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 >106c/ml (3x105iu/ml)

Comorbidities Alcohol 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 biopsy A 1 F 4 + steatohepatitis

Therapy IFN2b 3mu ttw + RBV daily

Mr R.H. – 2002 Referred for re-treatment

Hb146 g/L ALT 110 iu/mL Bili 11mmol/L HCVRNA 106

WBC 6 x106 AST 65 iu/mL Alb 41 g/L Cryoglobulins not detected

Pt 158x109 ALP N INR 1.03 U/S – no focal lesion (fat)

FBS 5.2mmol/L

Mr. R.H.

May 2003

• Peg IFN2b 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 8x105 iu/ml

Nomenclature of Initial Virologic Response

0 1 2 31

2

3

4

5

6

7

7 14 21 28

detection limit

Days

Se

rum

HC

V R

NA 1st phase

2nd 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 HCVRNA @ 4 and 8 weeks

> 2 log drop HCVRNA @ 12 weeks

Relapser: Undetectable HCVRNA @ EOT

HCVRNA detectable 6 months off therapy

Rates of Viral Clearance Predicts SVR PegIFN/RBV

0

10

20

30

40

50

60

70

80

90

100 91

72

60

4843

Week 4 Negative 2log <2log >2log <2log

Week 12 Negative Negative Negative 2log 2log

Week 24 Negative Negative Negative Negative Negative

HCVRNA Status

Ferenci P et al., J Hepatol 2005;43:425

Pa

tient

s w

ith S

VR

(%

)

Factors Influencing Response to Therapy PEGIFN + RBV

Therapy Virus Host

dose genotype hepatic fibrosis

duration viral load steatosis/ high BMI

?type Peg IFN

HIV, HBV & schistosomiasis

(co-infection)

ethnicity (genes)

adherence mutations age (adherence)

Virus-host interaction

alcohol (adherence)

Ribavirin Dose % Optimal (1000-1200 mg/d)Response in Genotype 1 Patients

Copegus cumulative exposure levels (weeks 1–12Copegus cumulative exposure levels (weeks 1–12)

321 151 7202250

10

20

30

40

50

60

70

SV

R

(%)

SV

R

(%)

≥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

Ribavirin Exposure and Virologic Response: Predictors of EVR and SVR

EVR SVR

RBV exposure (%) P=0.0173* P<0.001*

Bodyweight P=0.0125 NS

Baseline HCV-RNA NS P<0.001

Race NS P<0.001

Metavir F4 NS P<0.001

Age NS P<0.001

*Variables in MLR which showed significance in 1 or both modelsBain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.

Geno 1 HVL: PegIFN2a 180mcg/wk + high dose RBV: (1660-3600mg/d)

Mean baseline VL (n=10) 2.5x106 iu/mL

4 wk EVR 0% (<50 iu/mL)

12 wk EVR 50% (<50 iu/mL)

24 wk EVR 80% (<50 iu/mL)

72 wk SVR 90%

Lindhal et al., Hepatology 2005;41:275

NB: Erythropoetin 100% - all severe fatigue

Dynamically Individualized vs. Standard TreatmentChronic 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 dose 60%

Peg IFN 2a + RBV

Standard regimen 66%

SVR

72-wk Peg-IFN + RBV for HCVGenotype 1

• Extending PegIFN2a + 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

0

10

20

30

40

50

60

70

80

90

100

EOT SVR

48 weeks72 weeks

7267

52 53

0

10

20

30

40

50

60

70

80

90

100

EOT SVR

81

52

3240

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Unselected population HCVRNA positive pts at wk 4

Daily Consensus IFN + RBV: NR to Rebetron/standard IFN Induction dose 18 mc vs. standard 9 mc

0 10 20 30 40 50

IFN non responder (n=36)

IFN+RBV non-responder, all HCVgenotype 1 (n=41)

HCV-genotype 1 (n=69)

Liver cirrhosis (n=16)

High viral load (n=44)

All patients (n=77) 30%

32%

19%

30%

22%

39%

Cornberg et al., J Hepatology 2006;44:291

SVR Rates

PegIFN2b1.5g/kg + RBV1-1.2g in Rebetron NRETR and SVR: ITT

No. of Patients

Week 24, n (%)

Week 48, n (%)

End of follow-up,

n (%)

Genotype 1 110 24 (22) 33 (30) 21 (19)

Genotype 2 7 4 (57) 4 (57) 4 (57)

Genotype 3 13 3 (23) 4 (31) 2 (15)

Genotype 4 10 1 (10) 1 (10) 1 (10)

All patients 140 32 (23) 42 (30) 28 (20)

Taliani et al, Gastroenterology 2006;130:1098

SVR Rates According to Adherence

McHutchison et al., Gastroenterol 2002: 123(4): 1061-9

43

52

60

51

62

71

4751

56

0

10

20

30

40

50

60

70

80

IFN+RBV PegIFN+RBV PegIFN+RBV>10.6 mg/kg

ITT

80/80/80

<80/<80/>80

% S

VR

Proportion of Patients Dispensed >12, 24 or 48 PegIntron Injections:

BIC Enrollees vs. Controls (matched groups)

72%

52%

22%

64%

41%

13%

0%

20%

40%

60%

80%

100%

12+ 24+ 48+

Number of Peg-Intron Injections Dispensed

BIC Control

n=780 n=638 n=333n=780 n=638 n=333

Per

cen

t o

f p

atie

nts

P= 0.0005

P<0.001

P=0.0020

72%

52%

22%

64%

41%

13%

0%

20%

40%

60%

80%

100%

12+ 24+ 48+

Number of Peg-Intron Injections Dispensed

BIC Control

n=780 n=638 n=333n=780 n=638 n=333

Per

cen

t o

f p

atie

nts

P= 0.0005

P<0.001

P=0.0020

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

(1990-2000)

Adapted from Bressler et al., Hepatology 2003;38:641

Genotype Cirrhosis Obese (>30kg/m2) Predicted probability (95% CI)

1 No No 0.22 (0.15-0.32)

1 No Yes 0.062 (0.019-0.18)

1 Yes No 0.054 (0.017-0.16)

1 Yes Yes 0.013 (0.0023-0.069)

2 or 3 No No 0.75 (0.56-0.87)

2 or 3 No Yes 0.40 (0.18-0.67)

2 or 3 Yes No 0.36 (0.15-0.66)

2 or 3 Yes Yes 0.12 (0.029-0.37)

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 + RBVSummary

• 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 HCVRNA @ 12 weeks

2. Has undetectable HCVRNA @ 12 weeks

3. Has < 2 log fall in HCVRNA @ 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 undetectable @12 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%