How to manage non responders Lawrence Serfaty Service d’Hépatologie, UMR S 893 Hôpital Saint-Antoine, UPMC, Paris Clinical case 1

Clinical Case oFemale, 58 yrs, african o80kg/162 cm (BMI 31) oHBP tt amlodipine, high cholesterol tt lovastatin oBlood transfusion in 1983 oHCV diagnosis in 2005 oGenotype 1b oHCV VL 3.6 M IU/ml, HIV and HBV - oLiver biopsy : A3F2

Clinical case D0W12W24 HCV VL IU/ml 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 viral load Breakthrough PEG + Riba McHutchison JG et al. N Engl J Med 2009 Buti M et al. Hepatology 2010: 48: log

Clinical Case: 5 yrs later oP=74kg oALT 67, AST 73, GGT 61 oPT 84%, bili 11 µm/l, albumin 36g/l oHb 14.3, PNN 1161, platelets oHOMA=3.6 oHCV VL 2M IU/ml oFibroscan: 10±1.4 Kpa oUS: normal liver oLiver 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 SVR (%) Prior relapsers Prior partial responders Pbo/ PR48 4/27 T12/ PR48 29/49 LI T12/ PR48 26/48 n/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 W4W8W12*W24*W28W36W48 Undetectable HCV RNA at W8 Detectable HCV RNA at W8

Telaprevir + PegIFN + RBV Naive patients and relapsers (excepted F4) - F4 patients - non responders W0 W48 W12 W24 PegIFN + RBV Telaprevir + PegIFN + RBV Undetectable HCV RNA at W4 and W12 Incivo ® (Telaprevir) : treatment regimen (EMA) Detectable HCV RNA at W4 and/or W12

RelapsersPartial 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

D0W4 PNN Hb 1410 Platelets HCV VL IU/ml PEG 2b 100µg + RBV 1.2g Clinical Case EPO UI/w

D0W4W6W8 PNN Hb Platelets HCV VL IU/ml PEG 2b 100µg + RBV 1.2g Clinical Case Boc 800mgx3 EPO 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 W4W8W12*W24*W28W36W48

D0W4W6W8W12W16 PNN Hb Platelets HCV VL IU/ml <12 PEG 2b 100µg + RBV 1.2g Clinical Case Boc 800mgx3 EPO IU/w

Conclusion oTriple therapy is now the reference treatment in G1 non responders oFixed treatment duration 48 weeks oLead in phase in nul responders  VL decline > 1log: triple therapy  VL decline < 1log: discussion