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase Incidence of rash (%) Incidence of rash (%) >90% of all rash = mild/moderate (N=1346) (N=764)

10 Summary of rash data from placebo-controlled Phase II and III trials: telaprevir treatment phase Incidence of rash (%) Incidence of rash (%) >90% of all rash = mild/moderate (N=1346) (N=764) Features: Typically pruritic and eczematous, and involving <30% BSA Progression was infrequent (<8% of cases) Time to onset: Approximately 50% of rashes started during the first 4 weeks But rash can occur at any time during telaprevir treatment Reported within a special search category Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf; Data on file: TVR/DoF/January2011/EMEA01

11 Summary of rash data from Phase II and III placebo-controlled trials:* discontinuations Discontinuations (%) Telaprevir alone Discontinuations (%) All treatment at the same time Improvement of rash occurs after telaprevir discontinuation Rashes may take weeks for complete resolution *During telaprevir treatment phase; analyzed within SSC INCIVO (telaprevir) draft EU SmPC [TBC]

12 Grading of skin eruption severity Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body) Moderate: diffuse rash involving 50% of body surface area Severe: extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment SCAR: generalized bullous eruption, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) INCIVO (telaprevir) draft EU SmPC [TBC]

13 Mild rash Moderate rash Severe rash

14 Estimating body surface area (BSA) 9% 9% Front 18% Back 18% 9% Adult body BSA Perineum 1% Arm 9% Head (front and back) 9% 18% 18% Leg 18% Chest 18% Back 18% Hettiaratchy S, et al. BMJ 2004;329:101 3

15 SCAR ( Severe Cutaneous Adverse Reactions) reported with telaprevir Collective term for severe drug-related skin conditions that can be associated with significant morbidity Acute generalized exanthematous pustulosis (AGEP) and Erythema Multiforme Major (EMM) SCAR encompasses several conditions Drug rash/reaction with eosinophilia and systemic symptoms (DRESS) Toxic epidermal necrolysis (TEN) and Stevens- Johnson Syndrome (SJS) 3 cases suggestive of SJS (of which 1 case considered not related to telaprevir, onset 11 weeks after telaprevir discontinuation) 11 cases suggestive of DRESS Roujeau JC, Stern RS. N Eng J Med 1994;331: Roujeau JC, et al. Dermatol Sinica 2009;27:203 9; Mockenhaupt M. J Dtsch Dermatol Ges 2009;7:

Telaprevir interruption guidance TELAPREVIR must not be restarted if discontinued Mild Monitor for progression or systemic symptoms until the rash is resolved Rash Moderate Severe SCAR Monitor for

For moderate rash that progresses to severe ( 50% body surface area), permanently discontinue telaprevir Permanently discontinue telaprevir immediately Monitor for progression or systemic symptoms

16 Telaprevir interruption guidance TELAPREVIR must not be restarted if discontinued Mild Monitor for progression or systemic symptoms until the rash is resolved Rash Moderate Severe SCAR Monitor for progression or systemic symptoms until the rash is resolved For moderate rash that progresses, permanent discontinuation of telaprevir should be considered. For moderate rash that progresses to severe ( 50% body surface area), permanently discontinue telaprevir Permanently discontinue telaprevir immediately Monitor for progression or systemic symptoms until the rash is resolved. If no improvement within 7 days of stopping telaprevir (or earlier if rash worsens), sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon should be considered Permanent and immediate discontinuation of telaprevir, peginterferon and ribavirin is required INCIVO (telaprevir) draft EU SmPC [TBC]

17 Drug considerations: mild and moderate rash Rash Mild Moderate Monitor for progression or systemic symptoms until the rash is resolved For moderate rash that progresses, permanent discontinuation of telaprevir should be considered If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted. Interruption of ribavirin may be required sooner if the rash worsens despite discontinuation of telaprevir Peginterferon alfa may be continued unless interruption is medically indicated For moderate rash that progresses to severe ( 50% body surface area), permanently discontinue telaprevir Treating patients with mild or moderate rash Use topical corticosteroids Permitted topical antihistaminic drugs may be tried Limit exposure to sun/heat Suggest baking soda or oatmeal baths, and loose-fitting clothes Treatment of rash with systemic corticosteroids is not recommended* *Concomitant telaprevir and systemic dexamethasone should be used with caution or alternatives should be considered. Co-administration with fluticasone or budesonide is not recommended unless the potential benefit outweighs the risk of corticoseroid side effects INCIVO (telaprevir) draft EU SmPC [TBC]

