Clinical Cases Hepatitis C Naïve Patients Rafael Esteban Liver Unit. Hospital General Universitari Vall Hebron. Barcelona.
Case study 1 27 year old woman, Diagnosed with Chronic Hepatitis C 3 years ago Never treated Risk factor: occasional IVDU 10 years ago Weight: 65 kg No comorbidity, no medications Genotype 1b, HCV RNA 1.000.000 UI/mL Fibroscan: 8 KPa
Case study 1 Asymptomatic She wants to clear the viral infection quickly before being pregnant, so she wants to start a treatment rapidly No contraindication for the treatment
Would you treat her? No, because she has no significant fibrosis Yes, because she is really motivated
Would you perform an IL28B genotyping in this patient? Yes, because the IL28B polymorphism can influence the treatment strategy No
Impact of IL28B polymorphisms on SVR in naïve patients RVS (%) 100 80 60 40 20 78 CC 82 80 28 CT 65 71 27 TT 55 59 RVS (%) 100 80 60 40 20 64 CC 90 25 CT 71 23 TT 73 0 n/n= PR48 50/64 BOC RGT 63/77 BOC44/ PR48 44/55 PR48 BOC RGT 33/116 67/103 BOC44/ PR48 82/115 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 PR48 10/37 BOC RGT 23/42 BOC44/ PR48 26/44 0 PR48 n/n= 35/55 T12PR PR48 T12PR PR48 T12PR 45/50 20/80 48/68 6/26 16/22 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
RVS (%) 100 80 60 40 20 Impact of IL28B polymorphisms on SVR in CC CT TT 82 78 80 71 65 59 55 28 27 naïve patient RVS (%) 100 CC 90 CT TT 80 71 73 64 60 40 25 23 20 0 n/n= PR48 50/64 BOC RGT 63/77 BOC44/ PR48 44/55 PR48 BOC RGT 33/116 67/103 BOC44/ PR48 82/115 Poordad F, et al. J Hepatol 2011;54(Suppl.):S6 PR48 10/37 BOC RGT 23/42 BOC44/ PR48 26/44 0 PR48 n/n= 35/55 T12PR PR48 T12PR PR48 T12PR 45/50 20/80 48/68 6/26 16/22 Jacobson IM, et al. J Hepatol 2011;54(Suppl.):S542 89 % of CC patients treated with BOC/PR were eligible for shorter therapy 80 % of CC patients treated with TVR/PR were eligible for shorter therapy
IL28B genotyping: CC Case study 1
Are you going to treat her? PegInterferon +Ribavirin PegInterferon +Ribavirin+Telaprevir PegInterferon+Ribavirinin + Boceprevir
SVR Rates by First Time to PCR Negativity in HCV-1 ( 600,000 IU/mL), 24 vs. 48 Weeks Tx. PEG-IFN α-2b 1.5 µg/kg QW + ribavirin 800-1400 mg/day 24 Weeks Tx. 1, N=235 48 Weeks Historical Control 2, N=38 100% 89% 100% 85% 93% 80% 80% 67% % of Patients 60% 40% 20% 25% 17% % of Patients 60% 40% 20% 0% 4, (n=110) 12, (n=61) 24, (n=24) 0% 4, (n=13) 12, (n=15) 24, (n=3) 47% HCV RNA PCR Negative (<29IU/mL at Week 4. 1. S. Zeuzem et al., Journal of Hepatology 44 (2006) 97 103. 2. Manns M. et al., Lancet 2001; 358: 958 65.
Standard of Care for Genotype 1 Treatment-Naive Patients Boceprevir [1,2] PegIFN + RBV BOC + PegIFN + RBV BOC + PegIFN + RBV 0 4 8 12 24 28 36 Telaprevir [2,3] TVR + PegIFN + RBV PegIFN + RBV 0 4 12 24 *Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). Undetectable HCV RNA at Wks 4 and 12 of triple therapy. Early response*; stop at Wk 28; f/u 24 wks PegIFN + RBV ervr ; stop at Wk 24, f/u 24 wks No ervr; PegIFN + RBV 48 48 F/u 24 wks F/u 24 wks 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011.
