Upload
gervais-simmons
View
214
Download
0
Tags:
Embed Size (px)
Citation preview
Quali sono i limiti dell’attuale terapia
Terapia dell’epatite C tra passato e futuro
Alessandro GrassoS.C. Medicina Interna e
GastroenterologiaOsp. San Paolo Savona
PegIFN alfa-2b
0.5 + RBV800
SVR Rates by HCV Treatment Drug Combination and Dose
1. Manns MP, et al. Lancet. 2001 2. Fried MW, et al. N Engl J Med. 2002.
100
80
60
40
20
0
SVR
(%)
IFN + RBV
PegIFN alfa-2b 1.5
+ RBV800
IFN + RBV
PegIFN alfa-2a
PegIFN alfa-2a +
RBV1000-1200
Manns et al[1] Fried et al[2]
47 4754*
4456†
29
n = 505 514 800 224 444 453n =
*P = .01 vs both arms, †P = .001 vs both arms
2011Almost 50% of
patients do not respond to treatment
DISEASE RELATED
Genotype 1 (1)
High viral load (1)
Cirrhosis/bridging fibrosis (1)
Steatosis (1)
Factors associated with a reduction of SVR rate with PegIFN + RBV
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
PATIENTS RELATED
Age > 40 years (1)
Male sex (2)
Afro-american race (1)
Increased BMI (1)Metabolic Syndr – Diabetes (2)
Immunosuppression (3)
Alcool (4)
Genetic polimorphysm (5)
TREATMENT RELATED
Aderence (1)
Duration and schedule (6-8)
Dose reduction (9)
Controindications (7)
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
Overall GT 1 GT 2/3
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]
Manns M, et al. Lancet. 2001
42
82
100
80
60
40
20
0
54
SV
R (
%)
n = 348 n = 163n = 511
46
76
56
Overall GT 1 GT 2/3n = 298 n = 140n = 453
Fried MW, et al. N Engl J Med. 2002
N = 96 144 99 153 34 47 33 48 62 97 66 105N =101 118 250 271 51 71 60 85 50 47 190 186
SVR Rates by HCV Treatment Duration Genotype, and Baseline HCV RNA
Hadziyannis SJ, et al. Ann Intern Med. 2004
Genotype 2/3Genotype 1
100
80
60
40
20
0
Pat
ien
ts (
%)
AllPatients
Low HCV RNA
High HCV RNA
24w Low Dose 24w Standard Dose
29
42 41
5241
52 5565
1626
3647
100
80
60
40
20
0P
atie
nts
(%
)
AllPatients
Low HCV RNA
High HCV RNA
84 81 79 8085 83 88
7784 80
7482
48w Low Dose 48w Standard Dose
Hadziyannis SJ, et al. Ann Intern Med. 2004.
SVR at End of Follow-up24 wks of RBV 800 mg/day + pegIFN alfa-2a24 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a48 wks of RBV 800 mg/day + pegIFN alfa-2a48 wks of RBV 1000-1200 mg/day + pegIFN alfa-2a
26 26 28
41
75 7470 73
29
46 45
57
87 84 81 83100
80
60
40
20
0
Pat
ien
ts (
%)
Advanced Fibrosis Minimal Fibrosis
Genotype 1 Genotype 2/3 Genotype 1 Genotype 2/3
SVR With PegIFN and Ribavirin according with genotype and stage
of Fibrosis
On-treatment Viral Response and Outcome
*Subset of Nonresponse
7
6
5
4
3
2
1
00-2-4-8 4 8 12 16 20 24 32 40 48 52 60 72
Wks After Start of Therapy
HC
V R
NA
(lo
g10
IU/m
L)
Undetectable
RVR EVR ETR SVR
Relapse
Partial Response*
Null Response*
PegIFN alfa and RBV
Ghany MG, et al. Hepatology. 2009 on behalf of American Association for the Study of Liver Diseases
Slow Response
PPV for SVR in genotype 1 HCV
•RVR 75-90%•EVR 50%•Slow responders 20-30%
DVR
82 80
16 Wks (n = 71)
24 Wks (n = 71)
7985*
16 Wks (n = 733)
24 Wks (n = 732)
SVR
(%)
SVR
(%)
1. Von Wagner M, et al. Gastroenterology. 2005;129:522-527. 2. Shiffman M, et al. N Engl J Med. 2007;357:124-134.
Comparing Treatment Durations in GT 2/3 Patients Achieving RVR
*P = .002 vs 16 wks.