18 When to suspect DRESS Alarm signs: Relatively late eruption (2 6 weeks after treatment initiation) Prolonged fever >38.5 C Facial oedema Lymphadenopathy (at least 2 sites) What to do? Check for biological alterations Eosinophilia (absolute count and/or %) Atypical lymphocytes Leucocytosis Lymphocytosis Involvement of at least one internal organ (liver, kidney, lungs); raised alanine aminotransferase, creatinine Platelet levels below normal If DRESS is suspected Stop all drugs Hospitalize the patient Roujeau JC, et al. Dermatol Sinica 2009; 27: Walsh SA, et al. Clin Exp Dermatol 2011;36:6 11 Jeung Y-J, et al. Allergy Asthma Immunol Res 2010;2: Wolf R, et al. Clin Dermatol 2005;23:

19 When to suspect SJS/TEN Acute onset and rapid progression of skin and mucous lesions Small blisters arising on purple macules, widespread and usually predominantly on the trunk Severe and painful erosions of mucous membranes (buccal, ocular, genital) Epidermal detachment led by confluence of blisters Stevens-Johnson Syndrome: 1 10% of body surface area Toxic epidermal necrolysis: >30% of body surface area) Positive Nikolsky sign (epidermis detaches easily under lateral pressure with thumb) High fever What to do? Erythema Stop all drugs Hospitalize the patient Get dermatological advice Roujeau JC, et al. Dermatol Sinica 2009; 27: ; French LE, et al. Allergol Int 2006;55:9 16 Jeung Y-J, et al. Allergy Asthma Immunol Res 2010;2: ; Mockenhaupt M, et al. J Invest Dermatol 2008;128:35 44

20 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy 20

21 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 21

22 Anorectal disorders* during the telaprevir treatment period in Phase 2 and 3 studies Mechanism is unknown Proportion (%) of patients with: 1 T12/PR (750 mg q8h) N=1346 Placebo/PR48 N=764 AE AE of at least Grade AE leading to permanent discontinuation of telaprevir/placebo In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing 2 *Reported within a special search category 1. Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf; 2. Telaprevir EU SmPC

23 Anorectal signs and symptoms: management Standard, short-term symptomatic care may be warranted Consider proprietary combination hemorrhoid preparations according to the nature of the event Topical corticosteroids Antihistamines Topical local anaesthetics (e.g. lidocaine 2% cream) Hézode C. Liver International 2012;32 Suppl 1:32-8

24 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment 24

25 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 25

26 Summary of anemia data from Phase II and III placebo-controlled studies Incidence and severity of anemia increased with telaprevir combination treatment compared with PR alone Hemoglobin <10 g/dl Hemoglobin <8.5 g/dl Patients (%) T12/PR Control T12/PR Control INCIVO (telaprevir) draft EU SmPC [TBC]

Summary of anemia data from the boceprevir SPRINT-2 study over course of therapy Incidence and severity of anemia increased with boceprevir combination treatment compared

27 Summary of anemia data from the boceprevir SPRINT-2 study over course of therapy Incidence and severity of anemia increased with boceprevir combination treatment compared with PR alone Hemoglobin <10 to 8.5 g/dl Hemoglobin <8.5 g/dl Patients (%) BOC RGT BOC44/ PR48 Control BOC RGT BOC44/ PR48 Control Poordad F, et al. N Engl J Med 2011;364:

