Managing the Difficult-to-Treat HCV Patient

1
Managing the Difficult-to-Treat HCV Patient
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2
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Participants have an implied responsibility to
use the newly acquired information to enhance
patient outcomes and their own professional
development. The information presented in this
activity is not meant to serve as a guideline for
patient management. Any procedures, medications,
or other courses of diagnosis or treatment
discussed or suggested in this activity should
not be used by clinicians without evaluation of
their patients conditions and possible
contraindications on dangers in use, review of
any applicable manufacturers product
information, and comparison with recommendations
of other authorities.
3
HCV Infection Magnitude of the Problem

• Approximately 3.9 million persons in United
  States infected
• Approximately 35,000 new cases yearly
• 85 of new cases become chronic
• 10,000-20,000 HCV-related deaths per year
• Number expected to triple in next 10-20 years
• Leading cause of
• Chronic liver disease
• Cirrhosis
• Liver cancer
• Liver transplantation

CDC. MMWR Morb Mortal Wkly Rep. 1998471-39.
NIH Consensus Conference Statement. Available
at http//consensus.nih.gov/2002/
2002HepatitisC2002116html.htm. Accessed August
19, 2008. Rustgi VK. J Gastroenterol.
200742513-521.
4
Goals of HCV Therapy

• Primary goal of treatment is to eradicate the
  virus
• Additional goals
• Slow disease progression
• Minimize risk of HCC
• Improve liver histology
• Enhance quality of life
• Prevent transmission of virus
• Reduce extrahepatic manifestations

Lindsay KL. Hepatology. 200236(suppl
1)S114-S120.
5
SVR Rates With Standard IFN
100
80
60
SVR ()
43
40
19
20
6
0
IFN 24 Weeks
IFN 48 Weeks
IFN/RBV 48 Weeks
McHutchison J, et al. N Engl J Med.
19983391485-1492. Poynard T, et al. Lancet.
1998352 1426-1432.
6
SVR With PegIFN gt 50 of GT 1 Patients Do Not
Respond

• PegIFN alfa-2b 1.5 µg/kg/week RBV 800 mg/day
  for 48 weeks1

• PegIFN alfa-2a 180 µg/week weight-based RBV
  (1000 or 1200 mg/day) for 48 weeks2

100
82
76
80
56
60
54
46
SVR ()
42
40
20
n 348
n 163
n 511
n 298
n 140
n 453
0
Overall
GT 1
GT 2/3
Overall
GT 1
GT 2/3
1. Manns M, et al. Lancet. 2001358958-965. 2.
Fried MW, et al. N Engl J Med. 2002347975-982.
7
Patterns and Predictors of Response
8
Virologic Responses
8
PegIFN/RBV
7
6
5
EVR
2 log10 decline
HCV RNA (log10 IU/mL)
4
3
Slow virologic response
2
Limit of detection
cEVR
1
RVR
SVR
0
0
4
12
18
24
30
36
42
48
54
60
66
72
8
78
Weeks
9
Suboptimal Virologic Responses
8
PegIFN/RBV
7
Relapse
Null response
6
5
Partial response
2 log10 decline
Breakthrough
HCV RNA (log10 IU/mL)
4
3
2
Limit of detection
1
0
0
4
12
18
24
30
36
42
48
54
60
66
72
8
78
Weeks
10
HCV Treatment Key Predictors of Response
Manns MP, et al. Lancet. 2001358958-965. Fried
MW, et al. N Engl J Med. 2002347975-982. Muir
AJ, et al. N Engl J Med. 20043502265-2271.
Conjeevaram HS, et al. Gastroenterology.
2006131470-477.
11
Key Principles Regarding Nonresponse

• Inadequate dosing/treatment
• Patient factors may require higher treatment
  dosages
• Compliance
• Adverse effects can require dose reductions or
  interruptions
• May be able to maintain treatment through better
  management of adverse effects
• Steatosis
• Insulin resistance can impair response to HCV
  therapy
• Differences in mechanisms, management according
  to HCV genotype
• Some patients may be inherently resistant to IFN

