Management of non response or relapse following HCV therapy. Greg Dore Darrell Crawford

Transcription

1 Management of non response or relapse following HCV therapy Greg Dore Darrell Crawford

2 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

3 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

4 Case study 1: HCV treatment relapse Initial consultation November 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 grams

5 Case study 1: HCV treatment relapse Investigations Liver biopsy March 2004: Scheuer score (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

6 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

7 Case study 1: HCV treatment relapse Subsequent monitoring Repeat LB June 2008: (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?

8 Case study 1: HCV treatment relapse Further investigations IL28B testing IL28B testing: rs TT (favourable), rs TT (unfavourable)

9 EPIC study: PEG IFN 2b/RBV retreatment Poynard T et al. Gastroenterology 2009;136:

10 EPIC study: SVR by genotype and fibrosis stage % SVR (%) % 48% Genotype 1 Genotype 2/ % 16% 10% 0 F2 F3 F4 Poynard T et al. Gastroenterology 2009;136:

11 EPIC study: SVR by genotype and prior response SVR (%) % 60% 46% Genotype 1 Genotype 2/ % % 10% 0 Relapser Failure Non responder Poynard T et al. Gastroenterology 2009;136:

12 EPIC study: SVR by genotype and prior response Predictive factors OR P value Genotype (2/3 vs 1) 4.9 < Fibrosis stage (F2 vs F4) HCV RNA level (<600,000 vs >600,000 IU/mL) 1.9 < Previous regimen (IFN/RBV vs PEG IFN/RBV) 2.0 < Previous response (relapser vs non responder) 3.8 < Poynard T et al. Gastroenterology 2009;136:

13 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 Study week Jensen DM et al. Ann Intern Med 2009;150:

14 REPEAT: SVR by treatment arm PEG IFN 2a 180 μg/wk +RBV PEG IFN 2a 360 μg/wk + RBV SVR (%) % 7% 14% 16% 0 n=313 n= week duration n=156 n= week duration Jensen DM et al. Ann Intern Med 2009;150:

15 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

16 RESPOND 2: SVR by prior treatment response SVR (%) % 52% 75% 40% 69% Partial response Relapse % 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:

17 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 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

18 REALIZE: SVR by prior treatment response % 80 SVR (%) % 57% 50 TVR/PR 40 31% PEG/RBV % 24% 15% 10 0 Overall Relapsers Partial responders Null responders 5% Zeuzem S et al, EASL 2011

19 Case 2 Where to from here? Darrell Crawford

20 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

21 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

22 Laboratory details ALT U/L, AST U/L Se albumin, bilirubin: normal FBC: normal Genotype 1b HCV viral load of log 5,830,000 IU/mL

23 HCV IN CHILDHOOD Treat now, or defer?

24 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

25 Treatment responses in children with HCV Wirth, 2005 Wirth, 2010 Schwarz, 2008 Sokal, 2010 Age (yrs) 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%

26 Decision was made to delay therapy

27 Laboratory details (age 20 yrs) ALT U/L, AST 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

28 DISCUSSION POINT Discordance between the Metavir fibrosis score and TE score

29 Decision was made to commence therapy

30 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?

31 WEEK 4 VIRAL LOAD (IU/mL) < ,000 10, ,000 >100,000 Total (n) SVR (n) SVR/Total (%) WEEK 8 80% 81.2% 80% 55.5% 34.8% 10.9% Total (n) SVR (n) SVR/Total (%) WEEK % 42.8% 44.4% 33% 11.5% 0% Total (n) SVR (n)

32 Treatment details

33 WHERE TO FROM HERE? Does IL 28B testing help? What is the role of retreatment?