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1
Hemoglobin Decline Associated with
SVR Among HCV G1-Infected
Persons: Analysis from the IDEAL
Study
Sulkowski MS, Shiffman ML, Afdhal N, Reddy R, McCone J, Lee WM,
Herrine SK, Harrison S, Deng W, Brass CA, Koury K, Noviello S, Albrecht
JK, McHutchison JG on behalf of the IDEAL Study Team
EASL 2009
Copenhagen, Denmark
April 25, 2009
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Background and Study Design

Treatment-Related Anemia (30% of patients)
 Hemolysis (RBV) and bone marrow suppression (PegIFN)
 RBV dose reductions and treatment discontinuations
 Erythropoietin (EPO) supplementation
 Maintains RBV dose levels and improves patient quality of life

Study objectives
 To test the hypothesis that treatment related hemoglobin decline are
associated with virologic response during treatment with
peginterferon and ribavirin therapy
 To assess the relationship of anemia, epoetin alfa use and virologic
response during treatment with peginterferon and ribavirin
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
3
Study Schema
and Treatment Regimens
Screening
HCV RNAa
24
N = 1019
PEG-IFN alfa-2b 1.5 μg/kg/wk
+ RBV 800-1400 mg/d
×48 weeks
Follow-up
24 weeks
N = 1016
PEG-IFN alfa-2b 1.0 μg/kg/wk
+ RBV 800-1400 mg/d
×48 weeks
Follow-up
24 weeks
N = 1035
PEG-IFN alfa-2a 180 μg/wk
+ RBV 1000-1200 mg/d
×48 weeks
Follow-up
24 weeks
12
24
48
4
12
24
Stratified by baseline viral load (> or ≤ 600,000 IU/mL) and race (African American)
 Standard response stop criteria applied at weeks 12 (no EVR) and 24 (HCV RNA-positive)

a LLQ
<27 IU/mL (COBAS TaqMan; Roche)
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Anemia and EPO Use

Anemia
 Protocol defined as Hb level <10 g/dL

RBV dose reductions
 PEG-IFN alfa-2b + RBV arms
 Full dose 800-1200 mg  decrease by 200 mg (first dose reduction) then
by 200 mg (second dose reduction)
 Full dose 1400 mg  decrease by 400 mg (first dose reduction) then by
200 mg (second dose reduction)
 PEG-IFN alfa-2a + RBV arm
 Full dose 1000-1200 mg  decrease to 600 mg (product insert)