12
Preventing Relapse
13
Key Principles Regarding Relapse

• Viral kinetics
• Importance of duration of HCV RNA negativity
• Slow responders may not be treated for adequate
  duration
• Key for GT 1 patients
• RBV dosage
• Inadequate dosage of RBV associated with higher
  rates of relapse

14
Longer Duration of Undetectability on Treatment
Increases Chance for SVR

• Retrospective analysis of GT 1 patients receiving
  48 weeks of pegIFN alfa-2a RBV (N 453)

100
91
80
66
60
45
SVR ()
40
20
2
0
HCV RNA Positive at Week 24
4
12
24
Week Became HCV RNA Negative
Ferenci P, et al. J Hepatol. 200543425-433.
15
GT 1 Patients Without RVR Benefit From Longer
Therapy
Treatment-Naive Patients Received PegIFN alfa-2a
180 µg/week RBV 800 mg/day
100
48 weeks
80
72 weeks
P .003
P .01
60
SVR ()
44
45
40
32
28
20
149
142
165
161
n
0
All Patients Without RVR
GT 1, No RVR
Sanchez-Tapias JM, et al. Gastroenterology.
2006131451-460.
16
Longer Therapy in GT 1 Pts Without cEVR but Week
24 Negative HCV RNA
Post Hoc Analysis of Slow Responders Who
Completed PegIFN alfa-2a 180 µg/week RBV 800
mg/day and Follow-up
100
48 weeks (n 147)
P .02
80
72 weeks (n 158)
64
60
Patients ()
P .04
40
40
29
17
20
30/47
21/52
17/100
31/106
0
SVR
Relapse
Berg T, et al. Gastroenterology.
20061301086-1097.
17
Ribavirin Is Critical to the Success of HCV
Combination Therapy

• Role of RBV in successful antiviral therapy
• Antiviral activity
• Prevention of relapse
• Can we optimize treatment by fine tuning the use
  of RBV?
• How important is the initial dose of RBV?
• Do we need to maintain the RBV dose for the
  duration of treatment?

Dusheiko G, et al. Antivir Ther. 200813(suppl
1)23-30.
18
Increase in SVR by Prevention of Relapse With
Addition of RBV

• 48 weeks of treatment with pegIFN alfa-2a RBV

100
PegIFN alfa-2a 180 µg/week
PegIFN alfa-2a 180 µg/week RBV 1000/1200 mg/day
P .01
80
69
P lt .001
59
60
56
51
Patients ()
40
29
19
20
n 224 453 224 453
132 313
0
SVR
Relapse
ETR
P value not specified.
Fried MW, et al. NEJM. 2002 347975-982.
19
Increased SVR Rate With Higher RBV Starting Dose
in Clinical Trials

• GT 1 patients treated with pegIFN alfa-2a 180
  µg/week RBV for 48 weeks

100
80
60
52
SVR ()
41
40
20
N 250 271
0
RBV 800 mg/day
RBV 1000/1200 mg/day
Hadziyannis S, et al. Ann Intern Med.
2004140346-355.
20
Dose-Dependent Increase in SVR With RBV Dosage gt
10 mg/kg/day

• GT 1 patients treated with pegIFN alfa-2a 180
  µg/week RBV 1000/1200 mg/day

Snoeck E, et al. Br J Clin Pharmacol. 200662
699-709.
21
Dose-Dependent Increase in Anemia With RBV Dose gt
15 mg/kg/day

• All patients treated with pegIFN alfa-2a 180
  µg/week RBV 1000/1200 mg/day

Snoeck E, et al. Br J Clin Pharmacol 2006 62
699-709.
22
RBV Exposure and SVR GT 1 and Treatment
Completers

