Treatment of Hepatitis C in patients with thalassaemia. Where are we now? • Telaprevir and boceprevir harbingers of important treatment advance • Improved response rates observed : – naive and experienced patients • SVR > 70% have been reported – in genotype 1 infection • Efficacy in the treatment of genotype 2-6 has not been fully tested. The natural history of fibrosis in chronic viral hepatitis F0 Courtesy Pierre Bedossa F2 F3 F4 Telaprevir ADVANCE: SVR in naïve patients Percent of patients with HCV RNA Undetectable T12PR T8PR PR P<0.0001 100 90 P<0.0001 75 80 69 70 60 44 50 40 30 20 10 0 n/N = 271/363 250/364 158/361 SVR Jacobson IM, et al. N Engl J Med 2011;364:2405-16; 2. Evidence for efficacy: boceprevir in treatment-naïve, genotype 1 patients (SPRINT-2) 100 SVR (%) 80 63* 66 * PR48 BOC RGT BOC44/PR48 137/363 233/368 242/366 60 38 40 20 0 n/N = *p<0.001 for both boceprevir arms versus PR48 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 The first generation protease inhibitors. Where are we now? • Response rates in patients with cirrhosis improved but suboptimal • Naïve patients without severe fibrosis – respond better • Prior null response and cirrhosis less likely to respond to retreatment • Inherited IL28b haplotypes continue to influence response rates • Response rates lower in subtype 1a vs 1b. • Side effects testing for patients REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV Prior relapsers Prior partial responders Prior null responders 100 Pbo/PR48 87 85 84 80 SVR (%) Pooled T12/PR48 77 56 60 40 34 32 20 13 Stage 20 18 7 6 0 0 n/N= 42 41 12/38 145/167 2/15 53/62 No, minimal Bridging or portal fibrosis fibrosis 1/15 48/57 3/17 36/47 0/5 10/18 Cirrhosis No, minimal Bridging or portal fibrosis fibrosis 1/5 11/32 1/18 24/59 10 0 0/9 16/38 Cirrhosis No, minimal Bridging or portal fibrosis fibrosis SVR was defined as 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 14 1/10 7/50 Cirrhosis Pol S, et al. Hepatology 2011;54(Suppl. S1):374A The paradox of progress • Advances have brought higher rates of cure – but more complexity to treatment of hepatitis C- a paradox of progress – Do not make treatment more straightforward – Complex process of decision making is required to assess • Side effects? • Resistance in patients who fail treatment Managing adverse events: – Rashes • varying grades of severity and duration have been reported in 55% telaprevir • Most drug related dermatitis moderate severity • Unpredictably progress • 5 % of patients experienced severe rash • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) occurred in 0.4% and Stevens-Johnson syndrome in 0.1% in clinical trials. – Anaemia • Particular relevance in patients with thalassaemia Still stuck with IFN • The requisite backbone of PEG IFN: – other problems associated with PEG IFN and RBV use • Including depression, psychiatric symptoms worsening of liver function and severe infections – render a large group intolerant of PEG IFN ineligible for treatment. ATOMIC study: GS7977 + IFN + RBV 12 weeks Interferon sparing: a new threshold 100 94 98 94 98 90 99 92 97 99 92 Patients (%) 75 Wk 4 EOT SVR4 SVR12 50 25 0 GS-7977 + PR 12 wk GS-7977 + PR 24 wk SVR12 not yet reported for the 24 week groups Kowdley KV, et al. EASL 2012, Barcelona, #1 GS-7977 + PR 12 + 12 wk BMS-790052 + BMS-650032: AI447011 Quad versus DAA combination In null-responders, BMS-790052 + BMS-650032 appear to require PegIFN/RBV to prevent breakthrough and the occurrence of resistance BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 7 6 6 Log10 HCV RNA Log10 HCV RNA Quadruple regimen 7 5 4 3 2 1 5 4 LOQ 25 IU/mL LOD <10 IU/mL 3 2 LOQ LOQ LOD LOD 0 1 1 2 3 4 6 Week 8 10 12 0 * 1 2 3 4 6 Week 8 10 12 initiation of PegIFN/RBV (NS5a inhibitor and Protease inhibitor) Lok A, et al NEJM ASPIRE (TMC435): SVR24 by prior response and Metavir score Partial responders Null responders Patients with SVR24 (%) Relapsers n= PR48 TMC435 TMC435 100mg* 150mg* PR48 PR48 PR48 TMC435 100mg* PR48 TMC435 150mg* PR48 PR48 16 10 6 48 29 10 12 10 2 38 29 13 48 21 11 13 3 2 *All TMC435 duration pooled 52 26 15 TMC435 TMC435 100mg* 150mg* PR48 PR48 30 20 11 29 21 13 Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1 Will we have better, more tolerable interferons? Lambda interferon No haematological toxicity Daclatasvir and GS-7977 across HCV genotypes 1–3 mITT* Patients achieving endpoint (%) 100 100 100 100 G1a/b 87 86 93 G2/3 100 100 100 100 75 75 50 50 25 25 0 87 93 73 87 86 93 100 100 100 Wk 4 Wk 24 (EOT) f/u (SVR4) Group A Group C Group E Sulkowski M, et al. EASL 2012, Barcelona, #1422 0 100 100 100 % <LLOQ 94 100 86 88 100 86 88 79 64 93 93 86 % 88 100 79 <LOD Wk 4 Wk 24 (EOT) Group B Group D f/u (SVR4) Group F *Bars <100% after 4 weeks reflect missing values All oral regimens: a realistic dream? • Therapeutic landscape is undoubtedly forever changed for the better • High barrier to resistance and pan-genotypic effects. • Do not yet know whether RBV remains important, or the appropriate dose of RBV in these regimens • Null responders to PEG IFN and RBV are null responders to both agents? • Multiple DAAs without RBV? • Costs will escalate DAA + IFN (IFN freer) or IFN free? Treatm en t: n ext w ave 12 weeks D A A + P E G IFN RBV T M C 435 + P E G IFN RBV 7977 + P E G IFN RBV D aclatisvir + P E G IFN RBV A sunaprevir + P E G IFN RBV BI 1201335 + P E G IFN RBV M K 5172 + P E G IFN RBV DAA + DAA + (D A A , R ) Q u ad ru p le th erap y