Individualisation of HCV Therapy

1
Individualisation of HCV Therapy

• Achieving an SVR
• What is the evidence?
• Dr Allister J Grant

2
Achieving an SVR

• The ability to achieve SVR is the result of two
  independent steps
• 1. Achieving a virologic response
• a. Interferon/peginterferon dose
• b. The presence of ribavirin
• 2. Not relapsing
• a. How fast the patient becomes HCV RNA
  undetectable
• b. How long the patient remains on treatment
• c. Dose of ribavirin

3
Wk 12 PCR EVR
Rx duration
48 weeks
Neg/2log drop
Genotype 1,4-6
Stop
Pos
24 weeks
Genotype 2,3
4
2004 Regimes
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WIN-R trial Weight based Interferon and
Ribavirin TrialAASLD 2005

• Ribavirin 800mg/d (FD) vs 800-1400mg/d
• PEG IFN 2b
• G1 48wks
• G2/3 randomised to 24/48 wks

• Community based US study
• 4913 patients
• G1 significant advantage in WBD of RBV
• No advantage for G2/3 but..

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WIN-R Trial

• Analysis of SVR by weight
• More dose reductions
• No more discontinuations

49
52
45
44
42
39
47
34
Plt0.0001 p0.11
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WINR Trial
G2 had a higher SVR and lower relapse rate than
those with G3 (72 vs. 60 and 6 vs.10
respectively). Investigators concluded that
higher weight-based doses of ribavirin appear to
be necessary to achieve similar SVR rates in G3
patients
8
What is the clinical evidence to support the
value of EVR as a predictor of SVR?
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EVR Treatment Outcome (All Genotypes)
PEG IFN alfa-2a 180 ?g ribavirin 1,0001,200 mg
Week 72
Week 12
Start of study
No SVR 35 (n137/390)
EVR 86 (n390/453)
SVR 65 (n253/390)
Overall SVR 56 (255/453)
Total study population (n453)
SVR 3 (n2/63)
No EVR 14 (n63/453)
No SVR 97 (n61/63)
Fried et al. NEJM 2002
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EVR Treatment Outcome (All Genotypes)
PEG IFN alfa-2b 1.5 ?g/kg ribavirin ?10.6 mg/kg
Week 72
Week 12
Start of study
No SVR 20 (n29/143)
EVR 76 (n143/188)
SVR 80 (n114/143
Total study population (n188)
Overall SVR 61 (114/188)
SVR 0 (n0/45)
No EVR 24 (n45/188)
No SVR 100 (n45/45)
Davis G, et al. Hepatology 2003
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But what about the difficult-to-treat Genotype 1
patients?
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EVR Week 12 in Genotype 1
(Patients HCV RNA negative and patients HCV RNA
positive gt2 Log at week 12)
PEG-IFN a-2a 180 ?g ribavirin 1,000-1,200
mg N298
19 No EVR N58
81 Achieved EVR N240
58 Achieve SVR N139
2 Achieve SVR N1
PPV58
NPV98
Ferenci P et al. J Hepatol 200543(3)425-33.
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EVR Week 12 in Genotype 1
(Patients HCV RNA Negative and patients HCV RNA
positive gt2 Log at week 12)
PEG-IFN a-2a 180 ?g ribavirin 1,000-1,200
mg N569
84 Achieved EVR N477
16 No EVR N58
58 Achieve SVR N264
NA Achieve SVR NNA
PPV58
NPVNA
Reddy K et al. DDW2005, Abstract S1540
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So are we able to push prediction back further?
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Treatment Of Chronic HCVPredicting SVR Over Time
PEG-IFN-2a Ribavirin
The later a patient becomes HCV RNA undetectable,
regardless of EVR the lower the chance for SVR.
HCV RNA at week 24
P Ferrenci et al. J Hepatology 2005 43425-33.
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Relapse Rate Relationship to First Time HCV RNA
Negativity
Data on file Schering-Plough Corp. Adapted
Poynard T. et al, Lancet 1998, McHutchison JG,
NEJM, 1998, Lindsay K. et al, Hepatology 2001
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RAPID VIROLOGIC RESPONSE

• Rapid virologic response (RVR) defined as HCV RNA
  (-) by week 4
• Occurs regardless of the interferon type or if
  ribavirin utilised or not

P Ferrenci et al. J Hepatology 2005 43425-33.
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RVR- Effect Of Genotype
P Ferrenci et al. J Hepatology 2005
43425-33. ML Shiffman et al. EASL 2006.
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RVR- Frequency
P Ferrenci et al. J Hepatology 2005 43425-33 ML
Shiffman et al. EASL 2006.
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Individualisation of Therapy According to HCV
Genotype and Viral Load
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Zeuzem et al J.Hepatol 2006