• Retrospective analysis of pegIFN alfa-2a/RBV
  phase III trials

SVR (P .006)
Relapse
100
80
67
62
57
54
60
Patients ()
33
40
32
22
19
20
0
gt 97
gt 80-97
gt 60-80
0-60
Cumulative RBV Exposure
Reddy KR, et al. Clin Gastroenterol Hepatol.
20075124-129.
23
RBV Exposure Weeks 13-48 After Full Exposure
During Weeks 1-12

• Retrospective analysis of pegIFN alfa-2a/RBV
  phase III trials

End-of-treatment response
SVR (P .0107)
100
87
83
82
81
80
69
67
60
52
Patients ()
36
40
20
0
gt 97
gt 80-97
gt 60-80
0-60
Cumulative RBV Exposure
Reddy KR, et al. Clin Gastroenterol Hepatol.
20075124-129.
24
Steatosis in HCV

• Steatosis a common comorbidity of HCV
• Found in 50 to 60 of HCV-infected patients1,2
  vs 14 to 30 in general population3,4

Proportion of Patients With Fatty Liver Disease
Among 121 HCV-Infected Individuals With
Available Liver Biopsies1
NASH (18)
No steatosis (41)
Steatosis (41)
1. Younossi ZM, et al. J Clin Gastroenterol.
200438705-709. 2. Asselah T, et al. Gut.
200655123-130. 3. Browning JD, et al.
Hepatology. 2004401387-95. 4. Nomura H, et al.
Jpn J Med. 198827142-149.
25
Metabolic Syndrome in HCV

• Having at least 3 of the following conditions
• Abdominal circumference gt 40" for men or gt 35"
  for women
• Elevated triglycerides ( 150 mg/dL)
• Low levels of high density lipoprotein (lt 40
  mg/dL in men and lt 50 mg/dL in women)
• Hypertension (blood pressure 130 mm Hg systolic
  or 85 mm Hg diastolic)
• Hyperglycemia (fasting glucose 100 mg/dL)

Torpy JM, et al. JAMA. 2006295850.
26
2 Types of Steatosis in Hepatitis C
Metabolic steatosis Insulin resistance
HCV
Viral steatosis (viremia)
Overweight Diabetes
Steatosis
GT 3
Alcohol
Rubbia-Brandt L, et al. J Hepatol.
200033106-115. Adinolfi LE, et al. Hepatology.
2001331358-1364. Serfaty L, et al. Am J
Gastroenterol. 2002971807-1812. Monto A, et al.
Hepatology. 200236729-736. Poynard T, et al.
Hepatology. 20033875-85.
27
Calculation of Insulin Resistance

• HOMA
• Convert glucose in mg/dL to mmol/L, divide
  glucose by 18
• Values gt 1.8-2.0 are consistent with insulin
  resistance
• QUICKI
• Fasting insulin (µU/L) ? fasting glucose (mg/dL)
• Take log, then 1/?
• Values lt 0.35 are consistent with insulin
  resistance
• Rough estimate multiply fasting insulin ?
  glucose values gt 700 are typically consistent
  with insulin resistance