Case study 1 IL28B genotyping: CC Day 1: start of antiviral therapy Peginterferon α-2a 180 ug/week Ribavirin: 400 mg BID Telaprevir 750 mg every 8 hours Week 4: Side effect: fatigue Hb decline to 11 g/dl Bad Tolerance to High fat- food every 8 h HCV RNA undetectable
100 OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection Primary endpoint: SVR12 80 72,8 74,3 SVR12 (%) 60 40 20 0 270/371 274/369 T12(q8h)/PR T12(bid)/PR T12(bid)/PR was non-inferior to T12(q8h)/PR for SVR12 Difference (95% CI): 1.5% ( 4.9%, 12%) Buti M, et al. AASLD 2012. Abstract LB-8.
Case study 1 Week 4 Therapy adjusted Peginterferon α-2a 180 ug/week Ribavirin: 400 mg BID Telaprevir bid Week 8 Better tolerance and compliance Minimal Rash in arms
Case study 1 Week 10 Rash increases arms and thorax (Moderate rash- Grade 2) HCV-RNA undetectable
Management of mild rash: which antihistamine? Chlorpheniramine Promethazine OK to use with HCV PIs Desloratidine Levocetirizine In this patient, desloratidine was initiated http://www.hep-druginteractions.org
Case study 1 Week 10 Rash increased arms and thorax (Moderate rash- Grade 2) Topic steroids and desloratidine was initiated Anemia stable HCV-RNA undetectable Week 11 No improvement in rash Telaprevir was stopped
Drug considerations: mild and moderate rash Mild Telaprevir discontinuation is generally NOT required Rash Moderate Telaprevir discontinuation is generally NOT required For moderate rash that progresses, permanent discontinuation (do not dose-reduce) of telaprevir should be considered If the rash does not improve within 7 days following telaprevir discontinuation, ribavirin should be interrupted. Peginterferon alfa may be continued unless interruption is medically indicated Treating patients with mild or moderate rash Use topical corticosteroids* Permitted systemic antihistaminic drugs may be tried for the treatment of associated pruritus Limit exposure to sun/heat and wear loose-fitting clothes *Concomitant use of systemic dexamethasone with telaprevir may result in loss of therapeutic effect of telaprevir. This combination should be used with caution or alternatives should be considered Telaprevir EU SmPC
Case study 1 Week 10 Rash increased arms and thorax (Moderate rash-grade 2) Topic steroids and desloratidine was initiated Anemia stable HCV-RNA undetectable Week 11 No improvement in rash Telaprevir was stopped Week 12 No Changes in rash All the drugs were stopped HCV RNA undetectable
What are the chances to get an SVR? 40% 60% > 90% 20
PROVE2 (telaprevir): study design Phase IIb, randomized, placebo-controlled, partially double-blind trial in 323 treatment-naïve patients with chronic HCV genotype 1 infection PR48 (n=82) Placebo + Peg-IFN + RBV Peg-IFN + RBV T12PR24 (n=81) T12PR12 (n=82) T12P12 (n=78) (no RBV) TVR + Peg-IFN + RBV TVR + Peg-IFN + RBV TVR + Peg-IFN Peg-IFN + RBV PR: peginterferon/ribavirin; Peg-IFN: peginterferon alfa-2a; RBV: ribavirin; TVR: telaprevir; HCV: hepatitis C virus 0 12 24 36 48 Weeks Hézode C, et al. N Engl J Med 2009;360:1839 50
PROVE2 (telaprevir): overall SVR Rates 100 Patients with SVR (%) 80 60 40 20 46 36 60 69 0 38/82 28/78 49/82 56/81 PR48 T12P12 (no RBV) T12PR12 T12PR24 SVR: sustained virologic response Hézode C, et al. N Engl J Med 2009;360:1839 50
SVR according to the treatment and IL28B genotype (telaprevir PROVE2 post-hoc analysis) 100 100 94 CC CT TT Proportion of patients (%) 80 60 40 20 0 12 12 44 12 27 20 1 5 15 16 67 12 18 33 1 3 T12PR12 T12PR24 T12P12 PR48 75 3 4 18 4 22 0 3 64 7 11 31 5 16 25 1 4 Bronowicki J-P, et al. J Hepatol 2012;56 (Suppl 2):S430 1
