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

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%