1. Lead in – or NOT? Graham R Foster Professor of Hepatology Queen Marys University of London

2. Lead in or NOT? Conflicts of interest I have received funding from Janssen, Merck, Roche, Gilead, BMS, BI, Abbott. The views expressed here are for the purposes of argument (and may, or may not) reflect my own views.

3. Why lead in is of no value The evidence The convenience of starting therapy The dangers of lead-in

4. Why lead in is of no value The evidence The convenience of starting therapy The dangers of lead-in

5. REALIZE (Telaprevir): Study Design (N=662) 48 4 16012 8 Weeks 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV N=266 Follow-up SVR assessment TVR + Peg-IFN + RBV Peg-IFN + RBV LI T12/ PR48 N=264 Follow-up Pbo + Peg-IFN + RBV PR48 (control) Pbo + Peg-IFN + RBVPeg-IFN + RBV N=132 Follow-up Zeuzem NEJM 2011

6. REALIZE (Telaprevir): Study Design (N=662) 48 4 16012 8 Weeks 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV N=266 Follow-up SVR assessment TVR + Peg-IFN + RBV Peg-IFN + RBV LI T12/ PR48 N=264 Follow-up Pbo + Peg-IFN + RBV PR48 (control) Pbo + Peg-IFN + RBVPeg-IFN + RBV N=132 Follow-up Zeuzem NEJM 2011

7. Impact of lead in (treatment experienced) SVR (%) PR48 16/68 T12/PR48 121/145 LI T12/ PR48 124/141 n/N= PR48 6/64 T12/PR48 50/121 LI T12/ PR48 51/123 Prior relapsersPrior non-responders (prior partial responders + null responders) * * * * Zeuzem S, et al. J Hepatol 2011;54(Suppl. 1):S3 *p<0.001 vs PR48

8. Why lead in is of no value The only proper evaluation of lead-in shows no benefit

9. Controlled trial of 3 day lead in (SILEN-C1 (BI 201335)) n=71 n=69 n=143 n=146 PRPlacebo + PR PR 120mg QD LI BI 201335 + PR a PR 240mg QD BI 201335 + PR a PR 240mg QD LI BI 201335 + PR D1D4Week 24Week 48 Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 226

10. Controlled trial of 3 day lead in (SILEN-C1 (BI 201335)) n=71 n=69 n=143 n=146 PRPlacebo + PR PR 120mg QD LI BI 201335 + PR a PR 240mg QD BI 201335 + PR a PR 240mg QD LI BI 201335 + PR D1D4Week 24Week 48 Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 226

11. Controlled trial of 3 day lead in (SILEN-C1 (BI 201335)) 40/7149/69103/142118/14211/7155/69111/142124/142 100 80 60 40 20 0 Proportion of patients (%) eRVRSVR PR120mg QD LI240mg QD LI240mg QD Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 226

12. Why lead in is of no value The only proper evaluation of lead-in shows no benefit There is a suggestion that lead in may be harmful!

13. Why lead in is of no value The evidence The convenience of starting therapy The dangers of lead-in

14. Lead in is unpopular with patients Patients have waited 10 years for these drugs, now you want them to start with the old stuff? Patients don’t want to come back in four weeks and start again

15. Lead in is unpopular with patients

17. Patients want to start with the new therapy Patients want the best treatment straight away

18. Why lead in is of no value The evidence The convenience of starting therapy The dangers of lead-in

19. The Dangers of Lead In Lead-in may persuade you NOT to start the protease inhibitor (If your patient is HCV RNA negative at 4 weeks, would you start a PI?)

20. How do patients fail therapy? Detection limit Relapse Null response Breakthrough Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52; Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22 Partial response Treatment Non-response 04812162024283236404448525660646872 HCV RNA level Weeks

21. How do patients fail therapy? Detection limit Relapse Null response Breakthrough Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46–52; Neumann A, et al. Science 1998;282:103–7; De Bruijne J, et al. Neth J Med 2008;66:311–22 Partial response Treatment Non-response 04812162024283236404448525660646872 HCV RNA level Weeks

22. Relapse – the hidden rocks You only know who is going to relapse when you stop therapy All Peg+ Riba relapsers will need re-treating

23. What happens if 95% of RVR patients respond? What happens to those who fail? Pre-treatment prediction accuracy 95% Another 12 months + DAA

24. What happens to those who fail? Pre-treatment prediction accuracy 75% Another 12 months + DAA Is this cost effective? What happens if 75% of RVR patients respond?

25. Lead - in Lead in is of unproven value Lead in is unpopular with patients Lead in leads you to make bad treatment choices

26. Lead in Lead – in is NOT being used in any of the current DAA trials Is lead in really such a good idea?