Jenny HEATHCOTE Chronic Hepatitis C “The Non Responder”! Jenny Heathcote MD University of Toronto.
Download ReportTranscript Jenny HEATHCOTE Chronic Hepatitis C “The Non Responder”! Jenny Heathcote MD University of Toronto.
Slide 1
Jenny HEATHCOTE
Slide 2
Chronic Hepatitis C
“The Non Responder”!
Jenny Heathcote MD
University of Toronto
Slide 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 >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
Therapy
A 1 F 4 + steatohepatitis
IFN2b 3mu ttw + RBV daily
Slide 4
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
Slide 5
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
Slide 6
Nomenclature of Initial
Virologic Response
7
Nonresponder
(c < 0.2)
Serum HCV RNA
6
1st
phase
Flat partial responder
5
(0.0 d < 0.05)
4
2nd phase
Slow partial responder
(0.05 d < 0.35)
3
detection limit
2
Rapid responder
1
0
1
2
3
14
7
21
28
(d 0.35)
Days
Zeuzem et al., Gastroenterology 2001;120:1438
Slide 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
Relapser:
> 2 log drop HCVRNA @ 12 weeks
Undetectable HCVRNA @ EOT
HCVRNA detectable 6 months off therapy
Slide 8
Rates of Viral Clearance Predicts SVR
PegIFN/RBV
Patients with SVR (%)
100
91
90
80
70
60
50
40
30
20
10
0
HCVRNA Status
Week 4
Negative
Week 12
Negative
72
60
48
43
2log
<2log
>2log
<2log
Negative
Negative
2log
2log
Negative
Negative
Week 24 Negative Negative Negative
Ferenci P et al., J Hepatol 2005;43:425
Slide 9
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)
mutations
ethnicity (genes)
Virus-host
interaction
alcohol (adherence)
adherence
age (adherence)
Slide 10
Ribavirin Dose % Optimal (1000-1200 mg/d)
Response in Genotype 1 Patients
70
720 pts
64%
60%
60
55%
SVR (%)
50
41%
40
35%
30
20
10
0
321
151
225
≥97%
80–<97%
60–<80%
23
720
<60%
Overall
Copegus cumulative exposure levels (weeks 1–12)
Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.
Slide 11
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 models
Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.
Slide 12
Geno 1 HVL: PegIFN2a 180mcg/wk + high dose
RBV: (1660-3600mg/d)
Mean baseline VL (n=10)
4 wk EVR
2.5x106 iu/mL
0% (<50 iu/mL)
12 wk EVR
50% (<50 iu/mL)
24 wk EVR
80% (<50 iu/mL)
72 wk SVR
90%
NB: Erythropoetin 100% - all severe fatigue
Lindhal et al., Hepatology 2005;41:275
Slide 13
Dynamically Individualized vs. Standard Treatment
Chronic Hepatitis C
Patients categorized:• Rapid (64 %)
• Slow (24 %)
• Flat (3.7 %)
responders at 6
weeks
• Null (8.2 %)
SVR
Individualized dose
Randomized at 6
weeks
60%
Peg IFN 2a + RBV
Standard regimen
Zeuzem, J. Hepatol 2005; 43:250
66%
Slide 14
72-wk Peg-IFN + RBV for HCV
Genotype 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
Unselected population
90
Patients (%)
80
70
72
48 weeks
72 weeks
HCVRNA positive pts at wk 4
100
90
81
80
67
60
52
50
53
40
30
Patients (%)
100
70
60
50
32
30
20
10
10
0
0
SVR
40
40
20
EOT
52
EOT
Berg T et al., Gastroenterology 2006;130:1086
Sanchez-Tapias et al, Gastroenterology 2006;131:451
SVR
Slide 15
Daily Consensus IFN + RBV: NR to Rebetron/standard IFN
Induction dose 18 mc vs. standard 9 mc
All patients (n=77)
30%
32%
High viral load (n=44)
19%
Liver cirrhosis (n=16)
HCV-genotype 1 (n=69)
30%
IFN+RBV non-responder, all HCV
genotype 1 (n=41)
22%
39%
IFN non responder (n=36)
0
10
20
30
SVR Rates
Cornberg et al., J Hepatology 2006;44:291
40
50
Slide 16
PegIFN2b1.5g/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 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
Slide 17
SVR Rates According to Adherence
80
ITT
80/80/80
<80/<80/>80
71
70
62
60
60
56
52
51
% SVR
50
51
47
43
40
30
20
10
0
IFN+RBV
PegIFN+RBV
PegIFN+RBV>10.6 mg/kg
McHutchison et al., Gastroenterol 2002: 123(4): 1061-9
Slide 18
Proportion of Patients Dispensed >12, 24 or 48
PegIntron Injections:
BIC Enrollees vs. Controls (matched groups)
100%
P= 0.0005
80%
72%
Percent of patients
64%
60%
P<0.001
52%
41%
40%
P=0.0020
22%
20%
0%
13%
n=780
n=780
n=638
12+
n=638
24+
n=333
n=333
48+
Number of Peg-Intron Injections Dispensed
BIC
Control
Hussein et al, Schering-Plough data presented at ISPOR,
Philadelphia, PA, USA, May 20-24, 2006
Slide 19
Predicted Probability (95% CI) of SVR
Viral Genotype, Presence of Cirrhosis, BMI
(1990-2000)
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)
Adapted from Bressler et al., Hepatology 2003;38:641
Slide 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
Slide 21
Host Factors that influence Response to
Therapy
• Ethnicity (Blacks
– 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
Slide 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
Slide 23
QUESTIONS
Slide 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
Slide 25
Not a Risk Factor for Treatment Failure: CHC
1. High viral load
2. Marijuana
3. Hepatic steatosis
4. Cirrhosis
Slide 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
Slide 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%
Jenny HEATHCOTE
Slide 2
Chronic Hepatitis C
“The Non Responder”!