28 Management of anemia observed with telaprevir and boceprevir in clinical trials Ribavirin dose reductions due to anemia EPO use Transfusions Discontinuation *SPRINT-2 data only 2 Telaprevir Phase II/III placebocontrolled trials % (telaprevir arms) vs 9.4% (control) Not permitted (1% use) Telaprevir/placebo dosing phase: 2.5% (telaprevir arms) vs 0.7% (control) Overall study period: 4.6% (telaprevir arms) vs 1.6% (control) Telaprevir alone: 1.9% All treatment at the same time: 0.9% (telaprevir arm) vs 0.5% (control) Boceprevir Phase III trials 2,3 21% (boceprevir arms) vs 13% (control)* 41 46% (boceprevir arms) vs 21 24% (control) 2 9% (boceprevir arms) vs 0 1% (control) 0 3% (boceprevir arms) vs 0 1% (control) 1. INCIVO (telaprevir) draft EU SmPC [TBC] 2. Poordad F, et al. N Engl J Med 2011;364: Bacon BR, et al. N Engl J Med 2011;364:

SVR by minimum RBV dose/day during telaprevir/pbo treatment

Prior relapsers Patients with SVR (%) Never reduced 800 1000 mg

38/ 51 13/ 24 291/ 395 16/ 38 73/ 89 11/ 55 20/ 24 2/ 7 27/ 29

29 SVR by minimum RBV dose/day during telaprevir/pbo treatment phase (1 of 2) Treatment-naïve patients T12/PR or T12/PR48 PR Prior relapsers Patients with SVR (%) Never reduced mg 600 mg Never reduced mg 600 mg n/n= 346/ / / 51 13/ / / 38 73/ 89 11/ 55 20/ 24 2/ 7 27/ 29 2/ 6 Pbo: placebo Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459 S460

160/ 221 171/ 237 85/ 99 36/ 43 0 to 4 >4 to 12 >12 to 24 >24 to 48 Time to first dose reduction (weeks)* 6/ 10 40/

30 SVR according to timing of first RBV dose reduction in T12/PR or T12/PR48 groups Treatment-naïve patients Previously treated patients Patients with SVR (%) n/n= 0 to 4 >4 to 12 >12 to 24 >24 to 48 Time to first dose reduction (weeks)* 160/ / / 99 36/ 43 0 to 4 >4 to 12 >12 to 24 >24 to 48 Time to first dose reduction (weeks)* 6/ 10 40/ 53 19/ 24 6/ 8 *Time from first dose to first dose reduction Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459 S460

31 SVR according to time of first RBV dose reduction (during telaprevir/pbo treatment phase) and HCV RNA status Treatment-naïve patients in ADVANCE/ILLUMINATE (N=885) Time after first dose (weeks) HCV RNA status RBV dose reduction status SVR with T12/PR 0 4 Undetectable Had RBV dose reduction No RBV dose reduction 0 4 Detectable Had RBV dose reduction No RBV dose reduction >4 to 12 Undetectable Had RBV dose reduction No RBV dose reduction >4 to 12 Detectable Had RBV dose reduction No RBV dose reduction 40/45 (89) 347/405 (86) 120/176 (68) 168/259 (65) 163/206 (79) 502/594 (85) 8/31 (26) 2/48 (4) Small sample sizes among previously treated patients limit interpretation of data in REALIZE, however similar trends were observed Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459 S460

32 SVR according to permanent RBV discontinuation during overall treatment phase and HCV RNA status (TVR) Treatment-naïve patients in ADVANCE/ILLUMINATE (N=885) HCV RNA status RBV discontinuation status SVR with T12/PR Undetectable Detectable Did not discontinue Discontinued RBV Did not discontinue Discontinued RBV 591/659 (90) 84/171 (49) 0/8 (0) 0/47 (0) Small sample sizes among previously treated patients limit interpretation of data in REALIZE, however similar trends were observed Sulkowski MS, et al. J Hepatol 2012;56 (Suppl 2):S459 S460

33 Efficacy end points: EPO vs RBV dose reduction for managing anemia with boceprevir (95% CI) 0.7% ( 8.6, 7.2)* Patients (%) RBV DR EPO 203/ / / /251 19/196 19/197 *The stratum-adjusted difference (EPO vs RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort CI: confidence interval; EOT: end of treatment Poordad FF, et al. J Hepatol 2012;56 (Suppl 2):S559

