How to manage non respondersHow to manage non responders

Lawrence SerfatyLawrence Serfaty

Service d’Hépatologie, UMR S 893Service d’Hépatologie, UMR S 893

Hôpital Saint-Antoine, UPMC, ParisHôpital Saint-Antoine, UPMC, Paris

Clinical case 1Clinical case 1

Clinical Case o Female, 58 yrs, africano 80kg/162 cm (BMI 31)o HBP tt amlodipine, high cholesterol tt lovastatino Blood transfusion in 1983o HCV diagnosis in 2005o Genotype 1bo HCV VL 3.6 M IU/ml, HIV and HBV -o Liver biopsy : A3F2

Clinical case

D0 W12 W24

HCV VL

IU/ml

3 600 000 228 659 44 843

PEG2b 120µg/d + ribavirin 1.2g/d

Question Type of response ?

• Breakthrough

• Partial response

• Nul response

Relapse

Question Type of response ?

• Breakthrough

• Partial response

• Nul response

Relapse

Patterns of treatment failure with SOC in HCV patients

Log

vira

l loa

d

Breakthrough

PEG + RibaPEG + Riba

McHutchison JG et al. N Engl J Med 2009Buti M et al. Hepatology 2010: 48: 1700-1712

2 log

Clinical Case: 5 yrs later

o P=74kgo ALT 67, AST 73, GGT 61o PT 84%, bili 11 µm/l, albumin 36g/lo Hb 14.3, PNN 1161, platelets 139 000o HOMA=3.6o HCV VL 2M IU/mlo Fibroscan: 10±1.4 Kpao US: normal livero Liver biopsy : A2F3

Question : Management of patient ?

Correction of insulin resistance

Retreatment with SOC

PIs-based triple therapy

Change of concomitant treatments

Question : Management of patient ?

Correction of insulin resistance

Retreatment with SOC

PIs-based triple therapy

Change of concomitant treatments

REALIZE: SVR in Prior Relapsers, Partial Responders and Null Responders

SV

R (

%)

Prior relapsers

Prior partial responders

Pbo/PR48

4/27

T12/PR48

29/49

LI T12/PR48

26/48n/N=

Pbo/PR48

2/37

T12/PR48

21/72

LI T12/PR48

25/75

Pbo/PR48

16/68

T12/PR48

121/145

LI T12/PR48

124/141

Prior null responders

**

**

**

*p<0.001 vs Pbo/PR48

HOMA and SVR in patients treated with SOC: Metaanalysis

Deltenre et al. J Hepatol 2011

Serfaty L et al. Gut 2012

HOMA and VR in patients treated with telaprevir-based regimen

147 G1 naive patients treated with telaprevir-based triple therapy

Question Management of patient: triple therapy regimen

?

Response guided therapy

Fixed treatment duration

Lead-in phase

48 weeks treatment

Question Management of patient: triple therapy regimen

?

Response guided therapy

Fixed treatment duration

Lead-in phase

48 weeks treatment

Victrelis® (Boceprevir) : treatment regimen (EMA)

Naive patients (excepted F4)

Treatment failure patients (excepted nul responder and F4 )

- F4

- Nul responder

W0 W4 W8 W12* W24* W28 W36 W48Undetectable HCV RNA at W8

Detectable HCV RNA at W8

Telaprevir +PegIFN + RBV

Naive patients and relapsers (excepted F4)

- F4 patients- non responders

W0 W48W12 W24

PegIFN + RBV

Telaprevir +PegIFN + RBV

PegIFN + RBV

PegIFN + RBV

Undetectable HCV RNA at W4 and W12

Incivo® (Telaprevir) : treatment regimen (EMA)

Detectable HCV RNA at W4 and/or W12

Relapsers Partial responders

Nul responders

%RVS

Treatment failure patients: SVR according to HCV viral load decline at W4 of lead-in (Telaprevir)

Poordad F et al. J Hepatol 2011; 54: S6

Balance : to treat or not to treat poor interferon responder ?

- Resistant variants occurrence

- New or higher rate of side effects

- Cost of Pis (±EPO)

Lead in phase

Dosage adjustment (tolerance)

Resistant variant occurrence and sensitivity to interferon

n patients

41%

6%

* SPRINT-2 + RESPOND-2 pooled data

• 4 weeks lead in phase, then 44 weeks boceprevir-based triple therapy

Clinical Case: treatment decision

+ Stop lovastatin

D0 W4

PNN 900 1710

Hb 14 10

Platelets 139 000 174 000

HCV VL

IU/ml

2 000 000 143 700

PEG 2b 100µg + RBV 1.2g

Clinical Case

EPO 30 000 UI/w

D0 W4 W6 W8

PNN 900 1710 880 1320

Hb 14 10 10 9.8

Platelets 139 000 174 000 136 000 118 000

HCV VL

IU/ml

2 000 000 143 700 118 16

PEG 2b 100µg + RBV 1.2g

Clinical Case Boc 800mgx3

EPO 30 000 IU/w

Question : Management of patient ?

Stop treatment because breakthrough

Stop treatment because non response

Looking for resistance mutations

Continuing treatment

Question : Management of patient ?

Stop treatment because breakthrough

Stop treatment because non response

Looking for resistance mutations

Continuing treatment

Stopping rules with boceprevir

- HCV RNA rebound > 1 log - HCV RNA ≥ 100 IU/ml at W12

- Detectable HCV RNA at W24

W0 W4 W8 W12* W24* W28 W36 W48

D0 W4 W6 W8 W12 W16

PNN 900 1710 880 1320 1630 1270

Hb 14 10 10 9 8.6 9.3

Platelets 139 000 174 000 136 000 118 000 121 000 130 000

HCV VL

IU/ml

2 000 000 143 700 118 16 <12 <12

PEG 2b 100µg + RBV 1.2g

Clinical Case Boc 800mgx3

EPO 30 000 IU/w

Conclusion

o Triple therapy is now the reference treatment in G1 non responders

o Fixed treatment duration 48 weeks

o Lead in phase in nul respondersVL decline > 1log: triple therapyVL decline < 1log: discussion