28
Insulin Resistance Common in Nondiabetic HCV
Patients

• 462 HCV nondiabetic patients HOMA-IR gt 3 in 35

P lt .001
40
35
30
HOMA-IR gt 3 ()
20
10
5
0
HBV (n 80)
HCV (n 240)
Age, sex, BMI, inflammation and fibrosis matched.
Moucari R, et al. Gastroenterology.
2008134416-423.
29
Insulin Resistance and SVR in HCV GT 1 Patients
100
P .007
80
61
60
SVR ()
40
33
20
0
With Insulin Resistance
Without Insulin Resistance
Romero-Gomez M, et al. Gastroenterology.
2005128636-641.
30
Effect of Weight Loss on Antiviral Response
32 treatment-naive GT 1HCV patients with
metabolic syndrome
15 patients on low-calorie diet 10 ? in BMI
17 control patients
HOMA 4.86-3.45 (P .0018)
pegIFN alfa-2b RBV
Response 17.6
Response 60.0
Tarantino G, et al. Gut. 200655585.
31
Retreatment Options for Patients With Previous
Treatment Failure
32
PegIFN RBV in Previous Standard IFN
Nonresponders
100
Previous HCV RNA reduction predicts
response high relapse rate (gt 50) in responders
80
60
40-50
SVR ()
40
25-30
10-15
20
0
NR IFN RBV
Relapse IFN RBV
NR IFN
Jacobson IM, et al. Am J Gastroenterol.
20051002453-2462. Lawitz E, et al. DDW 2003.
Abstract 9. Shiffman ML, et al. Gastroenterology.
20041261015-1023. Gross J, et al. Hepatology.
200542220A. Krawitt EL, et al. J Hepatol.
200543243-249.
33
Outcomes in Nonresponders to IFN-Based Therapy
1. Jacobson IM, et al. Am J Gastroenterol.
20051002453-2462. 2. Sherman M, et al. Gut.
2006551631-1638. 3. Gross J, et al. AASLD
2005. Abstract 60. 4. Shiffman ML, et al.
Gastroenterology. 20041261015-1023. 5. Poynard
T, et al. EASL 2008. Abstract 988.
34
Outcomes in Nonresponders to PegIFN/RBV
1. Jensen DM, et al. AASLD 2007. Abstract LB4. 2.
Bacon B, et al. AASLD 2007. Abstract 168. 3.
Nelson DR, et al. AASLD 2007. Abstract 51. 4.
Poynard T, et al. EASL 2008. Abstract 988.
35
Outcomes in Relapsers to IFN-Based Therapy
1. Jacobson IM, et al. Am J Gastroenterol.
20051002453-2462. 2. Sherman M, et al. Gut.
2006551631-1638. 3. Gross J, et al. AASLD
2005. Abstract 60.
36
Outcomes in Relapsers to PegIFN-Based Therapy
1. Kaiser S, et al. AASLD 2007. Abstract 1310. 2.
Gross J, et al. AASLD 2005. Abstract 60.
37
DIRECT SVR12 Rates With CIFN RBV in PegIFN/RBV
Nonresponders
100
Modified ITT
80
60
P lt .001
SVR12 ()
40
P .002
20
9.5
0
5.3
0
No Treatment(n 172)
9 µg CIFN RBV(n 245)
15 µg CIFN RBV(n 242)
Patients with at least 12 weeks of viral
negativity after end of treatment RBV dosed at
1000-1200 mg/day.
Bacon B, et al. AASLD 2007. Abstract 168.
38
REPEAT PegIFN alfa-2a Treatment of PegIFN
alfa-2b Nonresponders
Week 48
Week 96
Week 72
Week 12
Randomization 2112
PegIFN alfa-2a 180 µg/week RBV 1000/1200
mg/day (n 317)
PegIFN alfa-2a 360 µg/week RBV 1000/1200 mg/day
Follow-up
PegIFN alfa-2a 180 µg/week RBV 1000/1200
mg/day (n 156)
PegIFN alfa-2a 360 µg/week RBV 1000/1200 mg/day
Patients with chronic HCV infection not
responsive to pegIFN alfa-2b/ RBV therapy
Follow-up
PegIFN alfa-2a 180 µg/week RBV 1000/1200
mg/day (n 156)
Follow-up
PegIFN alfa-2a 180 µg/week RBV 1000/1200
mg/day (n 313)
Follow-up
Jensen D, et al. AASLD 2007. Abstract LB4.
39
REPEAT 72-Week Treatment Duration Associated
With Higher SVR Rate
100
Modified ITT
Pooled 72 weeks (n 473) vs 48 weeks (n 469)
80
60
SVR ()
40
P .0006
16
20
8
0
72 Weeks(360/180 µg and 180 µg)
48 Weeks(360/180 µg and 180 µg)
Patients randomized who received at least 1 dose
of study medication.
Jensen D, et al. AASLD 2007. Abstract LB4.
40
REPEAT Predictive Value of HCV RNA lt 50 IU/mL at
Week 12
All treated patients (N 942)
HCV RNA lt 50 IU/mL at Week 12?
Yes 17 (157/942)
No 83 (785/942)
360/180 µg 72 weeks
360/180 µg 48 weeks
180 µg 72 weeks
180 µg 48 weeks
100
100
80
80
68
60
53
60
36
34
40
40
20
20
6
5
3
2
0
0
Jensen D, et al. AASLD 2007. Abstract LB4.
41
EPIC3 SVR by Previous Treatment and Response
PegIFN alfa-2b 1.5 µg/kg/week Weight-Based RBV
800-1400 mg/day for 48 Weeks
60
All
Previous nonresponders
Previous relapsers
43
38
40
34
32
Patients ()
25
22
18
18
17
20
14
7
6
0
PegIFN a-2a RBV (n 375)
All(N 2293)
IFN/RBV(n 1423)
PegIFN a-2b RBV (n 488)
Previous Regimen
Poynard T, et al. EASL 2008. Abstract 988.
42
EPIC3 Predictors of SVR

