Management of non response or relapse following HCV therapy Greg Dore Darrell Crawford
Learning objectives To understand importance of characterisation of prior HCV therapy response To explore options for retreatment with current standard of care (PEG IFN/RBV) To understand impact of prior HCV therapy response ( IFN responsiveness ) on HCV retreatment outcome, including with PEG IFN/RBV and DAA containing regimens
HCV treatment response definitions Response Definition Null response <2 log 10 drop from baseline at week 12 Partial response 2 log 10 drop from baseline at week 12, but detectable HCV RNA at week 24 Breakthrough Undetectable HCV RNA on treatment followed by detectable HCV RNA on treatment Relapse Undetectable HCV RNA at end of treatment followed by detectable HCV RNA post treatment Re infection Relapse with evidence on HCV RNA sequencing of infection with new HCV strain
Case study 1: HCV treatment relapse Initial consultation November 2003 37 yr old male, married, sports administrator HCV diagnosed 1993, probable BT acquisition (1987) HCV genotype 1 Persistently elevated LFTs Symptoms: nil Past medical history: MVA 1987 with # femur Medications: nil Alcohol: 5 7 days/week x 30 40 grams
Case study 1: HCV treatment relapse Investigations Liver biopsy March 2004: Scheuer score 2 + 2 + 2 (mod. fibrosis), mod. steatosis HCV genotype 1b HCV RNA >700,000 IU/mL LFTs: Alb 46, bilirubin 7, AST 68, ALT 110, GGT 220 Platelet count 282,000, PT 13
Case study 1: HCV treatment relapse HCV treatment PEG IFN 2a/RBV from October 2005 Well tolerated HCV RNA: Wk 4: 82,900 (4.9); Wk 8: 9,300 (4.0); Wk 12: <600; Wk 48: <50 Post treatment relapse
Case study 1: HCV treatment relapse Subsequent monitoring Repeat LB June 2008: 2 + 2 + 2 (mod. fibrosis) HCV RNA 463,000 IU/mL LFTs: Alb 46, bilirubin 8, AST 54, ALT 118, GGT 206 Fibroscan April 2010: 8.9 kpa (mod. fibrosis) What would you do now? What factors would influence decision to retreat?
Case study 1: HCV treatment relapse Further investigations IL28B testing IL28B testing: rs8099917 TT (favourable), rs12979860 TT (unfavourable)
EPIC study: PEG IFN 2b/RBV retreatment Poynard T et al. Gastroenterology 2009;136:1618 1628
EPIC study: SVR by genotype and fibrosis stage 100 90 80 70 68% SVR (%) 60 50 40 55% 48% Genotype 1 Genotype 2/3 30 20 10 21% 16% 10% 0 F2 F3 F4 Poynard T et al. Gastroenterology 2009;136:1618 1628
EPIC study: SVR by genotype and prior response 100 90 80 SVR (%) 70 60 50 40 61% 60% 46% Genotype 1 Genotype 2/3 30 27% 20 10 15% 10% 0 Relapser Failure Non responder Poynard T et al. Gastroenterology 2009;136:1618 1628.
EPIC study: SVR by genotype and prior response Predictive factors OR P value Genotype (2/3 vs 1) 4.9 <0.0001 Fibrosis stage (F2 vs F4) 2.2 0.0001 HCV RNA level (<600,000 vs >600,000 IU/mL) 1.9 <0.0001 Previous regimen (IFN/RBV vs PEG IFN/RBV) 2.0 <0.0001 Previous response (relapser vs non responder) 3.8 <0.0001 Poynard T et al. Gastroenterology 2009;136:1618 1628
REPEAT: G1 non responders to PEG IFN 2b/RBV A B C D 360 μg PEG-IFN-2a 180 μg RBV 1000/1200 mg/day PEG-IFN-2a 360 μg 180 μg RBV 1000/1200 mg/day 180 μg 180 μg Follow up Follow up PEG IFN 2a 180 μg Follow up RBV 1000/1200 mg/day PEG IFN 2a 180 μg Follow up RBV 1000/1200 mg/day 0 12 24 36 48 72 96 Study week Jensen DM et al. Ann Intern Med 2009;150:528 540
REPEAT: SVR by treatment arm PEG IFN 2a 180 μg/wk +RBV PEG IFN 2a 360 μg/wk + RBV 100 80 SVR (%) 60 40 20 9% 7% 14% 16% 0 n=313 n=156 48 week duration n=156 n=317 72 week duration Jensen DM et al. Ann Intern Med 2009;150:528 540