Jenny Heathcote MD
University of Toronto
Slide 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 >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
Therapy
A 1 F 4 + steatohepatitis
IFN2b 3mu ttw + RBV daily
Slide 4
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
Slide 5
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
Slide 6
Nomenclature of Initial
Virologic Response
7
Nonresponder
(c < 0.2)
Serum HCV RNA
6
1st
phase
Flat partial responder
5
(0.0 d < 0.05)
4
2nd phase
Slow partial responder
(0.05 d < 0.35)
3
detection limit
2
Rapid responder
1
0
1
2
3
14
7
21
28
(d 0.35)
Days
Zeuzem et al., Gastroenterology 2001;120:1438
Slide 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
Relapser:
> 2 log drop HCVRNA @ 12 weeks
Undetectable HCVRNA @ EOT
HCVRNA detectable 6 months off therapy
Slide 8
Rates of Viral Clearance Predicts SVR
PegIFN/RBV
Patients with SVR (%)
100
91
90
80
70
60
50
40
30
20
10
0
HCVRNA Status
Week 4
Negative
Week 12
Negative
72
60
48
43
2log
<2log
>2log
<2log
Negative
Negative
2log
2log
Negative
Negative
Week 24 Negative Negative Negative
Ferenci P et al., J Hepatol 2005;43:425
Slide 9
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)
mutations
ethnicity (genes)
Virus-host
interaction
alcohol (adherence)
adherence
age (adherence)
Slide 10
Ribavirin Dose % Optimal (1000-1200 mg/d)
Response in Genotype 1 Patients
70
720 pts
64%
60%
60
55%
SVR (%)
50
41%
40
35%
30
20
10
0
321
151
225
≥97%
80–<97%
60–<80%
23
720
<60%
Overall
Copegus cumulative exposure levels (weeks 1–12)
Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.
Slide 11
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 models
Bain et al. Presented at AASLD. Oct 27-31, 2006. Boston, MA. Abstract 388.
Slide 12
Geno 1 HVL: PegIFN2a 180mcg/wk + high dose
RBV: (1660-3600mg/d)
Mean baseline VL (n=10)
4 wk EVR
2.5x106 iu/mL
0% (<50 iu/mL)
12 wk EVR
50% (<50 iu/mL)
24 wk EVR
80% (<50 iu/mL)
72 wk SVR
90%
NB: Erythropoetin 100% - all severe fatigue
Lindhal et al., Hepatology 2005;41:275
Slide 13
Dynamically Individualized vs. Standard Treatment
Chronic Hepatitis C
Patients categorized:• Rapid (64 %)
• Slow (24 %)
• Flat (3.7 %)
responders at 6
weeks
• Null (8.2 %)
SVR
Individualized dose
Randomized at 6
weeks
60%
Peg IFN 2a + RBV
Standard regimen
Zeuzem, J. Hepatol 2005; 43:250
66%
Slide 14
72-wk Peg-IFN + RBV for HCV
Genotype 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
Unselected population
90
Patients (%)
80
70
72
48 weeks
72 weeks
HCVRNA positive pts at wk 4
100
90
81
80
67
60
52
50
53
40
30
Patients (%)
100
70
60
50
32
30
20
10
10
0
0
SVR
40
40
20
EOT
52
EOT
Berg T et al., Gastroenterology 2006;130:1086
Sanchez-Tapias et al, Gastroenterology 2006;131:451
SVR
Slide 15
Daily Consensus IFN + RBV: NR to Rebetron/standard IFN
Induction dose 18 mc vs. standard 9 mc
All patients (n=77)
30%
32%
High viral load (n=44)
19%
Liver cirrhosis (n=16)
HCV-genotype 1 (n=69)
30%
IFN+RBV non-responder, all HCV
genotype 1 (n=41)
22%
39%
IFN non responder (n=36)
0
10
20
30
SVR Rates
Cornberg et al., J Hepatology 2006;44:291
40
50
Slide 16
PegIFN2b1.5g/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 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
Slide 17
SVR Rates According to Adherence
80
ITT
80/80/80
<80/<80/>80
71
70
62
60
60
56
52
51
% SVR
50
51
47
43
40
30
20
10
0
IFN+RBV
PegIFN+RBV
PegIFN+RBV>10.6 mg/kg
McHutchison et al., Gastroenterol 2002: 123(4): 1061-9
Slide 18
Proportion of Patients Dispensed >12, 24 or 48
PegIntron Injections:
BIC Enrollees vs. Controls (matched groups)
100%
P= 0.0005
80%
72%
Percent of patients
64%
60%
P<0.001
52%
41%
40%
P=0.0020
22%
20%
0%
13%
n=780
n=780
n=638
12+
n=638
24+
n=333
n=333
48+
Number of Peg-Intron Injections Dispensed
BIC
Control
Hussein et al, Schering-Plough data presented at ISPOR,
Philadelphia, PA, USA, May 20-24, 2006
Slide 19
Predicted Probability (95% CI) of SVR
Viral Genotype, Presence of Cirrhosis, BMI
(1990-2000)
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)
Adapted from Bressler et al., Hepatology 2003;38:641
Slide 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
Slide 21
Host Factors that influence Response to
Therapy
• Ethnicity (Blacks
– 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
Slide 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
Slide 23
QUESTIONS
Slide 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
Slide 25
Not a Risk Factor for Treatment Failure: CHC
1. High viral load
2. Marijuana
3. Hepatic steatosis
4. Cirrhosis
Slide 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
Slide 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%