1. Jenny HEATHCOTE

2. Chronic Hepatitis C “The Non Responder”! Jenny Heathcote MD University of Toronto

3. Mr R.H. Canadian First Nation’s Person 54 yrs July 2000 Routine check up:  ALT Tested HCV Ab +ve, (genotype 1a) Viral titre >10 6 c/ml (3x10 5 iu/ml) ComorbiditiesAlcohol 60-80g/d 20 yrs Generalized psoriasis 25 yrs BMI 27 (wt 77 kg) No smoking, depression, HIV Risk Factors:Blood transfusion in 1976 IDU and cocaine snorting 1983-1985 Examination:Normal Liver biopsyA 1 F 4 + steatohepatitis Therapy IFN  2b 3mu ttw + RBV daily

4. Mr R.H. – 2002 Referred for re-treatment Hb146 g/LALT 110 iu/mLBili 11mmol/LHCVRNA 10 6 WBC 6 x10 6 AST 65 iu/mLAlb 41 g/LCryoglobulins not detected Pt 158x10 9 ALP NINR 1.03U/S – no focal lesion (fat) FBS 5.2mmol/L

5. Mr. R.H. May 2003 Peg IFN  2b 1.5 mcg/kg + RBV 1000 mg/d EVR (12 wk): >2 log  HCVRNA (full dose therapy continued for 48 wk) Wk 24-HCVRNA 253 iu/ml EOT (48 wk) HCVRNA 331 iu/ml 6m post Rx HCVRNA 8x10 5 iu/ml

6. Nomenclature of Initial Virologic Response 0123 1 2 3 4 5 6 7 7 142128 detection limit Days Serum HCV RNA 1 st phase 2 nd phase Flat partial responder (0.0   < 0.05) Slow partial responder (0.05   < 0.35) Rapid responder (  0.35) Nonresponder (c < 0.2) Zeuzem et al., Gastroenterology 2001;120:1438

7. Definitions of Non-Response Null responder:no fall in HCVRNA with therapy Flat non responder:phase I response, no phase 2 Slow responder:Detectable HCVRNA @ 4 and 8 weeks > 2 log drop HCVRNA @ 12 weeks Relapser:Undetectable HCVRNA @ EOT HCVRNA detectable 6 months off therapy

8. Rates of Viral Clearance Predicts SVR PegIFN/RBV 91 72 60 48 43 Week 4Negative  2log  <2log  >2log  <2log  Week 12Negative  2log  Week 24Negative HCVRNA Status Ferenci P et al., J Hepatol 2005;43:425 Patients with SVR (%)

9. Factors Influencing Response to Therapy PEGIFN  + RBV TherapyVirusHost dosegenotypehepatic fibrosis durationviral loadsteatosis/ high BMI ?type Peg IFN HIV, HBV & schistosomiasis (co-infection) ethnicity (genes) adherencemutationsage (adherence) Virus-host interaction alcohol (adherence)

10. Ribavirin Dose % Optimal (1000-1200 mg/d) Response in Genotype 1 Patients Copegus cumulative exposure levels (weeks 1–12 Copegus cumulative exposure levels (weeks 1–12) 321 151 720 225 0 10 20 30 40 50 60 70 SVR (%) ≥97% 80–<97% 60–<80% <60% Overall 23 64% 60% 41% 55% 35% Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388. 720 pts

11. Ribavirin Exposure and Virologic Response: Predictors of EVR and SVR EVRSVR RBV exposure (%)P=0.0173*P<0.001* BodyweightP=0.0125NS Baseline HCV-RNANSP<0.001 RaceNSP<0.001 Metavir F4NSP<0.001 AgeNSP<0.001 * Variables in MLR which showed significance in 1 or both models Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.