• HCV GT
• GT 2/3 vs GT 1 OR 4.9 (P lt .0001)
• Baseline METAVIR fibrosis score
• F2 vs F4 OR 2.2 (P lt .0001)
• F3 vs F4 OR 1.4 (P .0183)
• Baseline HCV RNA
• 600,000 IU/mL vs gt 600,000 IU/mL OR 1.9 (P
  lt .0001)
• Previous treatment
• IFN RBV vs pegIFN RBV OR 2.0 (P lt .0001)
• Previous treatment response
• Relapser vs nonresponder OR 3.8 (P lt .0001)

Poynard T, et al. EASL 2008. Abstract 988.
43
Maintenance Therapy
44
COPILOT Event-Free Survival With and Primary
Endpoints (ITT)

• 49 of patients did not achieve 4-year event-free
  survival

Primary Endpoints at Year 4
Colchicine 0.6 mg twice daily (n 55)
30
27
PegIFN alfa-2b 0.5 µg/kg/week (n 51)
23
22
20
Events (No.)
13
10
10
4
4
1
1
1
0
Death
OLT
VaricealBleed
CTP gt 2
HCC

• Primary endpoints more common in both colchicine
  and pegIFN arms in patients with portal HTN (32
  and 23, respectively) vs without portal HTN (9
  and 13, respectively)

Afdhal N, et al. EASL 2008. Abstract 3.
45
HALT-C Long-term Maintenance Therapy Study Design
Liver biopsy(1.5 years)
Liver biopsy(3.5 years)
Liver biopsy
PegIFN alfa-2a 90 µg/week(n 517)
Chronic HCV-infectedpatients with
advancedfibrosis/cirrhosisand previous
nonresponseto pegIFN/RBV(N 1050)
No treatment(n 533)
Di Bisceglie A, et al. AASLD 2007. Abstract LB1.
46
HALT-C Long-term PegIFN alfa-2a 90 µg/week in
Nonresponders

• No reduction in fibrosis and no 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)

Outcomes at 3.5 Years
100
(P NS for all comparisons)
80
No treatment (n 533)
PegIFN alfa-2a 90 µg/week (n 517)
60
Patients ()
40
31.9
28.2
14.3
13.2
20
6.6
4.6
3.2
2.8
0
Death
Decompensation
HCC
Increasein Fibrosis
17 discontinued at 1.0 year and 30
discontinued at 3.5 years.
Di Bisceglie A, et al. AASLD 2007. Abstract LB1.
47
HALT-C Impact of Viral Suppression on Outcomes

• Magnitude of viral suppression during lead-in
  associated with a reduction in clinical outcomes
  but not in fibrosis progression