• Open multicentre, historical controlled trial to
  test whether HCV-1 patients with low viral load
  can be treated with 24 weeks therapy
• (PEG IFN 2b Ribavirin 800-1400mg/)
• 724 patients screened and 235 enrolled

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Virologic response in patients with HCV-1 and HCV
RNA lt 600,000 IU/mL
89
80
75
Patients ()
50
37
25
17
8
(47)
(26)
(10)
Time to first negative HCV RNAPEG-IFN a-2b RBV
Zeuzem et al., J Hepatol 2006
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Shorter treatment in HCV-2 and HCV-3 ?
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Peginterferon alfa-2a 180 µg qw Ribavirin
1000-1200 mg qd
HCV-RNA


A
N 71
lt 600 IU/mL

B
N 153
N 69

C
N 13
? 600 IU/mL
0 4 8 12 16 20
24 48
follow-up period
weeks
v. Wagner, Gastroenterology 2005
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End-of-treatment (EOT) and sustained virologic
response (SVR)- HCV genotypes 2 and 3 combined -
SVR B vs C P 0.003
94
86
82
81
69
Virologic response ()
39
67/71
58/71
59/69
56/69
9/13
5/13
(16 weeks)
(24 weeks)
(24 weeks)
v. Wagner et al, Gastroenterology 2005
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SHORTENING TREATMENT FOR G2-3RAPID VIROLOGIC
RESPONDERS
Shortening therapy even in patients with RVR
doubles the relapse rate
M Von Wagner et al. Gastroenterology.
2005129522-527.
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Peginterferon alfa-2b 1.0 µg/kg Ribavirin
1000-1200 mg qd

A
N 70
HCV-RNA


B
-
N 133
N 213

C

N 80
0 4 8 12 16 20
24 48
follow-up period
weeks
Mangia et al, N Engl J Med 2005
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Sustained virologic response (SVR) according to
HCV genotype
Rx PEG-IFN alfa-2b 1.0 µg/kg RBV 1000-1200 mg
87
77
76
76
72
SVR ()
41
40/53
13/17
89/102
24/31
42/58
9/22
(24 weeks)
(12 weeks)
(24 weeks)
Mangia et al, N Engl J Med 2005
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HCV Genotypes 2 3ACCELERATE TRIAL
N1469
PEGASYS 180 mcg/wk Ribavirn 800 mg/d
PEGASYS 180 mcg/wk Ribavirin 800 mg/day
24
48
16
4
12
0
Weeks
ML Shiffman et al. EASL 2006.
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HCV Genotypes 2 3ACCELERATE TRIAL
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HCV Genotypes 2 3ACCELERATE TRIAL
N1469


ML Shiffman et al. EASL 2006.
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HCV Genotypes 2 3Impact Of Rapid Response
Rapid Virologic Response


ML Shiffman et al. EASL 2006.
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Viral load at baseline
Rx duration
Wk 4 PCR
Wk 12 PCR
48 weeks
Neg/2log drop
Stop
Pos
Pos
Neg
Low
24 weeks
PPV 89
Genotype 1,4-6
Neg
48 weeks
High
PPV75-85 / 46-72
48 weeks
Pos
Neg/2log drop
Pos
Stop
24G2(48G3)
Pos
Low
16G2/24G3
Neg
Genotype 2,3
PPV 82-90
High
24 weeks
Neg
Pos
24G2(48G3)
Low lt600,000 IUml lt3x106 cpm
If 2 log drop then PCR at 24 weeks
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HCV Treatment in 2007
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SUMMARY OF RECOMMENDATIONS Shorten duration of
therapy for Genotype 1 LVL with RVR24
weeks instead of 48 Genotype 2 LVL with
RVR16 weeks instead of 24 Consider
lengthening duration of therapy for Genotype 3
who do not have RVR..48 weeks instead of 24 Do
PCR at 4 weeks for everyone If 4 week PCR
negative then no need for further PCR till 24
weeks post Rx If 4 week PCR positive then do PCR
at 12 weeks. If PCR positive at 12 weeks stop
therapy If PCR shows 2 log drop at 12 weeks do
PCR at 24 weeks
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EXTENDING TREATMENT DURATION
HCV RNA ()
N165
N162
96
0
4
72
48
Weeks
JM Sanchez-Tapias et al. Gastroenterology 2006
131 451-460.
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EXTENDING THERAPY
Extending the duration of therapy reduced relapse
from 47 to 13
P0.014
JM Sanchez-Tapias et al. Gastroenterology 2006
131 451-460.
G1 without RVR SVR 28(48w) vs 44(72w)
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Urgent Treatment Recommended For

• Acute HCV
• Stable compensated cirrhotics
• HCV with cryoglobulinaemia/renal involvement
• Occupation where HCV infection is hazardous