Case study 1 Follow-up 24-week HCV RNA: undetectable. 24
Summary Naïve patients infected with HCV genotype 1 Easy to treat patients IL28B CC, Caucasian/White Non-cirrhotic Can be cure with 12 weeks of triple combination treatment with telaprevir, peginterferon, and ribavirin
Case Study 2 54 year old man, lawyer IVDU sporadically 20 years ago Chronic Hepatitis C diagnosed 6 years ago HCV genotype 1 b, F3 Friends with HCV treated and non responders He was afraid about his disease He would like to be treated with DAAs but he was also afraid about therapy!!!!!! 26
Case study 2 He started Peginterferon α-2b 1.5 ug/kg/week Ribavirin: 600 mg BID Week 4: Side effect: fatigue Viral load: 4.2 log10 (vs 6.1 log10 at D1)
Lead-in Predicts SVR SVR (%) 121 234 PR48 3 62 187 228 BOC RGT 21 73 178 218 BOC/PR48 31 79 12 26 0 21 PR48 16 24 6 24 BOC RGT 22 36 5 16 BOC/PR48 Non-Black Patients 1 log 10 HCV RNA decline from baseline Black Patients <1 log 10 HCV RNA decline from baseline Poordad F. N Engl J Med. 2011; 364:1195-1206. 28
Case study 2 Started boceprevir 800 mg/8h at Week 4. Week 8. Side effects: fatigue, dysgeusia, no rash. Hb: 10.5 g/dl (vs 13 g/dl at Day 1). HCV RNA: undetectable. 29
SVR for Early and Late Viral Responders With Boceprevir ADVANCE SVR (%) 51 60 81 271 184 208 46 129 184 204 52 131 Undetectable HCV RNA at Week 8 Detectable HCV RNA at Week 8 Poordad F. N Engl J Med. 2011; 364:1195-1206. 30
SVR for Early and Late Viral Responders With Boceprevir ADVANCE SVR (%) 18 % 51 60 81 271 61 % 184 208 46 129 184 204 52 131 Undetectable HCV RNA at Week 8 Detectable HCV RNA at Week 8 Poordad F. N Engl J Med. 2011; 364:1195-1206. 31
Case study 2 Week 12. Side effects: fatigue. Hb: 9 g/dl. HCV RNA undetectable. How to manage anemia? 32
Impact of Anemia on SVR 100 SPRINT-2 100 RESPOND-2 SVR (%) 80 60 40 20 31 56 58 73 SVR (%) 80 60 40 20 20 25 50 76 0 Hgb 10 g/dl Hgb <10 g/dl Hgb Hgb 10 g/dl <10 g/dl 77 60 212 263 n/n = n/n = 246 108 263 363 0 Hgb 10 g/dl 12 60 Hgb <10 g/dl 5 20 Hgb 10 g/dl 83 165 Hgb <10 g/dl 119 157 PR48 BOC/PR48 Sulkowski M et al, EASL 2011
Efficacy endpoints: EPO vs RBV dose reduction for managing anemia with boceprevir Δ (95% CI) 0.7% ( 8.6, 7.2)* Patients (%) 178/249 178/251 RBV DR EPO Secondary anemia management intervention was used in 18% of RBV DR patients and in 37% of EPO patients *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
Case study 2 Week 12. Side effects: fatigue. Hb: 9 g/dl. HCV RNA undetectable Ribavirin was reduced to 800 mg/gay What are the chances to achieve an SVR? 35
Higher SVR Rates if Undetectable HCV RNA Levels at Start Time of Primary Anemia Management
Week 24. Case Report 2 Side effects: fatigue. HCV RNA: undetectable. What will be the duration of therapy? 37
Triple therapy with Boceprevir for Genotype 1 Treatment-Naive Patients Boceprevir [1,2] PegIF N + RBV BOC + PegIFN + RBV BOC + PegIFN + RBV 0 4 8 12 24 28 36 Early response*; stop at Wk 28; f/u 24 wks PegIFN + RBV 48 F/u 24 wks 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
SVR in Non-Black Patients with Undetectable HCV RNA Between Weeks 8-24 Column2 100 95 90 97 96 SVR (%) 85 80 75 70 65 60 55 50 143 147 BOC RGT 137 142 BOC/PR48
Case study 1 Treatment stopped at Week 28. Follow-up 12-week and 24-week visits: HCV RNA: <25 IU undetectable. 40
Summary Anaemia is the main effect of Triple therapy with Boceprevir, peginterferon, and ribavirin Anaemia is associated with a higher SVR rates Anaemia can be managed by Ribavirin dose reduction without impacting SVR rates