Jenny HEATHCOTE

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

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 Examination:Normal Liver biopsyA 1 F 4 + steatohepatitis Therapy IFN  2b 3mu ttw + RBV daily

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

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

Nomenclature of Initial Virologic Response 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

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

Rates of Viral Clearance Predicts SVR PegIFN/RBV 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 (%)

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)

Ribavirin Dose % Optimal ( mg/d) Response in Genotype 1 Patients Copegus cumulative exposure levels (weeks 1–12 Copegus cumulative exposure levels (weeks 1–12) SVR (%) ≥97% 80–<97% 60–<80% <60% Overall 23 64% 60% 41% 55% 35% Bain et al. Presented at AASLD. Oct 27-31, Boston, MA. Abstract pts

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, Boston, MA. Abstract 388.

Geno 1 HVL: PegIFN  2a 180mcg/wk + high dose RBV: ( mg/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

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

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: Patients (%) Unselected populationHCVRNA positive pts at wk 4

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

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 (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

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

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

Predicted Probability (95% CI) of SVR Viral Genotype, Presence of Cirrhosis, BMI ( ) Adapted from Bressler et al., Hepatology 2003;38:641 GenotypeCirrhosisObese (>30kg/m 2 )Predicted probability (95% CI) 1No 0.22 ( ) 1NoYes0.062 ( ) 1YesNo0.054 ( ) 1Yes ( ) 2 or 3No 0.75 ( ) 2 or 3NoYes0.40 ( ) 2 or 3YesNo0.36 ( ) 2 or 3Yes 0.12 ( )

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

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

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

QUESTIONS

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

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

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

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