12. Geno 1 HVL: PegIFN  2a 180mcg/wk + high dose RBV: (1660-3600mg/d) Mean baseline VL (n=10)2.5x10 6 iu/mL 4 wk EVR0% (<50 iu/mL) 12 wk EVR50% (<50 iu/mL) 24 wk EVR80% (<50 iu/mL) 72 wk SVR90% Lindhal et al., Hepatology 2005;41:275 NB: Erythropoetin 100% - all severe fatigue

13. Dynamically Individualized vs. Standard Treatment Chronic Hepatitis C Patients categorized:- Rapid (64 %) Slow (24 %) Flat (3.7 %) Null (8.2 %) responders at 6 weeks Zeuzem, J. Hepatol 2005; 43:250 Randomized at 6 weeks Individualized dose60% Peg IFN  2a + RBV Standard regimen66% SVR

14. 72-wk Peg-IFN + RBV for HCV Genotype 1 Extending PegIFN  2a + RBV from 48 to 72 weeks –Similar SVR rates in unselected cohort of HCV infected pts –  SVR,  relapse rate in pts without rapid virologic response Berg T et al., Gastroenterology 2006;130:1086 Sanchez-Tapias et al, Gastroenterology 2006;131:451 72 67 52 53 81 52 32 40 Patients (%) Unselected populationHCVRNA positive pts at wk 4

15. Daily Consensus IFN + RBV: NR to Rebetron/standard IFN Induction dose 18 mc vs. standard 9 mc 30% 32% 19% 30% 22% 39% Cornberg et al., J Hepatology 2006;44:291 SVR Rates

16. PegIFN  2b1.5  g/kg + RBV1-1.2g in Rebetron NR ETR and SVR: ITT No. of Patients Week 24, n (%) Week 48, n (%) End of follow-up, n (%) Genotype 111024 (22)33 (30)21 (19) Genotype 274 (57) Genotype 3133 (23)4 (31)2 (15) Genotype 4101 (10) All patients14032 (23)42 (30)28 (20) Taliani et al, Gastroenterology 2006;130:1098

17. SVR Rates According to Adherence McHutchison et al., Gastroenterol 2002: 123(4): 1061-9 % SVR

18. Proportion of Patients Dispensed >12, 24 or 48 PegIntron Injections: BIC Enrollees vs. Controls (matched groups) Hussein et al, Schering-Plough data presented at ISPOR, Philadelphia, PA, USA, May 20-24, 2006

19. Predicted Probability (95% CI) of SVR Viral Genotype, Presence of Cirrhosis, BMI (1990-2000) Adapted from Bressler et al., Hepatology 2003;38:641 GenotypeCirrhosisObese (>30kg/m 2 )Predicted probability (95% CI) 1No 0.22 (0.15-0.32) 1NoYes0.062 (0.019-0.18) 1YesNo0.054 (0.017-0.16) 1Yes 0.013 (0.0023-0.069) 2 or 3No 0.75 (0.56-0.87) 2 or 3NoYes0.40 (0.18-0.67) 2 or 3YesNo0.36 (0.15-0.66) 2 or 3Yes 0.12 (0.029-0.37)

20. Viral Factors that Influence Response to Therapy Genotype 2>3>4>1 Baseline viral load (HVL v LVL) Viral load decline (RVR v SVR) Co-infection (HIV/HBV) Quasispecies development Virus interferes with function of crucial genes in several antiviral pathways –? Host dependent

21. Host Factors that influence Response to Therapy Ethnicity (Blacks<Caucasians<Asians) (genes governing immune response) –eg: IP-10 level –IL polymorphisms –MHC Steatosis/ high BMI / insulin resistance Cirrhosis ‘Gene signature’ – pre-treatment interferon pathway already upregulated (liver tissue) Mr. R.H. has a gene signature indicating responsiveness to IFN Rx

22. Non Response to PegIFN  + RBV Summary Potentially reversible factors: –dose, duration, adherence, IR, BMI Viral interruption of viral clearance mechanisms –Can enzyme inhibitors abrogate viral ‘interference’? Host “gene signature”: –may explain ‘null’ response

23. QUESTIONS

24. A “Null” Responder: CHC 1.Has a > 2 log fall in HCVRNA @ 12 weeks 2.Has undetectable HCVRNA @ 12 weeks 3.Has < 2 log fall in HCVRNA @ 12 weeks

25. Not a Risk Factor for Treatment Failure: CHC 1.High viral load 2.Marijuana 3.Hepatic steatosis 4.Cirrhosis

26. Slow Responder to PegIFN  + Ribavirin: CHC 1.HCVRNA undetectable @12 weeks 2.Can enhance SVR rate with larger doses of PegIFN  3.Can enhance SVR rate with longer treatment PEGIFN  + RBV

27. Retreatment of Standard IFN+RBV failures (Genotype 1) with PEGIFN + RBV leads to SVR rate of:- 1.50% 2.30% 3.20% 4.0%