1. Controversies: Lead in or no lead in ? PRO Controversies: Lead in or no lead in ? PRO Lawrence Serfaty Hôpital Saint-Antoine Paris 5th Paris Hepatitis Conference, January 30-31 2012

2. Lead-in phase Lead-in phase W0 W4 PI + Peg-IFN  + RBV Weeks of treatment Peg-IFN  + RBV Triple therapyDual therapy

3. Lead-in phase Improvement of triple therapy effectiveness ? Prediction of triple therapy effectiveness ?

4. Lead-in phase Improvement of triple therapy effectiveness ? Prediction of triple therapy effectiveness ?

5. Impact of lead in phase on boceprevir effectiveness (SPRINT-1: naïve patients) % of patients with negative PCR Kwo PY et al. Lancet 2010

6. But higher rate of RVR at W4 of triple therapy Kwo PY et al. Lancet 2010 % RVR P < 0,001 Higher percentage of patients eligible for shorter treatment duration

7. Impact of lead in phase on telaprevir effectiveness ( REALIZE: tt-experienced patients) % SVR Zeuzem S et al. J Hepatol 2011; 54: S3

8. Lead-in phase Improvement of triple therapy effectiveness ? Prediction of triple therapy effectiveness ?

9. New molecules: new challenges Improvement of SVR but : - Resistant variants occurrence - New or higher rate of side effects - Cost of PIs (±EPO). Need for predictors of response

10. BOC RGT % SVR <0.5 Log 10 viral load decrease after 4 wks of P/R lead-in 0.5 – <1.0 1.0 – <1.51.5 – <2.02.0 – <3.03.0 – <4.0 ≥4.0 Undetectable Poordad F et al. NEJM 2011; 364: 1195-1206 Viral load decline after 4 wks of lead-in is predictive of boceprevir effectiveness (SPRINT-2: naïve patients)

11. High rate of SVR in patients with negative HCV RNA at W4 of lead-in (SPRINT-2) Vierling JM. et al. EASL 2011. J Hepatol 2011: 54: S197 (abstract 481) SVR (%) 0 20 40 60 80 100 97 48 P/R 29/30 89 BOC TGR 17/19 90 BOC/PR48 18/20 Patients with RVR

12. IL28B genotyping for selection of RVR patients Thompson AJ, Gastroenterology 2010

13. Place of PEG + RBV in G1 patients naïve of treatment ? PEG + RBV IL28B CC et F≤2 12 weeks triple therapy ? AFEF guidelines W4Undetectable HCV RNA (30%)Detectable HCV RNA Triple therapy PEG + RBV during 22/44 weeks according to viral load at baseline

14. RelapsersPartial responders Nul responders %SVR Treatment-experienced patients: SVR according to HCV viral load decline at W4 of lead-in (REALIZE) Poordad F et al. J Hepatol 2011; 54: S6

15. Resistant variant occurrence and sensitivity to interferon n patients 41% 6% * SPRINT-2 + RESPOND-2 pooled data

16. Proposal in prior nul responders PEG + RBV W4 VL decline < 1 log Stop treatment (excepted rescue) Triple therapy VL decline > 1 log AFEF guidelines

17. % of patients Bacon F et al. NEJM 2011; 364: 1207-1217 Reclassement of treatment-experienced patients (RESPOND-2) Viral load decline at W4 of lead in

18. Testing tolerance with PEG+Riba prior initiating triple therapy Dosage adjustment of PEG+Riba according to tolerance (hematological toxicity) Initiating growth factors prior to triple therapy

19. Conclusion Lead in phase Selection of patients eligible for PEG+RBV (naive RVR patients) Shorter treatment duration with boceprevir Reclassement of tt-experienced patients Highly predictive in nul responders (VL decline<1log) Tolerance to PEG+RBV (dosage adjustment)

21. sensitive resistant DAA resistant sensitive PEG+Riba Mechanism of resistance Interferon sensitivity and resistant variants occurence

22. sensitive resistant DAA resistant sensitive PEG+Riba Mechanism of resistance Interferon sensitivity and resistant variants occurence