34 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided 34

35 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 35

36 REALIZE: Baseline Characteristics According to Cirrhosis Status Characteristic Cirrhotics (F4) N=169 Non-cirrhotics (F0 3) N=493 Male, n (%) 126 (75) 334 (68) Caucasian race, n (%) 156 (92) 459 (93) Black race, n (%) 8 (5) 22 (4) Years of age, median (range) 54 (24 68) 50 (21 70) HCV RNA 800,000 IU/mL, n (%)* 150 (89) 436 (88) Body mass index, mean (SD) 28 (5.4) 27 (4.6) HCV genotype, n/n (%) 1a 1b Missing Prior response, n (%) Null responder Partial responder Relapser Lab measures, median (range) Platelet count, 10 9 /L Hemoglobin, g/l Neutrophil count, 10 9 /L 97 (57) 71 (42) 1 (1) 60 (36) 37 (22) 72 (43) 167 (88 425) 156 ( ) 3.3 (1.3 17) 255 (52) 229 (46) 9 (2) 124 (25) 87 (18) 282 (57) 225 (86 549) 154 ( ) 3.5 ( ) Pol.S et al. Hepatology 2011: 54: 374A

37 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 SSC 93 (67) 206 (53) Pruritus SSC 82 (59) 205 (52) Fatigue 62 (45) 214 (55) Headache 54 (39) 167 (43) Anemia SSC 59 (42) 134 (34) Nausea 52 (37) 129 (33) Influenza-like illness 55 (40) 124 (32) Insomnia 39 (28) 113 (29) Anorectal symptoms 33 (24) 101 (26) Diarrhea 33 (24) 102 (26) Pyrexia 34 (25) 97 (25) Pol.S et al. Hepatology 2011: 54: 374A

38 REALIZE: Laboratory Abnormalities in cirrhotics n (%) Hemoglobin 10g/dL 8.5g/dL Neutrophils Grade 3 (500 to <750/mm 3 ) Grade 4 (<500/mm 3 ) Grade 3/4 Platelets Grade 3 (25,000 to <50,000/mm 3 ) Grade 4 (<25,000/mm 3 ) Grade 3/4 Cirrhotics (F4) N= (46) 19 (14) 35 (25) 10 (7) 45 (32) 16 (12) 2 (1) 18 (13) Non-cirrhotics (F0 3) N= (40) 49 (13) 68 (17) 9 (2) 77 (19) 12 (3) 1 (<1) 13 (3) Pol.S et al. Hepatology 2011: 54: 374A

39 REALIZE: AEs Leading to Study Drug Discontinuation in Pooled TVR arms Cirrhotics (F4) N=139 Discontinuation of all study drugs during TVR treatment phase, n (%) Non-cirrhotics (F0 3) N=391 Any AE Rash SSC Anemia SSC Pruritus SSC 10 (7) 3 (2) 1 (<1) 1 (<1) 17 (4) 1 (<1) 3 (<1) 0 Discontinuation of TVR during TVR treatment phase, n (%) Any AE Rash SSC Anemia SSC Pruritus SSC 21 (15) 8 (6) 4 (3) 2 (1) 46 (12) 14 (4) 11 (3) 2 (<1) Pol.S et al. Hepatology 2011: 54: 374A

40 Compassionate Use of Protease Inhibitors in viral C Cirrhosis partial responders or relapsers: interim analysis after 16 weeks in 455 pts. (26-34% with phase 3 exclusion criteria; 15-16% with esophageal varices) Interim analysis Peg-IFN + RBV BOC + Peg IFN α 2b + RBV Follow-up BOC: 800 mg/8h; Peg IFNα 2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR + Peg IFN α 2a + RBV Peg IFN α 2a + RBV Follow-up TVR: 750 mg/8h; Peg IFNα 2a: 180 µg/week; RBV: 1000 to 1200 mg/day Weeks SVR assessment

41 Patients, n Telaprevir n=296 Boceprevir n=159 Serious adverse events (%) Premature discontinuation Due to SAEs (%) Death (%) Infection (Grade 3/4) (%) Asthenia (Grade 3/4) (%) Rash Grade 3 (%) Grade 4 (SCAR) (%) Preliminary safety findings Pruritus (Grade 3/4) (%) Hepatic decompensation (%)

