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An Updated Review of Management Strategies for the HCV
NonresponderDiscussion and Interactive Case Series
Infergen® Speaker Program 2008
Please see Important Safety Information including boxed warning in this presentation as well as complete Prescribing Information included on disk.
Outline
An Updated Review of Management Strategies for the HCV Nonresponder Infergen®, a Different Interferon Watch and Wait Future Therapies Peg Retreatment Double Dose Extending Therapy Maintenance Therapy
Interactive Case Discussion
Management Strategies for the HCV Nonresponder:
Infergen®, A Different Interferon
Standard of Care: Naïve HCV Genotype 1 Patients (SVR)
Pegasys® [package insert]. Nutley, NJ: Hoffman-La Roche Inc; 2005.
PEG-Intron® [package insert]. Kenilworth, NJ: Schering-Plough Corporation; 2005.
41%33%
0
20
40
60
80
100
44%36%
0
20
40
60
80
100
SV
R (
%)
PegIFN -2a 180 g + 1000-1200 mg/RBV
SV
R (
%)
PegIFN -2b 1.5 g/kg + 800 mg/RBV
IFN α2b+RBVIFN α2b+RBV
PegIFN + RBV Response Rates in HCV Populations
African Americangenotype 1
0
10
20
30
40
50
60
All Genotypes Genotype 1 HIV/HCV HIV/HCVgenotype 1
52%-53%
41%-44%27%-40%
17%-29%19%-26%
SV
R (
%)
Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Jeffers LJ, et al. Hepatology. 2004;39:1702-1708.Carrat F, et al. JAMA. 2004;292:2839-2848.Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.Fried MW, et al. N Engl J Med. 2002;347:975-982.
Manns MP, et al. Lancet. 2001;358:958-965.Poynard T et al. J Hepatol. 2005:42(Suppl 2):40-41.Shiffman M.L., et al. Gastroenterology 2004; 126:1015-1023.Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.
IFN+RBV and Peg Non-Responders
2%-15%
Retreatment
Naive
Treat With a Different Interferon: Infergen® (CIFN)
CIFN=consensus interferon; SC=subcutaneous; TIW=three times per week.
Generic name: Interferon alfacon-1
Formulation: Solution for injection
Indication: Infergen® is indicated for the treatment of chronic HCV infection in patients 18 years of age or older with compensated liver disease who have anti-HCVserum antibodies and/or the presence of HCV RNA
FDA Approved Dose: 9 g SC TIW for 24 weeks for naïves. 15 g SC TIW for 48 weeks for patients not responding or relapsing to previous IFN therapy
Infergen®: A Bio-optimized Type 1 IFN
Amino acid 1 2 3 4 5 6 7position
IFN- a gly asn gly phe leu lys asn
IFN- b thr gly val phe his lys asn
IFN- d trp asn leu asn leu glu leu
IFN- f trp phe gly gly leu lys leu
IFN- g trp asn gly asn his glu his
IFN- j gln gly val phe leu lys asn
Infergen® trp asn gly phe leu lys asn
Korn AP, et al. J Interferon Res. 1994:14;1-9.
IFN-2a S L R S K EIFN-2b S L R S K ECIFN R L R R K E
Differences Among Approved IFNs
Korn AP, et al. J Interferon Res. 1994:14;1-9.
IFN-2a C D L P Q T H S L G S R R T L M L L A Q M R K I S L F S C L K D R H D F G F P QIFN-2b C D L P Q T H S L G S R R T L M L L A Q M R R I S L F S C L K D R H D F G F P QCIFN- C D L P Q T H S L G N R R A L I L L A Q M R R I S P F S C L K D R H D F G F P Q
IFN-2a R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q EIFN-2b R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q ECIFN- K K Y F Q R I T L Y L T E K K Y S P C A W E V V R A E I M R S F S L S T N L Q E
IFN-2a E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E T
IFN-2b E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E TCIFN- E E F D G N Q F Q K A Q A I S V L H E M I Q Q T F N L F S T K D S S A A W D E S
High-affinity receptor-recognition sites
Another receptor-recognition site
IFN-2a L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VIFN-2b L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VCIFN- L L E K F Y T E L Y Q Q L N D L E A C V I Q E V G V E E T P L M N V D S I L A V
1 amino acid difference between IFN -2a and IFN -2b19 amino acid difference between IFN -2a and CIFN18 amino acid difference between IFN -2b and CIFN
2.5 x 109
IFN -2b
Comparison of Antiviral Activity In Vitro
CIFN IFN -2a
VSVHeLaME-180
HSV
VSV=vesicular stomatitis virus; HSV=herpes simplex virus.
Blatt LM, et al. J Interferon Cytokine Res. 1996;16:489-499.