0
20
40
60
80
100
0
20
40
60
80
100
Von Wagner et al[1]
Shiffman et al[2]
PegIFN α-2a 180 µg/wk + WB RBV
RVR16 wks total
24 wks total
PegIFN α-2a180 µg/wk + RBV 800 mg/day
RVR16 wks total
24 wks total
Extending Therapy in Treatment-Naive Genotype 1 HCV Pts With
Slow Response
SVRRelapse
0
20
40
60
80
100
48 Wks(n = 165)
72 Wks(n = 161)
Patie
nts
(%)
18
3859
20
1. Pearlman BL, et al. Hepatology. 20007 2. Buti M, et al. EASL 2010
Higher SVR rate with 72 vs 48 wks of treatment in slow responders*[1]
– Dose reductions, discontinuations similar
PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day
48 wks total
72 wks totalSlow responders
SUCCESS study had same study design and showed no overall benefit[2]
p=0.03
p=0.004
Response-guided therapy in patients with genotype 1 (applies also to genotype 4 at a B2 grade of evidence)
J Hepatol 2011*LVL Y<400,000-800,000 IU/ml
J Hepatol 2011
Response-guided therapy in patients with genotype 2 and 3
Retreatment of PegIFN/RBV Relapsers
1. McHutchison JG, et al. N Engl J Med. 2010 2. Poynard T, et al. Gastroenterology. 2009
PegIFN alfa-2a/RBV for 48 Wks
in PegIFN/RBV Relapsers
33
PegIFN alfa-2b/RBV for 48 Wks
in PegIFN/RBV Relapsers
20
McHutchison et al[1]
SV
R (
%)
0
20
40
60
80
100
SV
R (
%)
0
20
40
60
80
100
EPIC3[2]
1. Jensen D, et al. Ann Intern Med. 2009 2. Poynard T, et al. Gastroenterology. 20093. Bacon BR, et al. Hepatology. 2009
8.0
PegIFN alfa-2a/RBV for 48 Wks in
PegIFN alfa-2b/RBV Nonresponders
SV
R (
%)
0
20
40
60
80
100
6.3
PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV
Nonresponders
SV
R (
%)
0
20
40
60
80
100
10.7
cIFN for 48 Wksin PegIFN/RBV Nonresponders
SV
R (
%)
0
20
40
60
80
100
REPEAT[1] EPIC3[2] DIRECT[3]
Retreatment of PegIFN/RBV Nonresponders Yields Low SVR Rates
REPEAT: 72-Week Treatment Duration Associated With Higher SVR Rate
Pooled 72 weeks (n = 473) vs 48 weeks (n = 469)
16
8
72 Weeks(360/180 µg and 180 µg)
48 Weeks(360/180 µg and 180 µg)
SV
R (
%)
0
20
40
P = .0006
Modified ITT*
Patients with chronic HCV infection not responsive to pegIFN alfa-2b/ RBV therapy
n=417 n=469
Jensen D, et al. Ann Intern Med. 2009.
Thompson AJ, et al. Gastroenterology 2010.
Predictor 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
•ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n = 1604) plus 67 patients from another trial
Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV)
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
Neumann AU, et al. J Hepatol 2010 Thompson AJ, et al. Gastroenterology 2010.
Interleukin-28B polymorphism is associated with rapid virological response in genotype 1 HCV patients
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
33
61
0
20
40
60
80
100
SVR
(%)
HOMA-IR > 2 HOMA-IR<2
Romero-Gomez M, et al. Gastroenterology. 2005
P = .007
159 patients with chronic hepatitis C (113 G1; 46 non-G1) treated with PegIFN + RBV
Genotype , HOMA-IR and fibrosis were independently associated with SVR
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
Adherence
Psychological comorbidities
Injection Drug Use
Adverse events of
medication
Inadequate follow-up
Patient’s lack of belief in
treatment benefit
Poor relationship between the patient and
provider
Treatment complexity
Depression
Impact of HCV Infection on Quality of Life
Foster G, et al. Hepatology. 1998.
Controls HCV positive
P < .01 for all comparisons between control and HCV positive
SF
36 S
core
0
20
40
60
80
100
Physica
l Functi
oning
Socia
l Functi
oning
RL: Physi
cal
RL: Emotional
Mental H
ealth
Energy/Fa
tigue
Pain
Health Perce
ption
7993
66
91
57
91
60
86
59
75
48
64 7386
53
79
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.
Months
Inci
denc
e/Se
verit
y
Depression
Fatigue
Influenza-like symptoms
Time Course of Treatment-Associated Psychiatric Adverse Effects
Anxiety
1 2 3 400
20
40
60
80
100
Dan A, et al. J Hepatol. 2006
Constant A, et al. J Clin Psychiatry 2005
Genotype 1 Genotype 2 and 30
10
20
30
40
50
60
70
80
90
100
42
82
51
90
34
89
0-034
0-011
SVR according with Adherence to combination therapy in G1 chronic
hepatitis C
McHutchison JC, et al. Gastroenterology 2002
Analysis in a subgroup of 511 patients treated with Peginterferon alfa 2b plus ribavirin
SV
R %
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
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 3 (2016-2020): the holy grail Oral cocktails of DAAs, host cofactor
inhibitor, RBV Many roads to the same destination!
The new waves of HCV therapy
2001-2011 PegInterferon plus Ribavirin
> 90% cure of G1 with oral pills with no side effects