Treatment-naïve Treatment-experienced Treatment-experienced n=727

42 Clinical Trials vs Real World Telaprevir Boceprevir PegIFN/RBV Clinical trials (including cirrhotics) Real world (cirrhotics only) Treatment-naïve Treatment-experienced Treatment-experienced n=727 n=361 n=734 n=363 n=530 n=132 n=323 n=80 n=296 n=159 (courtesy F. Poordad)

43 Causes of death Telaprevir Boceprevir Septicemia, Septic shock, Pneumopathy, Oesophageal varices bleeding, Encephalopathy, Lung carcinoma Bronchopulmonary infection, Sepsis

44 Patients Anemia (%) Grade 2 (8.0 <10.0 g/dl) Grade 3/4 (<8,0 g/dl) EPO use Blood transfusion Neutropenia (%) Grade 3 (500 <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use Thrombopenia (%) Preliminary safety findings Grade 3 ( <50 000) Grade 4 (<25 000) Thrombopoïetin Use Telaprevir (n=296) Boceprevir (n=159)

45 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided Patients with cirrhosis should be treated with great caution and careful monitoring especially if advanced. Surveillance and prompt treatment of infections and decompensation play a key role 45

46 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 46

47 Phase 2 studies with HCV PI in HIV/HCV Naggie S et al. Submitted 2011

48 Proportion of patients with advanced fibrosis in HIV/HCV coinfected patients enrolled in previous studies with PR and in DAA Phase 2 studies

49 Ribavirin dose reductions in the event of anemia* Copegus + Telaprevir Hb <10g/dL: 600mg/day Hb <8.5g/dL: RBV discontinuation Rebetol+ Boceprevir Hb <10g/dL: reduce by 200mg (may reduce by 200mg more than once) Hb <8.5g/dL: RBV discontinuation *in patients without cardiac disease; 400mg in patients receiving 1,400mg/day Copegus and Rebetol SmPCs

50 Boceprevir in HCV/HIV co-infection: patient disposition n (%) PR BOC/PR Treated 34 (100) 64 (100) Discontinued during treatment phase Due to AE Due to treatment failure Did not wish to continue Non Compliance with protocol Lost to follow up 18 (53) 3 (9) 14 (41) 1 (3) (38)* 13 (20) 6 (9) 3 (5) 1 (2) 1 (2) Completed treatment phase 12 (35) 40 (63) *Four subjects in the BOC/PR group discontinued treatment for reasons unrelated to AE or treatment failure; AE: adverse event Sulkowski M, et al. IDSA 2011: Abstract LB-37

51 Telaprevir in HIV/HCV Reasons for early discontinuation from study drugs Reason T/PR (N=38) PR (N=22) Discontinued during 16 (45) 9 (41) treatment phase Futility Rules 2 (5) 7 (32) Adverse events* 3 (8) 0 (0) Other** 11 (32) 2 (9) *Adverse events were haemolytic anaemia, cholelitiasis, nausea and vomiting (n=3) ** Other reasons include: lost to follow up (n=3), withdrawal of consent (n=1), noncompliance (n=4), lack of response (n=1), thought completed therapy (n=1), moved (n=1), patient decision (2).

52 Telaprevir in HCV/HIV co-infection: summary of rash and hematologic AEs n (%) PR (n=22) TPV/PR (n=38) Severe Rash Mild and Moderate Rash 0 5 (23) 0 13 (34) Anemia AEs leading to discontinuation Grade 3-4 (<8.0 g/dl) Erythropoietin use Transfusions 0 5 (23) 1 (5) 1 (5) 1 (2) 11 (29) 3 (8) 4 (11) Neutropenia Grade 1-4 (<1.55 x 10 9 /L) Grade 3-4 (<07.5 x 10 9 /L)????) Sulkowski M, et al. IDSA 2011: Abstract LB-37

