Controversies: Lead in or no lead in ?

PRO 

Lawrence Serfaty

Hôpital Saint-Antoine

Paris

5th Paris Hepatitis Conference, January 30-31 2012

Lead-in phase

W0 W4

PI + Peg-IFN + RBV

Weeks of treatment

Peg-IFN + RBV

Triple therapyDual therapy

Lead-in phase

• Improvement of triple therapy effectiveness ?

• Prediction of triple therapy effectiveness ?

Lead-in phase

• Improvement of triple therapy effectiveness ?

• Prediction of triple therapy effectiveness ?

Impact of lead in phase on boceprevir effectiveness

(SPRINT-1: naïve patients)

% of patients with negative PCR

Kwo PY et al. Lancet 2010

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

Impact of lead in phase on telaprevir effectiveness (REALIZE: tt-experienced patients)

Previous relapser Previous partial responder

Previous null responder

0

20

40

60

80

10088

54

33

83

59

29

Lead-inNo Lead-in

% SVR

Zeuzem S et al. J Hepatol 2011; 54: S3

Lead-in phase

• Improvement of triple therapy effectiveness ?

• Prediction of triple therapy effectiveness ?

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

BOC RGT%

SV

R

<0.5

Log10 viral load decrease after 4 wks of P/R lead-in

0.5 – <1.0

1.0 – <1.5

1.5 – <2.0

2.0 – <3.0

3.0 – <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)

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)

SV

R (

%)

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

IL28B genotyping for selection of RVR patients

Thompson AJ, Gastroenterology 2010

Place of PEG + RBV in G1 patients naïve of treatment ?

PEG + RBV

IL28B CC et F≤2

12 weeks triple therapy ?

AFEF guidelines

W4 Undetectable HCV RNA (30%) Detectable HCV RNA

Triple therapyPEG + RBV during 22/44 weeks according to viral

load at baseline

<1 log >1 log <1 log >1 log <1 log >1 log0

20

40

60

80

100

62

88

56 59

15

54

Relapsers Partial 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

Resistant variant occurrence and sensitivity to interferon

> 1 log < 1 log0

100

200

300

400

500

600

700

800

536

93

87

52

39

115

Patients with resistancePatients without resis-tanceND

n patients

41%

6%

* SPRINT-2 + RESPOND-2 pooled data

Proposal in prior nul responders

PEG + RBV

W4 VL decline< 1 log

Stop treatment (excepted rescue)

Triple therapy

VL decline> 1 log

AFEF guidelines

Relapsers Partial responders0

102030405060708090

18

60

82

40 < 1log> 1log

% 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

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

Conclusion

Lead in phase

Selection of patientseligible 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)

sensitive

resistant

DAA

resistant

sensitive

PEG+Riba

Mechanism of resistanceInterferon sensitivity and resistant variants occurence

sensitive

resistant

DAA

resistant

sensitive

PEG+Riba

Mechanism of resistanceInterferon sensitivity and resistant variants occurence