lead in – or not? graham r foster professor of hepatology queen marys university of london

Lead in – or NOT?

Graham R FosterProfessor of Hepatology

Queen Marys University of London

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.

Why lead in is of no value

• The evidence

• The convenience of starting therapy

• The dangers of lead-in

REALIZE (Telaprevir): Study Design (N=662)

484 160 128Weeks

72

T12/PR48 Peg-IFN + RBVTVR + Peg-IFN + RBV

Pbo + Peg-IFN +

RBV N=266Follow-up

SVR assessment

TVR + Peg-IFN + RBV Peg-IFN + RBV

LI T12/PR48N=264

Follow-upPbo +

Peg-IFN + RBV

PR48 (control) Pbo + Peg-IFN + RBV Peg-IFN + RBV

N=132Follow-up

Zeuzem NEJM 2011

Impact of lead in (treatment experienced)

Series10

20

40

60

80

100

24

8883

9

41 41

SVR

(%)

PR48

16/68

T12/PR48

121/145

LI T12/PR48

124/141n/N=

PR48

6/64

T12/PR48

50/121

LI T12/PR48

51/123

Prior relapsers Prior non-responders(prior partial responders

+ null responders)

* *

**

Zeuzem S, et al. J Hepatol 2011;54(Suppl. 1):S3*p<0.001 vs PR48


• The only proper evaluation of lead-in shows no benefit

Controlled trial of 3 day lead in (SILEN-C1 (BI 201335))

n=71

n=69

n=143

n=146

PRPlacebo + PR

PR120mg QD LI BI 201335 + PRa

PR240mg QD BI 201335 + PR

a PR240mg QD LI BI 201335 + PR

D1 D4 Week 24 Week 48

Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 226

Controlled trial of 3 day lead in (SILEN-C1 (BI 201335))

16

56

8071

7873

87 83

40/71 49/69 103/142 118/14211/71 55/69 111/142 124/142

100

80

60

40

20

0Prop

ortio

n of

pati

ents

(%)

eRVR SVR

PR 120mg QD LI 240mg QD LI 240mg QD

Sulkowski MS, et al. Hepatology 2011;54(Suppl. S1): Abstract 226


• The only proper evaluation of lead-in shows no benefit

• There is a suggestion that lead in may be harmful!


• The evidence



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


• Patients want to start with the new therapy• Patients want the best treatment straight

away


• The evidence



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?)

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

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

HCV

RN

A le

vel

Weeks

Relapse – the hidden rocks

• You only know who is going to relapse when you stop therapy

• All Peg+ Riba relapsers will need re-treating

What happens if 95% of RVR patients respond?

• What happens to those who fail?

Pre-treatmentprediction accuracy

95%Another 12 months + DAA

• What happens to those who fail?

Pre-treatmentprediction accuracy

75%Another 12 months + DAAIs this cost effective?

What happens if 75% of RVR patients respond?

Lead - in

• Lead in is of unproven value

• Lead in is unpopular with patients

• Lead in leads you to make bad treatment choices

Lead in

• Lead – in is NOT being used in any of the current DAA trials

• Is lead in really such a good idea?

lead in – or not? graham r foster professor of hepatology queen marys university of london

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