RESPOND 2: Phase III, G1, treat. exp. Arm 1 (control) (n=80) PEG IFN + RBV 4 Weeks Placebo + PEG IFN + RBV Arm 2 (n=162) PEG IFN + RBV 4 Weeks BOC + PEG IFN + RBV Undetectable Week 8 No further treatment Detectable Week 8, Undetectable Week 12 Placebo + PEG IFN + RBV Arm 3 (n=161) PEG IFN + RBV 4 Weeks BOC + PEG IFN + RBV 4 weeks 8 weeks 28 weeks 36 weeks 48 weeks
RESPOND 2: SVR by prior treatment response 100 90 SVR (%) 80 70 60 50 40 30 29% 52% 75% 40% 69% Partial response Relapse 20 10 0 7% 15/51 2/29 30/58 77/103 23/57 72/105 PEG/RBV48 BOC/PR48 BOC/RGT Bacon BR et al. NEJM 2011;364:1207 1217
REALIZE: Phase III, G1, treat. exp. PR48 (control) (n=130) PEG IFN + RBV Follow up T12/PR48 (n=260) TVR + PEG IFN + RBV PEG IFN + RBV Follow up T12/PR48 (n=260) TVR + PEG IFN + RBV PEG IFN + RBV Follow up Weeks 0 12 24 36 48 60 72 Dosing: PEG IFN = PEG IFN alfa 2a 180 µg/week, RBV = RBV 1000 or 1200 mg/day, TVR = TVR 750 mg q8h Zeuzem S et al, EASL 2011
REALIZE: SVR by prior treatment response 100 90 86% 80 SVR (%) 70 60 65% 57% 50 TVR/PR 40 31% PEG/RBV 30 20 17% 24% 15% 10 0 Overall Relapsers Partial responders Null responders 5% Zeuzem S et al, EASL 2011
Case 2 Where to from here? Darrell Crawford
Case study 2 20 year old male music student Mother has type 1 diabetes mellitus Her pregnancy with this child was complicated by blindness and premature labour This child was delivered at 28 weeks of gestation and received a blood transfusion during his neonatal care
Case study 2 Aged 7, parents were notified that a look back program had identified that child received blood from an HCV positive blood donor On testing, the child was HCV Ab positive Family were very keen for treatment Asymptomatic; no other relevant health issues
Laboratory details ALT 35 45 U/L, AST 35 45 U/L Se albumin, bilirubin: normal FBC: normal Genotype 1b HCV viral load of log 5,830,000 IU/mL
HCV IN CHILDHOOD Treat now, or defer?
Paediatric HCV: Natural history Spontaneous clearance is uncommon (5%) Most (75%) have low fibrosis/activity scores Risk of fibrosis ~ duration of disease Indications for treatment are to prevent disease progression and gain psychosocial benefits
Treatment responses in children with HCV Wirth, 2005 Wirth, 2010 Schwarz, 2008 Sokal, 2010 Age (yrs) 2 17 3 17 5 17 6 17 Treatment PEG a2b 1.5ug/kg RBV 15mg/kg G2/3 24 /48 wks G1 48 wks PEG a2a 60mg/m 2 RBV 15mg/kg G2/3 24 /48 wks G1 48 wks PEG a2a 180 mg/1.73 m 2 RBV 0 15mg/kg G2/3 48 wks G1 48 wks PEG a2a 100mg/m 2 RBV 15mg/kg G2/3 24 wks G1 48 wks SVR G2/3 100% G1 48% G2/3 93% G1 55% G2/3 80% G1 47% G2/3 94% G1 57% Wt Loss 20% 20% NR 0% Abnormal TSH 10.3% 23% NR 0%
Decision was made to delay therapy
Laboratory details (age 20 yrs) ALT 35 45 U/L, AST 35 45 U/L Se albumin, bilirubin: normal FBC: normal Genotype 1b HCV Viral load of log 5,830,000 IU/mL TE score 9.0 (IQR 30% 10/10) Liver biopsy Metavir A1 F1
DISCUSSION POINT Discordance between the Metavir fibrosis score and TE score
Decision was made to commence therapy
Treatment details Tolerated therapy very well Pre treatment VL: 5,830,000 IU/mL Log viral load: 6.8 Week 4 VL: 3,710,000 IU/mL Log viral load: 6.6 Should we cease treatment?
WEEK 4 VIRAL LOAD (IU/mL) <15 15 100 100 1000 1000 10,000 10,000 100,000 >100,000 Total (n) 80 16 25 45 43 82 SVR (n) 64 13 20 25 15 9 SVR/Total (%) WEEK 8 80% 81.2% 80% 55.5% 34.8% 10.9% Total (n) 147 14 27 33 26 43 SVR (n) 113 6 12 11 3 0 SVR/Total (%) WEEK 12 76.8% 42.8% 44.4% 33% 11.5% 0% Total (n) 185 15 18 23 13 40 SVR (n) 134 5 7 2 0 0
Treatment details
WHERE TO FROM HERE? Does IL 28B testing help? What is the role of retreatment?