Outcomes During Maintenance Phase
Log10 Decline in HCV RNA During Maintenance
gt 4 or (-)
2-4
1-2
lt 1
100
100
Clinical (n 378) (P .78)
80
80
Fibrosis (n 210) (P .67)
60
60
Outcomes ()
Patients ()
9
40
40
26
20
24
152
23
20
46
273
35
n
0
0
1-2
2-4
gt 4
lt 1
lt 2(n 210)
2-4(n 80)
gt 4(n 88)
Log10 Decline in HCV RNA During Maintenance
Log10 Decline in HCV RNA During Lead-in
Shiffman ML, et al. EASL 2008. Abstract 144.
48
Future Options for Retreatment
49
AlbIFN alfa-2b/RBV in Previous Nonresponders
48 or 72 weeks
AlbIFN alfa-2b 1200 µg every 4 weeks RBV
1000-1200 mg/day (n 24)
AlbIFN alfa-2b 900 µg every 2 weeks RBV
1000-1200 mg/day (n 23)
24-week follow-up
Nonresponders to previous IFN-based regimens (N
115)
AlbIFN alfa-2b 1200 µg every 2 weeks RBV
1000-1200 mg/day (n 24)
AlbIFN alfa-2b 1500 µg every 2 weeks RBV
1000-1200 mg/day (n 22)
AlbIFN alfa-2b 1800 µg every 2 weeks RBV
1000-1200 mg/day (n 22)
6 patients with slow virologic response had
treatment extension to 72 weeks.
Nelson D, et al. AASLD 2007. Abstract 51.
50
AlbIFN Retreatment of IFN/RBV and PegIFN/RBV
Nonresponders
RBV 1000-1200 mg/day based on body weight.

• Overall SVR rate 17.4
• GT1, pegIFN RBV nonresponder SVR rate 10.7

Nelson D, et al. AASLD 2007. Abstract 51.
51
Boceprevir PegIFN/RBV Phase II Nonresponder
Study, GT 1

• Response dependent on IFN responsiveness

Patients With Detectable HCV RNA or lt 2 log10
Decline in HCV RNA at 12 Weeks of Previous
PegIFN RBV (N 357)
100
80
60
SVR ()
40
7-14
20
2
0
Boceprevir PegIFN alfa-2b RBV (Various Arms)
PegIFN alfa-2b RBV
100, 200, 400, and 800 mg TID.
Schiff E, et al. EASL 2008. Abstract 104.
52
Telaprevir PegIFN alfa-2a RBV in
Nonresponders or Relapsers

• Open-label treatment of patients from control
  arms of PROVE1-3 trials

Week 4 (RVR)
Week 8
Week 12
100
100
100
100
100
100
100
100
100
89
80
79
80
67
Undetectable HCV RNA, lt 10 IU/mL ()
60
50
40
33
20
0
Week 4 Null Responder
Week 12 Null Responder
Partial Responder
Week 20 Breakthrough
Relapser
lt 1 log10 drop at Week 4. lt 2 log10 drop at
Week 12. 2 log10 drop at Week 12 detectable
HCV RNA at Week 24.
Poordad F, et al. EASL 2008. Abstract 1000.
53
Summary and Management Strategies
54
Principles of Retreatment

• Relapsers good candidates for retreatment
• Better chance of response when compared with
  nonresponders
• Nonresponders to suboptimal therapy (ie, standard
  IFN) more likely to respond to retreatment vs
  those previously treated with pegIFN/RBV
• Nonresponders with negative predictors of
  response (ie, advanced fibrosis, insulin
  resistance) may not be good candidates for
  retreatment
• Maintenance therapy has not been shown to be
  effective for reducing fibrosis progression,
  other disease outcomes
• Promising results with new compounds, even in the
  setting of null response

55
Key Questions for HCV Patients Facing Retreatment

• What were you treated with, at what dosage, and
  for how long?
• What type of response did you have?
• What is your GT?
• Did you require dose reductions or treatment
  interruptions during previous therapy? What
  adverse effects caused these interruptions/dose
  reductions?
• Were you overweight during previous courses of
  therapy?
• Were there adherence issues?
• Do you have any significant comorbidities/other
  conditions that may affect your response to
  treatment?
• Did you have a good support system during
  previous courses of treatment? What do you have
  now?

56
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