2.0 x 1010
2.5 x 109
2.0 x 1010
1.8 x 108
1.8 x 108
1.8 x 108
1.8 x 108
2.5 x 108
2.5 x 1082.5 x 108
1.8 x 108
HeLaME-180
Correlation between in vitro activity and clinical activity of any IFN is unknown
Strength of Receptor Binding
Type 1 IFN Receptor kd (M)
IFN -2b 1.07 x 10-11
CIFN 3.90 x 10-12
JAK-STAT=Janus kinase signal transduction activator of transcription.
Klein SB, et al. J Interferon Cytokine Res. 1996;16:1-6.
CIFN binds to the type 1 IFN receptor with 10-fold higher affinity when compared with IFN -2b.
ISGs: Enhanced
CIFN
Enhanced magnitude of JAK-STAT signaling
0
20
40
60
80
100
0.0 0.2 0.4 0.6 0.8 1.0 1.2
Inh
ibit
ion
of
cell
gro
wth
(%
)
IFN concentration (g/mL)
IFN -2a and IFN -2b
Comparison of Antiproliferative Effects of IFNs in Vitro
CIFN
Ozes ON, et al. J Interferon Res. 1992;12:55-59.
Infergen® Initial Registration Studies
Tong MJ, et al. Hepatology. 1997;26:747-754.
Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.
Observe24 weeks
48 weeks
24 weeks
Relapsers
Nonresponders
337 patients704 patients
Responders
RetreatInfergen®
15 g TIW
Observe24 weeks
Treat 24 weeks
IFN -2b (3 MIU TIW)
Infergen® (9 g TIW)
Infergen® Has Significant Reduction in Mean Viral Load vs IFN a-2b
Note: 3 MIU15 g.
Tong MJ, et al. Hepatology. 1997;26:747-754.
HC
V R
NA
(co
pie
s/m
L)
0-12 12 24 36 48
10,000,000
1,000,000
100,000
10,000
Study week
IFN -2b 3 MIU TIW Infergen® 9 g TIW
Baseline Treatment Period Observation Period
P<0.01
0
10
20
30
ETR SVR
24%*
15%
8%
4%
Pat
ien
ts (
%)
IFN -2b 3 MIU TIW
Infergen® 9 g TIW
Note: 3 MIU15 g.
Tong MJ, et al. Hepatology. 1997;26:747-754.
Responses in Genotype 1 Naïve Patients Treated for 24 Weeks
P=0.04
Tong MJ, et al. Hepatology. 1997;26:747-754.
Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.
Infergen® in IFN α-2b Nonresponders
704 patients
Observe24 weeks
Treat 24 weeks
IFN -2b (3 MIU TIW)
Retreatment
Observe24 weeks
48 weeks
24 weeks
Relapsers
Nonresponders
337 patients
Responders
RetreatInfergen®
15 g TIW
Infergen® (9 g TIW)
SVR in IFN α-2b Nonresponders
0
10
20
ETR SVR
Infergen® 15 g TIW
17%
12%
48 Weeks Retreatment
Pat
ien
ts H
CV
RN
A
neg
ativ
e (%
)
Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.
Infergen® [package insert]; Costa Mesa, CA: VPNA 2006.
Laboratory Infergen Infergen Infergen Adverse 9 g TIW 15 g TIW 15 g TIWEvents 24 Weeks 24 Weeks 48 Weeks
ANC <1000 8% 19% 24%
ANC <500 1% 1% 0%
Platelets <50,000 3% 5% 3%
Platelets <25,000 1% 0% 0%
Laboratory Adverse Events With Infergen® Use: Hematologic Side Effects
ANC=absolute neutrophil count.
Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.
Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.
Tong MJ, et al. Hepatology. 1997;26:747-754.
Dropouts due to adverse events 7% 7% 5% 11%
Dosereductions 16% 12% 33% 36%
Initial Treatment Retreatment
Infergen® IFN -2b Infergen Infergen9 g TIW 3 MIU TIW 15 g TIW 15 g TIW24 Weeks 24 Weeks 24 Weeks 48 Weeks
Safety
Management Strategies for the HCV Nonresponder:
Watch and Wait
HCV Patient Projections
Decision Resources Hepatitis C Report & Interactive Forecast Tool 2005.
Future Disease Burden: Estimated Increase From 2000 to 2020
HCC=hepatocellular carcinoma.
Davis GL, et al. Liver Transpl. 2003;9:331-338.
106%
180%
81%
100%
0
50
100
150
200
Cirrhosis HCC Liver-related deaths
Liver decompensation
Incr
ease
(%
)
Adapted from: Fattovich G et al. Gastroenterology. 1997;112:463-472.
Natural History of HCV Cirrhosis
100
80
60
40
20
0
Time (years after diagnosis)
After 1st complication
Su
rvi v
al p
rob
abil
i ty
(%)
Compensated
1 2 3 4 5 6 7 8 9 100
DeathsLiver-related (70%)Other causes (30%)
Waitlist and Liver Transplant Activity: 1995-2004
OPTN/SRTR Annual Report: Table 1.3, 1.7,1.6.
Nu
mb
er o
f P
atie
nts
HCV is the most common indication for OLT accounting for 40%–50% of both individuals on the waiting list and those who have undergone liver transplants
Shiffman M.L., et al. Gastroenterology 2004; 126:1015-1023.
Effect of Cirrhosis on SVR in IFN+RBV Retreatment: Halt-C Lead-In Phase
HC
V R
NA
neg
ativ
e (%
)
37%
23%23%
11%
0
20
40
60
80
48 Weeks SVR
F3 Fibrosis
F4 Cirrhosis
Predicted Impact of Age on SVR
Adapted from: Foster G, et al. AASLD; October 24–28, 2003. Boston, MA. Abstract 189.
0
10
20
30
40
50
60
70
80
90
Cal
cula
ted
SV
R (
%)
553025 4035 504520 60
Age (completed life-years)
0 302010 400
0.25
1.00
0.75
0.50
Duration (y)
Pro
bab
ility
of
de
velo
pin
g c
irrh
osi
s
Age >50
Age 41-50
Age 31-40
Age 21-30
Age <21
Marcellin P, et al. Hepatology. 2002;36:S47-S56.
Progression to Cirrhosis Becomes Nonlinear with Age
Management Strategies for the HCV Nonresponder:
Future Therapies
New Therapies Will Not Be On the Market for the Next Several Years
100%
71%
21%
21%
32%
0
20
40
60
80
100
Preclinical Phase I-II Phase II-III Phase III-market
FDAapproval
1 Year 3 Years 3 Years
DiMasi JA, et al. J Health Econ. 2003;22:151-185.
Ad
van
cin
g t
o
the
nex
t p
has
e (%
)
1 Year
Timeline for New Therapies in Development
ITMN 191Protease Inhibitor
BLX-883Locetron Interferon
R1626Polymerase Inhibitor
SCH 503034Protease Inhibitor
VX-950Protease Inhibitor
TaribavirinRBV Pro Drug
Phase 1 Phase 2 Phase 3
FDA REVIEW
http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008
Franciscus A. Hepatitis C Support Project. Dec. 28, 2006.
1 Year 2-3 Years 2-3 Years
AlbuferonInterferon Albumin
BavituximabAnti phospholipid
GS-9190Polymerase Inhibitor
R7128Polymerase Inhibitor
TMC435350Protease Inhibitor
VCH-759 Polymerase inhibitor
GSK625433Polymerase inhibitor
BLX-883Locetron Interferon
Discontinued Clinical Programs
COMPANY PRODUCT PHASEREASON FOR
DISCONTINUATIONDESCRIPTION
Roche/Ribapharm
Levovirin Phase I Lack of activity and formulation issues
L-isomer of RBV
Boehringer Ingelheim
BILN 2061 Phase II Cardiac toxicity in animals Protease inhibitor
Vertex Pharmaceutical
Merimepodib (MMPD)
Phase II Lack of efficacy Polymerase inhibitor
Maxim Pharmaceuticals
Maxamine® Phase III Lack of efficacy Immune response modifier
Indevus IP 501 Phase III Unknown Antifibrotic
Coley Pharmaceutical
ACTILON (CPG 10101)
Phase I/II Lack of efficacy Toll-like receptor agonist
Achillion/Gilead ACH806 Phase II Safety Protease Inhibitor
Idenix/NovartisValopicitabineNM283
Phase IIClinical development on hold per FDA request for safety reasons
Polymerase Inhibitor
Anadys / Novartis ANA 975 Phase Ib Safety Toll-like receptor agonist
http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008
Management Strategies for the HCV Nonresponder: Peg Retreatment
AASLD Treatment Guidelines
“Retreatment with peginterferon plus ribavirin with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of peginterferon plus ribavirin, even if a different type of peginterferon is administered (Grade III).”
AASLD=American Association for the Study of Liver Diseases.
Strader DB, et al. Hepatology. 2004;39:1147-1171.
IFN-2a E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E TIFN-2b E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E T
IFN-2a L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VIFN-2b L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A V
IFN-2a R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q EIFN-2b R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q E
IFN-2a S L R S K EIFN-2b S L R S K E
IFN-2a C D L P Q T H S L G S R R T L M L L A Q M R K I S L F S C L K D R H D F G F P QIFN-2b C D L P Q T H S L G S R R T L M L L A Q M R R I S L F S C L K D R H D F G F P Q
There is 1 amino acid difference between IFN -2a and IFN -2b
Differences Among IFN -2a and IFN -2b
Korn AP, et al. J Interferon Res. 1994:14;1-9.
Retreatment of IFN + RBV Failures With PEG-IFN + RBV
Retreatment of IFN + RBV Failures With PEG-IFN + RBV
Investigator N Study Drug/Dose SVR
Teuber G, et al. DDW. 2003 240PEG-IFN α-2b 100 g + RBV 800 mg x 8 wk
PEG-IFN α-2b 50 g + RBV 800 mg x 40 wk6.3%
Jacobson I, et al. DDW. 2003 219PEG-IFN α-2b 1.0 g/kg + RBV 1–1.2 g x 48 wk
PEG-IFN α-2b 1.5 g/kg + RBV 800 mg x 48 wk
6%
10%
Sulkowski M, et al. DDW. 2003 517PEG-IFN α-2b 1.5 g/kg + RBV 800 mg x 48 wk
PEG-IFN α-2b 100/150 g + RBV 800 mg x 48 wk12%
Lawitz E, et al. DDW. 2003. 486PEG-IFN α-2b 1.5 g/kg + RBV 1–1.2 g x 12 wk
PEG-IFN α-2b 1.0 g/kg + RBV 800 mg x 36/48 wk5–10%
Shiffman ML, et al. Gastroenterology. 2004
210 PEG-IFN α-2a 180 g + RBV 1–1.2 g x 48 wk 12%
Poynard T, et al. EASL. 2005 978 PEG-IFN α-2b 1.5 g/kg + RBV 0.8–1.4 g x 48 wk 14%
Gaglio P, et al. AASLD. 2005 454PEG-IFN α-2b 1.5 g/kg/wk + RBV 800-1400 mg/d
x 48 wks14%
Gross JB, et al. AASLD. 2005 764PEG-IFN α-2b 0.5/1.5/3.0 g/kg + RBV 12–15 mg/kg
x 48 wk12-
17%
Teuber G, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1216. Jacobson IM, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract 504.Sulkowski M, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1292. Lawitz EJ, et al. DDW May 17–22, 2003; Orlando, FL. Abstract T1293. Shiffman ML, et al. Gastroenterology. 2004;126:1015-1023.
Poynard T, et al. EASL; April 13–17, 2005; Paris, France. Abstract 96. Gaglio P, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 59.Gross JB, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 60.
Retreatment of PEG-IFN + RBV Failures With PEG-IFN + RBV
Retreatment of PEG-IFN + RBV Failures With PEG-IFN + RBV
Investigator N Study Drug/Dose SVR
Afdhal N, et al.
EASL 2007178
PEG-IFN α-2a180 g QW + RBV (1–1.2 g/day) x 48 wks
3%
Schiff E, et al. 357PEG-IFN α-2b 1.5g/kg QW + RBV (800-1400mg/day) x 48 wks
2%
Afdhal N et al. Hepatol . 2007: 46 (Suppl S5).Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.
Management Strategies for the HCV Nonresponder: Double Dose Peg
To evaluate the efficacy, safety, and tolerability of PEG-IFN -2b + weight-based RBV in prior IFN + RBV nonresponders
PEG-IFN -2b: 1.5 g/kg/week, 3.0 g/kg/week
RBV: 12-15 mg/kg/d
Stratified for sex, race, genotype, and fibrosis
963 patients enrolled in study
Including152 African Americans, of these:
66 received 1.5 g/kg (11 did not start treatment)
64 received 3.0 g/kg (6 did not start treatment)
22 received 0.5 g/kg, this arm was discontinued
RENEW Trial: Study Aim
Gross et al. AASLD 2005; San Francisco, CA. Oral Session 60.
48 Weeks
SVR
Results
RBV --------------------- 12-15 mg/kg/d ---------------------------------------Discontinuation 32% 35% 36%
4% 12%17%
0
20
40
60
80
100
0.5 g/kg/week PEG-IFN
1.5 g/kg/week PEG-IFN
HC
V R
NA
neg
ativ
e (%
)
P=NS
N=704
3 g/kg/week PEG-IFN
Gross et al. AASLD 2005; San Francisco, CA. Oral Session 60.
24% 24%17%
Follow-up
REPEAT Trial: Study Design
A
B
C
D Follow-up
Follow-up
Follow-up
PEG-IFN -2a180 µg
plus RBV 1000-1200mg
PEG-IFN -2a180 µg
PEG-IFN -2a180 µg
PEG-IFN -2a180 µg
plus RBV 1000-1200mg
360 µg
360 µg
0 12 24 36 48 60 72 84 96
Study Week
942 patients randomized 2:1:1:2
Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4.
plus RBV 1000-1200mg
plus RBV 1000-1200mg
Patient Demographics
PEG-2a + RBVA (n=317)
360/180mcg/w (72w)
B (n=156) 360/180mcg/w
(48w)
C (n=156) 180mcg/w
(72w)
D (n=313) 180mcg/w
(48w)
Male (%) 64 60 69 68
Mean age+SD (y) 48.1+8.7 48.8+9.9 49.4+8.5 48.5+9.0
Mean weight+ SD (kg) 81.5+18.2 81.1+16.8 81.2+16 80.9+16.9
Caucasian (%) 88 90 88 90
G1 (%) 91 91 91 91
Cirrhosis (%) 25 29 30 28
Mean+SD baseline HCV RNA (x106
IU/ML)5.4+6.4 5.3+7.1 4.9+5.1 4.9+6.0
Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4.
Safety
Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4.
PEG-2a + RBVA (n=317)
360/180mcg/w (72w)
B (n=156) 360/180mcg/w
(48w)
C (n=156) 180mcg/w
(72w)
D (n=313) 180mcg/w
(48w)
Premature d/c for safety n (%) 37 (12%) 7 (4%) 18 (12%) 20 (6%)
Patients with serious adverse
events n (%)33 (10%) 14 (9%) 28 (18%) 33 (11%)
Overall Hematological 5 (2%) - 3 (2%) 6 (2%)
Peg dose modifications n (%) 72 (23%) 41 (26%) 36 (23%) 57 (18%)
Results
360/180 μg/wk 180 μg/wk
SVR in pooled 72-wk vs 48 wk arms: 16% vs 8% (P = .0006; OR: 2.22; 95% CI: 1.40-3.52)
PP Analysis
31 33 31 28
52
78
64 68
0
20
40
60
80
100
72 wk (n=317) 48 wk (n=156) 72 wk (n=156) 48 wk (n=313)
Per
cen
t, %
ETR Relapse SVR
716 14 9
Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4.
Management Strategies for the HCV Nonresponder: Extending Therapy
Study Design
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
Week 0 Week 48Weeks 12-24 Week 72
Berg (n=455)PegIFN -2a 180mcg QW +RBV 800 mg
Treatment Naive G1 only
48 weeks
72 weeks
n=230
n=225
Overall Results
63%
53% 54%
71%
Per
cen
t, %
EOT 48 Weeks
SVR 48 Weeks
SVR 72 Weeks
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
SVR by Viral Response Time Points in Treatment Naïve G1 Patients
“Note that only 1 patient in each group (2/455 – 0.4%) with HCV-RNA Levels greater than 6,000 IU/mL (12 weeks) achieved an SVR.”
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
Discontinuation Rates
Treatment Arm
Treatment Discontinuatio
n
Group A (48 Weeks) 24%
Group B (72 Weeks) 41%
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
Results and Conclusions
Overall, no significant differences could be observed in the treatment outcome in both groups (53% vs. 54%)
Patients with undetectable HCV-RNA levels at week 4 and 12 had excellent SVR rates ranging form 76% to 84% regardless of treatment groups
Patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 vs 48 weeks (29% vs. 17% P=0.04) A particular benefit from extended treatment duration was seen in
patients with low level viremia (<6000IU/mL at week 12)
Extended treatment duration generally is not recommended in HCV G1 infection and should be reserved only for patients with slow virologic response defined as HCV RNA positive at week 12 but negative at week 24
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
Management Strategies for the HCV Nonresponder:
Maintenance Therapy
PrimaryGoal
The Goals of Treatment
SecondaryGoal
Eradicate HCV infection
Slow disease progression
Improve histology
Reduce risk of HCC
Sethi A, et al. Clin Liver Dis. 2005;9:453-471.
HALT-C Final Results
Low dose peginterferon alfa-2a arm (90 µg/week) vs control group had Greater reductions in HCV RNA and ALT (P < .0001) Greater reductions in necroinflammation (P < .001)
No reduction in fibrosis or difference between arms No significant difference between arms in any primary outcome 34.1% vs 33.8%: HR 1.01 (95% CI, 0.81-1.26)
Di Bisceglie A, et al. AASLD 2007. Abstract LB1.
Study Arm Baseline Fibrosis*
Any primary outcome, %
Death, % HCC, % CTP score ≥ 7, %
Peginterferon alfa-2a90 µg/week (n = 517)
3/4 36.6 2.6 2.6 3.2
5/6 30.1 2.4 1.9 17.8
Control (n = 533)3/4 35.5 0.6 1.6 3.2
5/6 31.1 2.7 4.6 14.6
*Ishak Score
Impact of SVR on Fibrosis
Shiratori Y, et al. Ann Intern Med. 2000;132:517-524.
3 Years Post Therapy
Patients
0.59
0.15
-0.6Untreated No SVR SVR
IFN-treated
0.6
0.3
-0.3
-0.6
0
Ch
ang
e in
fib
rosi
s st
age
Summary
The primary goal of therapy is to eliminate the virus
Only 50% of naïve patients and 30% of difficult-to-treat naïve patients achieve SVR
The nonresponder patient population is growing
Infergen® is a unique, bioengineered IFN
Treating younger patients and earlier during the disease progression timeline can translate to more successful outcomes
It will be several years until new drugs enter the HCV marketplace, and interferon will always play a role
Interactive Case Discussion
Positive Predictive Factors for Achieving SVR
• Viral Factors Non-1 genotype (2/3) Lower HCV RNA level Early virologic response
Disease-Related Factors Absence of advanced fibrosis Lack of steatosis
• Appropriate RBV dosage
• Host Factors Lower body weight Younger age Female gender Race (non-AA)
• Adherence More than 80% of
intended treatment for more than 80% of intended duration
Ferenci P. Semin Liver Dis. 2004;24(suppl 2):25-31.
SustainedResponder
Null ResponderRelapserRelapser
Partial Responder
HCV RNAnegative
Time (weeks)
HCV RNA
12 (EVR)
24 48 (EOT)
72 (SVR)
Patient Profiles During HCV Therapy
Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460
4(RVR)
RVR = HCV RNA (-) at week 4EVR = ≥2log10 drop in HCV RNA or HCV RNA (-) at week 12 EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation
Treatment Duration: Positive and Negative Predictor Algorithms
PEG-IFN -2a/RBVWeek 12(n=453)
2-log drop orundetectable HCV RNA
86%(n=390)
14%(n=63)
Yes
No
Fried MW, et al. N Engl J Med. 2002;347:975-982.
65%(n=253)
35%(n=137)
3%(n=2)
97% (n=61)
SVR
No SVR
SVR
No SVR
Berg TA et al. Hepatology 2006;130:1086-1097
Treatment Naïve Patients – Genotype 1
SV
R b
y V
iral
Res
po
nse
Tim
e P
oin
ts (
%)
Treatment Duration: Positive and Negative Predictor Algorithms
Sensitive Testing Can Affect Your Treatment Duration Decisions:
TMA Positive Results from PCR-negative Samples – HALT-C
Morishima C et al. Hepatology 2006;44:360-367.
PCR – Roche COBAS Amplicor, Lower Limit of Detection 100 IU/mL
22%
37%
27%20%
Week 12
% T
MA
po
siti
ve
n=1294 n=241 n=373 n=361n=319
0
20
40
60
80
Overall Week 20 Week 24 Week 48
6%
The increased sensitivity offered by TMA testing may detect treatment failures earlier
22% of the patients who are PCR negative by Roche Amplicor are positive by TMA
Patients who are negative by Roche Amplicor at week 20 but positive by TMA had a 0% SVR
HCV Treatment Algorithm
* For information on early response for patient management purposes only; not a decision point in the protocol.**Patients should be maintained on treatment for 36-48 weeks from the first negative TMA test.www.point-of-hcv-care.com Barnett K. Review Paper
Testing
Quantitative
Qualitative (TMA)
End treatment
24-week follow-up
12 weeks
<2 log drop or +
HCV RNA
continue
therapy
24 weeks
≥48 weeks**
RELAPSER SVR
Negative or ≥2 log dropHCV RNA
HCV RNA
positive
HCV RNAnegative
HCV RNApositive
HCV RNAnegative
y×10z y×10z
Baseline
y×10z y×10z
+ –4 weeks*
y×10z y×10z
continue
therapy
continue
therapy
y×10z y×10z
HCV RNA
positive
+ –
+ –
+ –
+ –
HCV RNAnegative
Consider Alternative Treatment Options
Case 1- RVR
40 year old
Male
Caucasian
G1
Viral Load- 350,000 IU/mL
F2
91kg
Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1200mg
Week 4 HCV RNA – Negative
• Identify this patient’s positive vs. negative predictors for success?
• What strategies could you implement to optimize outcomes in this patient?
• What is this patient’s chance of SVR if he remains on Peg therapy for 48 wks?
Predictive Factors for SVR
Positive
Younger Age
Caucasian
Low Viral Load
F2
RVR
Negative
Male
Genotype 1
Heavier Weight
Berg TA et al. Hepatology 2006;130:1086-1097
Treatment Naïve Patients – Genotype 1
Treatment Duration: Positive and Negative Predictor Algorithms
Case 2- EVR Week 12 Negative
52 year old
Female
Caucasian
G1
Viral Load- 900,000 IU/mL
F2
60kg
Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1000mg
Week 4 HCV RNA – 450,000 IU/ML
Week 12 HCV RNA- Negative
• Identify this patient’s positive vs. negative predictors for success?
• What strategies could you implement to optimize outcomes in this patient?
• What is this patient’s chance of SVR if she remains on Peg therapy for 48 wks?
Predictive Factors for SVR
Positive
Female
Caucasian
F2
Lower body weight
EVR
Negative
Older Age
Genotype 1
High Viral Load
Berg TA et al. Hepatology 2006;130:1086-1097
Treatment Naïve Patients – Genotype 1
Treatment Duration: Positive and Negative Predictor Algorithms
Case 3- EVR Week 12 Positive
35 year old
Male
Caucasian
G1
Viral Load- 1,800,000 IU/mL
F3
68kg
Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1000mg
Week 4 HCV RNA- 180,000 IU/ML
Week 12 HCV RNA- 18,000 IU/ML
• Identify this patient’s positive vs. negative predictors for success?
• What strategies could you implement to optimize outcomes in this patient?
• What is this patient’s chance of SVR if he remains on Peg therapy for 48 wks?
• What other options could you consider in the treatment of this patient?
Predictive Factors for SVR
Positive
Younger Age
Caucasian
Lower Body Weight
EVR
Negative
Male
G1
High Viral Load
F3
Berg TA et al. Hepatology 2006;130:1086-1097
SVR by Viral Response Time Points in Treatment Naïve Patients – Genotype 1
Case 4- Nonresponder
68 year old
Female
African American
G1
Viral Load- 2,500,000 IU/mL
F3
63kg
Initiated on peginterferon alpha-2b 1.5mcg/kg QW and ribavirin 800 mg
Week 4 HCV RNA- 2,000,000 IU/ML
Week 12 HCV RNA- 1,000,000 IU/ML
• Identify this patient’s positive vs. negative predictors for success?• The clinician discontinued therapy in this patient at week 12 due to nonresponse. Do you
agree with this decision?• What strategies could you have implemented to optimize outcomes in this patient?• How would you manage this patient at this point?
Predictive Factors for SVR
Positive
Female
Lower body weight
Negative
Older Age
African American
G1
High Viral Load
F3
Negative Predictors of Response
PEG-IFN -2a/RBVWeek 12(n=453)
2-log drop orundetectable HCV RNA
86%(n=390)
14%(n=63)
Yes
No
Fried MW, et al. N Engl J Med. 2002;347:975-982.
65%(n=253)
35%(n=137)
3%(n=2)
97% (n=61)
SVR
No SVR
SVR
No SVR
Case 5- Relapser
42 year old
Male
Caucasian
G1
Viral Load- 850,000 IU/mL
F2
85kg
Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1200 mg
Week 4 HCV RNA- 85,000 IU/ML
Week 12 HCV RNA- 8,500 IU/ML
Week 24 HCV RNA- Negative
Week 48 HCV RNA- Negative- STOPPED THERAPY
Week 72 HCV RNA- 1000 IU/ML
• Identify this patient’s positive vs. negative predictors for success?• What strategies could you have implemented to optimize outcomes in this patient?• What options would you offer your patient at this point?
Predictive Factors for SVR
Positive
Younger Age
Caucasian
F2
Negative
Male
G1
High Viral Load
Higher Body Weight
SustainedResponder
Null ResponderRelapserRelapser
Partial Responder
HCV RNAnegative
Time (weeks)
HCV RNA
12 (EVR)
24 48 (EOT)
72 (SVR)
Patient Profiles During HCV Therapy
Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460
4(RVR)
RVR = HCV RNA (-) at week 4EVR = ≥2log10 drop in HCV RNA or HCV RNA (-) at week 12 EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation
References
Afdhal N et al. Hepatol . 2007: 46 (Suppl S5).Berg TA, et al. Hepatology 2006;130:1086-1097.Blatt LM, et al. J Interferon Cytokine Res. 1996;16:489-499.Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.Carrat F, et al. JAMA. 2004;292:2839-2848.Davis GL, et al. Hepatology. 2003;38:645-652.Davis GL, et al. Liver Transpl. 2003;9:331-338.Decision Resources Hepatitis C report 2005.Di Bisceglie A, et al. AASLD 2007. Abstract LB1.DiMasi JA, et al. J Health Econ. 2003;22:151-185. Fattovich G et al. Gastroenterology. 1997;112:463-472.Ferenci P. Semin Liver Dis. 2004;24(suppl 2):25-31.Foster G, et al. AASLD; October 24–28, 2003. Boston, MA. Abstract 189.Franciscus A, Hepatitis C Support Project. Dec. 28, 2006. Fried MW, et al. N Engl J Med. 2002;347:975-982.Gaglio P, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 59.Gross JB, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 60.Healthcote EJ, et al. Heptatology. 1998;27:1136-1143.Infergen® [package insert]. Costa Mesa, CA: VPNA, 2006Jacobson IM, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract 504.Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4. Klein SB, et al. J Interferon Cytokine Res. 1996;16:1-6.
References (cont’d)
Korn AP, et al. J Interferon Res. 1994;14:1-9.Lawitz EJ, et al. DDW May 17–22, 2003; Orlando, FL. Abstract T1293. Manns MP, et al. Lancet. 2001;358:958-965.Marcellin P, et al. Hepatology. 2002;36:S47-S56.Morishima C, et al. Hepatology 2006;44:360-367.Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.
OPTN/SRTR Annual Report: Table 1.3, 1.7,1.6.
Ozes ON, et al. J Interferon Res. 1992;12:55-59.
Pegasys® [package insert]. Nutley, NJ: Hoffman-La Roche Inc; 2005.
PEG-Intron® [package insert]. Kenilworth, NJ: Schering-Plough Corporation; 2005.
Poynard T, et al J Hepatol. 2005:42(Suppl 2):40-41.
Poynard T, et al. Abstract presented at: EASL, 2005; Paris, France. Abstract 96.
Sanchez-Tapias JM, Gastroenterology 2006;131:451-460.
Sethi A, et al. Clin Liver Dis. 2005;9:453-471.
Shiffman ML, et al. Gastroenterology. 2004;126:1015-1023.
Shiratori Y, et al. Ann Intern Med. 2000;132:517-524.
Strader, et al. Hepatology. 2004; 39 (4):1157-1171.
Sulkowski M, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1292.
Teuber G, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1216.
Torriani FJ, et al. N Engl J Med. 2004;351:438-450.
Tong MJ, et al. Hepatology.1997;26:747-754.
http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008.
Please see the Important Safety Information, including boxed warning, as well as the complete prescribing information included on the CD-Rom Disk.
Copyright © Three Rivers Pharmaceuticals 2008. All Rights Reserved. INFERGEN is a registered Trademark of Amgen, Inc. and Three Rivers Pharmaceuticals is the exclusive licensee from Amgen of this mark.
INFERGEN® is indicated for the treatment of chronic HCV infection in patients 18 years of age or older with compensated liver disease who have anti-HCV serum antibodies and/or the presence of HCV RNA. Other causes of hepatitis, such as viral hepatitis B or autoimmune hepatitis, should be ruled out prior to initiation of therapy with INFERGEN®. The most commonly reported adverse events during initial and subsequent treatment were headache, fatigue, fever, myalgia, rigors, body pain, arthralgia, and nausea.
Important safety information:
Alpha interferons, including Interferon alfacon-1, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping Interferon alfacon-1 therapy.See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in full prescribing information.
INFERGEN® is contraindicated in patients with known hypersensitivity to alpha interferons or to any component of the product, in patients with decompensated hepatic disease and autoimmune hepatitis. Development of or exacerbation of autoimmune disorders (e.g. autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis) have been reported in patients receiving alpha interferon therapies, including INFERGEN.
Treatment with INFERGEN should be administered under the guidance of a qualified physician, and may lead to moderate-to-severe adverse experiences requiring dose reduction, temporary dose cessation, or discontinuation of further therapy.
Severe psychiatric adverse events may manifest in patients receiving therapy with alpha interferons, including INFERGEN. Depression, suicidal ideation, suicide attempt, and suicide may occur. Other prominent psychiatric adverse events may also occur, including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted.
Bone Marrow Toxicity: Alpha interferons suppress bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. Alpha interferon therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 109/L) or platelet counts (<50 x 109/L).
Hypertension, tachycardia, palpitation, and tachyarrythmias have been reported in patients treated with INFERGEN. INFERGEN should be administered with caution to patients with preexisting cardiac disease. Supraventricular arrhythmias, chest pain, and myocardial infarction have been associated with alpha interferon therapies.Pneumonia and interstitial pneumonitis, some resulting in respiratory failure and/or patient deaths, have been induced or aggravated by alpha interferon therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN.Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with alpha interferons, including INFERGEN. During treatment, patients' clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin, are observed.
Ophthalmologic Disorders: Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, and papilledema are induced or aggravated by treatment with INFERGEN or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. INFERGEN therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Ischemic and hemorrhagic cerebrovascular events including hemorrhagic stroke have been observed in patients being treated with INFERGEN. In addition, transient ischemic attack has been reported in young patients being treated with INFERGEN without other reported risk factors.
INFERGEN should be discontinued immediately and appropriate medical treatment instituted if hypersensitivity reactions occur. INFERGEN should be administered with caution to patients with a history of endocrine disorders and should be discontinued immediately in patients who develop signs and symptoms of colitis. In addition, INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.
The most common adverse events reported for INFERGEN during clinical studies were headache (82%), fatigue (69%), fever (61%), myalgia (58%), rigors (57%), body pain (54%), arthralgia (51%), nausea (40%), insomnia (39%), pharyngitis (34%), nervousness (31%), infection upper respiratory (31%), diarrhea (29%), depression (26%), anorexia (24%), injection site erythema (23%), granulocytopenia (23%), dizziness (22%), cough (22%), dyspepsia (21%), thrombocytopenia (19%), anxiety (19%), sinusitis (17%), influenza-like symptoms (15%) and leucopenia (15%).
Please see complete Prescribing Information, including boxed warning, included on the disk.