EPO use criteria
 Permitted in patients with Hb level <10 g/dL with simultaneous RBV
dose reduction
 At the discretion of investigator and patient
 Not provided by study
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Subject Characteristics: Hgb Decline
Hb Decline ≤3 g/dL
n=771
Hb Decline >3 g/dL
n=2252
P
values
47%
64%
<.001
Caucasian
African American/Black
Age, y, mean (SD)
63%
27%
45.6 (8.6)
75%
15%
48.2 (7.7)
<.001
<.001
<.001
Weight, kg, mean (SD)
Baseline HCV RNA >600,000 IU/mL
Steatosis
Absence
Presence
METAVIR fibrosis score
F0/1/2
82.0 (16.9)
79%
83.9 (16.1)
83%
.007
.023
40%
56%
35%
60%
.011
.038
88%
83%
.002
8%
12%
.004
Baseline Hb conc, g/dL, mean (SD)
14.3 (1.2)
15.2 (1.2)
<.001
Baseline Cr, μmol/L, mean (SD)
70.6 (14.2)
75.4 (14.0)
<.001
Baseline estimated Cr clearance,a mL/min, mean (SD)
123.3 (34.0)
118.0 (30.8)
<.001
13.4 (1.6)
13.4 (1.5)
.640
Hb <10 g/dL during treatment
5%
37%
<.001
EPO Use
3%
20%
<.001
Male
Race
F3/4
Initial RBV dose (mg/kg/d), mean (SD)
a Using
Cockcroft-Gault equation. Cr = creatinine.
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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SVR and Maximum Hb Decline
Sustained Virologic Response: All Treated Patients (N = 3023)
1.0
Moving Average (10 %)
Fitted: P = 1/(1+exp(1.1594 - 0.1882*x))
0.9
0.8
Probability of SVR
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
9
10
Maximum Drop in Hemoglobin (g/dL) From Baseline
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Patients, %
EOTa and SVRb Responses by
Decline in Hb
70
60
50
40
30
20
10
0
61.6
43.7
41.8
≤ 3 g/dL
29.9
> 3 g/dL
SVR
EOT
Hemoglobin Decline
aEOT
bSVR
rates for >3 g/dL = 61.6% (1386/2250) and ≤3 g/dL = 41.8% (323/773); P < 0.0001.
rates for >3 g/dL = 43.7% (984/2250) and ≤3 g/dL = 29.9% (231/773); P < 0.0001.
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Subject Characteristics:
Anemia/EPO
No Anemia (A)
n = 2158
67%
Anemia/
No EPO (B)
n = 416
38%
Anemia/
EPO (C)
n = 449
44%
P
A vs B
<.0001
P
A vs C
<.0001
P
B vs C
.0667
Caucasian
African American/Black
Age, y, mean (SD)
Weight, kg, mean (SD)
Baseline HCV RNA >600,000 IU/mL
Steatosis
Absence
Presence
METAVIR fibrosis score
F0/1/2
F3/4
72%
17%
46.8 (7.9)
84.7 (16.1)
83%
68%
21%
48.7 (8.2)
79.8 (16.9)
77%
72%
20%
50.2 (7.6)
80.5 (15.9)
84%
.0958
.0595
<.0001
<.0001
.0048
.8048
.2422
<.0001
<.0001
.3971
.2689
.5704
.0040
.5281
.0053
36%
60%
38%
58%
38%
55%
.3415
.6161
.4020
.0528
.9134
.2826
85%
10%
85%
12%
80%
13%
.6419
.2175
.0021
.0675
.0614
.6896
Baseline Hb conc, g/dL, mean (SD)
15.2 (1.2)
14.3 (1.1)
14.3 (1.2)
<.0001
<.0001
.4108
Baseline Cr, μmol/L, mean (SD)
Baseline estimated Cr clearance,a
mL/min, mean (SD)
74.5 (14.1)
72.7 (13.5)
74.1 (15.1)
.0185
.6731
.1384
123.3 (31.6)
110.2 (30.8)
108.9 (28.9)
<.0001
<.0001
.4976
Male
Race
a Using
Cockcroft-Gault equation. Cr = creatinine.
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
9
Median and Mean RBV Exposure (mg/kg/d) Higher
in PEG-IFN alfa-2a Arm Than in alfa-2b Arms
No Anemiaa
Median RBV Exposure, mg/kg/d
25
Anemia/No EPOb
Anemia/EPOc
Mean (SD)
Mean (SD)
Mean (SD)
12.6 (1.3) 11.5 (1.7) 11.7 (2.0)
12.8 (1.2) 11.8 (1.7) 11.8 (1.4)
13.4 (2.0) 12.6 (2.7) 12.5 (2.3)
20
15
10
5
0
PEG-IFN alfa-2b 1.5
+ RBV
PEG-IFN alfa-2b 1.0
+ RBV
Treatment
PEG-IFN alfa-2a
+ RBV
a
P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV and for PEG-IFN alfa-2b 1.0 + RBV
vs PEG-IFN alfa-2a + RBV; P = .012 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV.