53 Boceprevir in HCV/HIV co-infection: summary of hematologic AEs n (%) PR (n=34) BOC/PR (n=64) Anemia Serious AEs AEs leading to discontinuation Grade 1-4 (<11g/dL) Grade 3-4 (<8.0 g/dl) Erythropoietin use Transfusions 2 (6) 1 (3) 18 (53) 1 (3) 7 (21) 2 (6) 1 (3) 1 (2) 40 (63) 3 (5) 24 (38) 4 (6) Neutropenia Grade 1-4 (<1.55 x 10 9 /L) Grade 3-4 (<07.5 x 10 9 /L) 3 (74) (12) 10 (86) (27) Sulkowski M, et al. IDSA 2011: Abstract LB-37

54 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided Patients with cirrhosis should be treated with great caution and careful monitoring especially if advanced. Surveillance and prompt treatment of infections and decompensation play a key role Safety profile in persons living with HIV is similar to anti HIV but data on cirrhotics are lacking 54

55 Side Effects of new and old HCV medications Rash Anorectal disorders Anemia Side effects in cirrhotics Side effects in HIV DDI in the management of AE 55

56 Telaprevir and Antidepressants DDI with escitalopram (major substrate of CYP3A4, mixed metabolism): LSM ratio (90% CI), based on AUC Co-administered drug Dosage Co-administered drug Telaprevir Escitalopram 10 mg 0.65 ( ) Others not studied: Class Drug CYP3A4 substrate CYP3A4 inhibitor CYP3A4 inducer SSRI Fluoxetine Minor Moderate (mixed metabolism) SSRI Citalopram Major (mixed metabolism) SSRI Paroxetine Minor (mixed metabolism) SSRI Sertraline Minor (mixed metabolism) SSRI Fluvoxamine Moderate (mixed metabolism) Other Bupropion Other Venlafaxine Minor (mixed metabolism) TCA Trazodone Major (mixed metabolism) TCA Mirtazapine Major (mixed metabolism) Caution is warranted, and consider dose reductions of trazodone SSRI: selective serotonin re-uptake inhibitors; TCA: tricyclic antidepressant; AUC: area under curve; LSM: least squares mean; CI: confidence interval van Heeswijk R, et al. IWCPHT Abstract 12 Spina E, et al. Clinical Therapeutics 2008;30:

57 Contraindications with Telaprevir/Boceprevir Class Agent Telaprevir 1 Antihistamines Astemizole, terfenadine Diphenhydramine hydroxyzine, levocetirizine and desloratadine can be used CI Benzodiazepines Oral midazolam, oral triazolam oxazepam can be used CI Digestive motility stimulants Cisapride Domperidone Metoclopramide could be given CI Contraceptives (oral) Estroprogestatives Oral contraceptive may not be reliable PDE5 inhibitors* Sildenafil, tadalafil Dose reduction maximum 25 mg SIL/24 hr; 10 mg TAD/72 hr; VAR 2.5 mg/24 H BOC or 2.5 mg per 72 h TPV CI *Pulmonary arterial hypertension; removed/not available in all countries BOLD: DDI study completed Telaprevir & Boceprevir EU SmPC

58 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manegeable with prompt symptomatic treatment Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided Patients with cirrhosis should be treated with great caution and careful monitoring especially if advanced. Surveillance and prompt treatment of infections and decompensation play a key role Safety profile in persons living with HIV is similar to anti HIV but data on cirrhotics are lacking Management of AE should take into consideration DDI 58

59 Side Effects of new and old HCV medications Key messages Rash frequent with TPV close monitoring, management plan and identification of SCAR might reduce its impact on Treatment safety and efficacy Anorectal discomfort is frequent but manageable with prompt symptomatic treatment Anemia could be managed with ribavirin dose reduction without reducing treatment efficacy ( ribavirin overdosed?). Ribavirin withdrawal should be avoided. Patients with cirrhosis should be treated with great caution and careful monitoring especially if advanced. Surveillance and prompt treatment of infections and decompensation play a key role Safety profile in persons living with HIV is similar to anti HIV but data on cirrhotics are lacking Management of AE should take into consideration DDI 59

Management of adverse effects of triple therapy

Management of adverse effects of triple therapy Giovanni Battista Gaeta Cattedra di Malattie Infettive UOC Epatiti Virali Seconda Università di Napoli Disclosures Advisory board: BMS, Gilead, Janssen Speaker: