Transcript SVR Rates by HCV Treatment Drug Combination and Dose

Terapia dell’epatite C tra
passato e futuro
Quali sono i limiti
dell’attuale terapia
Alessandro Grasso
S.C. Medicina Interna e Gastroenterologia
Osp. San Paolo Savona
SVR Rates by HCV Treatment Drug
Combination and Dose
100
Manns et al[1]
SVR (%)
80
60
47
47
54*
2011
Almost 50% of
[2]
patients doFried et al
not respond
to treatment
56†
44
40
29
20
0
n=
505
IFN +
RBV
514
800
PegIFN
PegIFN
alfa-2b alfa-2b 1.5
0.5 + RBV
+ RBV
800
800
n=
224
444
453
IFN +
RBV
PegIFN
alfa-2a
PegIFN
alfa-2a +
RBV
10001200
*P = .01 vs both arms, †P = .001 vs both arms
1. Manns MP, et al. Lancet. 2001
2. Fried MW, et al. N Engl J Med. 2002.
Factors associated with a reduction of
SVR rate with PegIFN + RBV
DISEASE RELATED
TREATMENT RELATED
Genotype 1 (1)
PATIENTS RELATED
Aderence (1)
High viral load (1)
Age
Cirrhosis/bridging fibrosis
(1) > 40 years (1) Duration and schedule
Male sex (2)
Dose reduction (9)
Steatosis (1)
Afro-american race (1)
Controindications (7)
Increased BMI (1)
Metabolic Syndr – Diabetes (2)
Immunosuppression (3)
Alcool (4)
Genetic polimorphysm (5)
(6-8)
1) Dienstag JL et al. Gastroenterology 2006; 2) Manns MP et al. Lancet 2001; 3) Bain VG et al. Aliment Pharmacol Ther
2008; 4) Hadziyannis SJ et al. Ann Intern Med 2004; 5) Hanouneh IA et al Clin Gastroenterol Hepatol 2008;
6) Backus LI et al. Hepatology. 2007; 7) Pol S et al. Expert Opin Biol Ther 2006;
8) Ge D et al. Nature 2009; 9) Falck-Y et al. Ann Intern Med 2002
Outline
 Impact of viral, host and genetic
factors on SVR
 Adherence to antiviral treatment
Outline
 Impact of viral, host and genetic
factors on SVR
 Adherence to antiviral treatment
SVR With PegIFN and Ribavirin
according with genotype
PegIFN alfa-2b 1.5 µg/kg/week +
RBV 800 mg/day for 48 weeks[1]
PegIFN alfa-2a 180 µg/week +
weight-based RBV (1000 or 1200
mg/day) for 48 weeks[2]
100
82
SVR (%)
80
60
76
56
54
46
42
40
20
0
n = 511
Overall
n = 348
GT 1
n = 163
GT 2/3
Manns M, et al. Lancet. 2001
n = 453
Overall
n = 298
GT 1
n = 140
GT 2/3
Fried MW, et al. N Engl J Med. 2002
SVR Rates by HCV Treatment Duration
Genotype, and Baseline HCV RNA
24w Low Dose
24w Standard Dose
100
48w Low Dose
100
80
65
60
42 41
40
52 55
52
47
41
36
29
26
16
20
0
Patients (%)
Patients (%)
80
84 81
79 80
48w Standard Dose
85 83 88
84 80
77
74
82
60
40
20
0
N =101 118 250 271 51 71 60 85
All
Patients
Low
HCV RNA
Genotype 1
50 47 190 186
High
HCV RNA
N = 96 144 99 153
All
Patients
34 47 33 48
Low
HCV RNA
62 97 66 105
High
HCV RNA
Genotype 2/3
Hadziyannis SJ, et al. Ann Intern Med. 2004
SVR With PegIFN and Ribavirin according
with genotype and stage of Fibrosis
SVR at End of Follow-up
24 wks of RBV 800 mg/day + pegIFN alfa-2a
24 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a
48 wks of RBV 800 mg/day + pegIFN alfa-2a
48 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a
100
75 74
Patients (%)
80
87 84
81 83
70 73
57
60
46 45
41
40
26 26 28
29
Genotype 1 Genotype 2/3
Advanced Fibrosis
Genotype 1 Genotype 2/3
Minimal Fibrosis
20
0
Hadziyannis SJ, et al. Ann Intern Med. 2004.
On-treatment Viral Response and
Outcome
PPV for SVR in genotype 1 HCV
PegIFN alfa and RBV
HCV RNA (log10 IU/mL)
7
•RVR
•EVR
•Slow responders
6
5
4
Null Response*
75-90%
50%
20-30%
Partial
Response*
3
Slow Response
Relapse
2
1
Undetectable
RVR
0
-8
-4
-2
0
4
EVR
8
12
ETR
DVR
16
20
24
32
40
48
SVR
52
60
72
Wks After Start of Therapy
*Subset of Nonresponse
Ghany MG, et al. Hepatology. 2009 on behalf of American Association for the Study of Liver Diseases
Comparing Treatment Durations in GT
2/3 Patients Achieving RVR
Von Wagner et al[1]
PegIFN α-2a
180 µg/wk +
WB RBV
100
16 wks total
RVR
24 wks total
PegIFN α-2a
180 µg/wk +
RBV 800 mg/day
16 wks total
RVR
24 wks total
100
82
80
80
SVR (%)
80
SVR (%)
Shiffman et al[2]
60
40
60
40
20
20
0
0
16 Wks
(n = 71)
24 Wks
(n = 71)
1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527.
2. Shiffman M, et al. N Engl J Med. 2007;357:124-134.
85*
79
16 Wks
(n = 733)
24 Wks
(n = 732)
*P = .002 vs 16 wks.
Extending Therapy in Treatment-Naive
Genotype 1 HCV Pts With Slow Response

Higher SVR rate with 72 vs 48 wks of treatment in slow responders*[1]
– Dose reductions, discontinuations similar
48 wks total
PegIFN alfa-2b 1.5 µg/kg/wk +
RBV 800-1400 mg/day
Slow responders
Patients (%)
100
p=0.03
SVR
Relapse
59
60
38
40
0

p=0.004
80
20
72 wks total
18
48 Wks
(n = 165)
20
72 Wks
(n = 161)
SUCCESS study had same study design and showed no overall benefit[2]
1. Pearlman BL, et al. Hepatology. 20007
2. Buti M, et al. EASL 2010
Response-guided therapy in patients with genotype 1 (applies also to
genotype 4 at a B2 grade of evidence)
*LVL Y<400,000-800,000 IU/ml
J Hepatol 2011
Response-guided therapy in patients with genotype 2 and 3
J Hepatol 2011
Retreatment of PegIFN/RBV Relapsers
McHutchison et al[1]
EPIC3[2]
80
80
SVR (%)
100
SVR (%)
100
60
40
20
20
60
40
33
20
0
0
PegIFN alfa-2a/RBV
for 48 Wks
in PegIFN/RBV
Relapsers
1. McHutchison JG, et al. N Engl J Med. 2010
PegIFN alfa-2b/RBV
for 48 Wks
in PegIFN/RBV
Relapsers
2. Poynard T, et al. Gastroenterology. 2009
Retreatment of PegIFN/RBV Nonresponders
Yields Low SVR Rates
REPEAT[1]
EPIC3[2]
DIRECT[3]
80
80
80
60
40
20
8.0
SVR (%)
100
SVR (%)
100
SVR (%)
100
60
40
20
6.3
0
0
PegIFN alfa-2a/RBV
for 48 Wks in
PegIFN alfa-2b/RBV
Nonresponders
PegIFN alfa-2b/RBV
for 48 Wks in
PegIFN/RBV
Nonresponders
60
40
20
10.7
0
cIFN for 48 Wks
in PegIFN/RBV
Nonresponders
1. Jensen D, et al. Ann Intern Med. 2009 2. Poynard T, et al. Gastroenterology. 2009
3. Bacon BR, et al. Hepatology. 2009
REPEAT: 72-Week Treatment Duration
Associated With Higher SVR Rate
Patients with chronic HCV infection not responsive to pegIFN alfa-2b/
RBV therapy
Modified ITT*
40
SVR (%)
Pooled 72 weeks (n = 473) vs 48 weeks (n = 469)
20
P = .0006
16
8
0
72 Weeks
(360/180 µg and 180 µg)
n=417
48 Weeks
(360/180 µg and 180 µg)
n=469
Jensen D, et al. Ann Intern Med. 2009.
Multivariate Analysis of Baseline Predictors
of SVR (Genotype 1 HCV)
•ITT analysis of patients from IDEAL study who consented to
genetic testing, regardless of adherence level (n = 1604) plus 67
patients from another trial
Adjusted Odds Ratio (95% CI)
P Value
rs12979860 CC
5.2 (4.1-6.7)
< .0001
HCV RNA level ≤ 600,000 IU/mL
3.1 (2.3-4.1)
< .0001
White vs black
2.8 (2.0-4.0)
< .0001
Hispanic vs black
2.1 (1.3-3.6)
.0041
METAVIR F0-F2
2.7 (1.8-4.0)
< .0001
Fasting blood sugar < 5.6 mmol/L
1.7 (1.3-2.2)
< .0001
Predictor
Thompson AJ, et al. Gastroenterology 2010.
A genome-wide association study of more than 1,600 individuals identified that a polymorphism
on chromosome 19, rs12979860, is strongly associated with SVR
The polymorphism resides 3 kilobases (kb)
upstream of the IL28B gene encoding IFN-λ-3
Interleukin-28B polymorphism is associated with rapid
virological response in genotype 1 HCV patients
Neumann AU, et al. J Hepatol 2010
Thompson AJ, et al. Gastroenterology 2010.
High body mass index is an independent
risk factor for nonresponse to antiviral
treatment in chronic hepatitis C


Retrospective analysis of all patients at a single center with chronic
hepatitis C treated with antiviral medication from 1989 to 2000
A total of 253 patients were treated with either IFN monotherapy (either
standard or pegylated) or IFN-2b in combination with ribavirin.
Bressler BL,et al. Hepatology 2003
Insulin-resistance and SVR in
HCV G1 patients
SVR (%)
 159 patients with chronic hepatitis C (113 G1; 46 non-G1) treated
with PegIFN + RBV
100
P = .007
80
61
60
40
33
20
0
HOMA-IR > 2
HOMA-IR<2
Genotype , HOMA-IR and fibrosis were independently associated with SVR
Romero-Gomez M, et al. Gastroenterology. 2005
Impact of insulin resistance on sustained
response in HCV patients treated with pegylated
interferon and ribavirin: A meta-analysis
Deltenre P. et al. J Hepatol 2011
Outline
 Impact of viral, host and genetic
factors on SVR
 Adherence to antiviral treatment
Many factors associated with poor
Adherence to PegIFN and Ribavirin
Psychological
comorbidities
Injection Drug
Use
Depression
Treatment
complexity
Adherence
Poor relationship
between the
patient and
provider
Patient’s lack of
belief in
treatment benefit
Adverse
events of
medication
Inadequate
follow-up
Impact of HCV Infection on Quality of
Life
Controls
HCV positive
P < .01 for all comparisons between control and HCV positive
SF36 Score
100
80
60
93
79
91
91
66
86
86
75
57
60
59
73
64
79
48
40
20
0
Foster G, et al. Hepatology. 1998.
53
Common Adverse Events Associated With
PegIFN/RBV Therapy
• Influenza like (fatigue, headache, fever, and rigors): > 50%
• Psychiatric (depression, irritability, and insomnia): 22% to
31%
• Neutropenia (ANC < 1500/mm3): 18% to 20%[1,2]
– Severe neutropenia* (ANC < 500/mm3): 4%
– Serious infections are uncommon and G-CSF is rarely necessary[3]
• Anemia (Hb < 12 g/dL): ~ 30%[1,2]
– Nadir within 6-8 wks
– Severe anemia† (Hb < 10 g/dL): 9% to 15%
• Laboratory abnormalities are the most common reasons for
HCV therapy dose reduction
Manns MP, et al. Lancet. 2001
Fried MW, et al. N Engl J Med. 2002. Soza A, et al. Hepatology. 2002.
*And treatment discontinuation.
†And dose modification.
Time Course of Treatment-Associated
Psychiatric Adverse Effects
Incidence/Severity
100
80
Anxiety
Depression
60
Fatigue
40
20
Influenza-like
symptoms
0
0
1
2
3
4
Months
Dan A, et al. J Hepatol. 2006
Constant A, et al. J Clin Psychiatry 2005
SVR according with Adherence to
combination therapy in G1 chronic hepatitis C
Analysis in a subgroup of 511 patients treated with Peginterferon alfa 2b plus
ribavirin
ITT
80/80/80
<80<80/80
100
90
89
90
0-011
82
80
0-034
SVR %
70
60
50
51
42
40
34
30
20
10
0
Genotype 1
Genotype 2 and 3
McHutchison JC, et al. Gastroenterology 2002
The new waves of HCV therapy
Wave 3 (2016-2020): the holy grail
 Oral cocktails of DAAs, host cofactor
inhibitor, RBV
 Many roads to the same destination!
> 90% cure
of G1 with
oral pills
with no
side effects
Wave 2 (2014-2016): the better mousetrap
 Substitution of 2° generation DAAs, nucs
 Substitution of better tolerated IFNs
 4 drug regimen for P/R/DAA failure
Wave 1 (2011-2014): add-on Tx
 1° generation DDAs + SOC: naive and experienced
-Naives: consider empiric Tx
-Experienced: offer Tx (particularly relapser)
-Nulls: stratify by stage
2001-2011 PegInterferon plus Ribavirin