b P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV; P = .002 for PEG-IFN alfa-2b 1.0 + RBV
vs PEG-IFN alfa-2a + RBV; P = .270 PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV.
c P < .001 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2a + RBV; P = .001 for PEG-IFN alfa-2b 1.0 + RBV
vs PEG-IFN alfa-2a + RBV; P = .616 for PEG-IFN alfa-2b 1.5 + RBV vs PEG-IFN alfa-2b 1.0 + RBV.
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
10
Early Anemia Treated with EPO
Resulted in Higher SVR Rate*
Anemia/No EPO
Anemia/EPO
% (n/N)
% (n/N)
≤4 weeks of treatment
23.5% (19/81)
43.0% (58/135)
.004
>4-8 weeks of treatment
29.0% (18/62)
47.6% (49/103)
.019
>8-12 weeks of treatment
51.6% (32/62)
47.4% (27/57)
.644
61.6% (130/211)
57.8% (89/154)
.462
Onset of Anemia
>12 weeks of treatment
P-value
*P<0.001 for early anemia (≤8 weeks of treatment).
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
11
Lower Discontinuation Rates in
Early Anemia Treated with EPO
Anemia/No EPO
Anemia/EPO
% (n/N)
% (n/N)
6% (5/81)
<1% (1/135)
.019
>4-8 weeks of treatment
29% (18/62)
2% (2/103)
<.001
>8-12 weeks of treatment
6% (4/62)
14% (8/57)
.170
22% (46/211)
27% (42/154)
.227
Onset of Anemia
≤4 weeks of treatment
>12 weeks of treatment
P-value
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
12
Odds Ratios for SVR (EPO vs No EPO)
Onset of Anemia
Model
Early (<=8 weeks)
Late (> 8 weeks)
All Anemic Subjects
Odds Ratio (95% CI)
P-Value
Unadjusteda
2.34 (1.49, 3.68)
<0.001
Model 1b
3.52 (2.05, 6.03)
<0.001
Model 2c
3.13 (1.86, 5.28)
<0.001
Unadjusteda
0.84 (0.58, 1.20)
0.336
Model 1b
0.95 (0.62, 1.45)
0.806
Model 2c
0.92 (0.61, 1.39)
0.699
Unadjusteda
1.08 (0.82, 1.41)
0.591
Model 1b
1.35 (0.99, 1.84)
0.059
Model 2c
1.29 (0.96, 1.75)
0.097
aNo
control for potentially confounding factors.
ratio adjusted for all potentially confounding factors (age, gender, race, BMI, baseline viral load,
fibrosis, steatosis, fasting glucose, ALT, hemoglobin, platelet count, ribavirin (mg/kg/day) assigned, genotype
(1a, 1b), and body weight).
cOdds ratio adjusted for factors related to outcome (stepwise variable selection procedure based on all
anemic subjects: race, baseline viral load, fibrosis, steatosis, fasting glucose, and body weight).
bOdds
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Safety
No Anemia
Anemiaa/ No EPO
Anemiaa/EPO
9%
12%
14%
64%
67%
74%
Anaemiab
Dyspnea/exertional dyspnea
9%
19%
87%
29%
97%
33%
Cardiac events
Hypertension
4%
4%
4%
Increased blood pressure
Myocardial infarction
Coronary artery disease
1%
<1%
<1%
<1%
<1%
<1%
1%
<1%
0
Congestive heart failure
Angina pectoris
0
<1%
<1%
0
<1%
0
<1%
0
<1%
<1%
0
<1%
0
0
0
1%
<1%
0
<1%
1%
Serious adverse events
Relevant adverse events, %
Fatigue
Thromboembolic events
Pulmonary embolism
Deep venous thrombosis
Cerebrovascular accident
Cerebral hemorrhage
a
b
Cancer
1%
Anemia based on Hb conc <10 g/dL.
Anemia based on adverse event as reported by the investigator.
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09
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Conclusions

Higher magnitude of Hb decline is associated with higher
likelihood of SVR

EPO use was associated with higher SVR rates if anemia
occurred in the first 8 weeks of treatment
 No benefit of EPO use in patients who became anemic
after 8 weeks of treatment

Magnitude of Hb decline may be a pharmacokinetic marker
for efficacy of treatment and EPO may prevent treatment
discontinuation in patients with early anemia
Sulkowski MS, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/25/09