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γλώσσες
Σελίδες
Νομικός
Truly naïve PatientsRafael Esteban‐Mur, MD (Spain)
Current Treatment Hepatitis C
SVR 70%
Peginterferon-α +1000-1200 mg Ribavirin+ BOC o
TVP 24-48 weeks
Peginterferon-α+800 mg Ribavirin24 wks
Genotype 1 Genotype 2/3
HCV Genotype
SVR 76-82%
SVR Rates With BOC or TVR in Genotype 1 Treatment‐Naive Patients
0
20
40
60
80
100
SVR (%
)
PegIFN/RBV BOC or TVR + PegIFN/RBV
38‐44
63‐75
Poordad F, et al. N Engl J Med. 2011;364:1195‐1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405‐2416.
Adverse Events of Triple Therapy
Boceprevir TelaprevirSevere AEs 11% 7%Discontinuationsdue to AEs
12% 14%
Anemia 43‐49% 32%Rash 17% 55%
Poordad F, et al. N Engl J Med. 2011;364:1195‐1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405‐2416. Bacon BR, et al. N Engl J Med. 2011;364:1207‐1217. Zeuzem S, et al. N Engl J Med 011;364:2417 ‐2428.
Predictors of Response to HCV Therapy• Pre‐treatment predictors
– Race/ethnicity – Age– Low viral load– Absence of cirrhosis– IL‐28B genotype– HCV genotype 1a vs 1b, 2/3
SPRINT-2 (Boceprevir): SVR rates by baseline viral load
SVR (%
)
n/N=
BOC RGT
41/54
PR
35/55
PR
102/308
BOC 44/PR48
197/313
≤800,000 >800,000
Poordad F, et al. N Engl J Med 2011;364:1195–206SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow‐up Week 24. If there was no such value, the follow‐up Week 12 value was carried forward
BOC RGT
192/314
BOC 44/PR48
45/53
PR48T12PRT8PR
SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving TVR + PegIFN/RBV
• Recommendation: All cirrhotic patients receiving TVR + PR may benefit from 48 weeks of therapy[1,2]
1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416.
78
62
73
5347
33
0
20
40
60
80
100
No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis
SVR (%
)[3,4]
134/288
n/N =
226/290
205/279
24/73
45/73
45/85
SVR by Advanced Fibrosis/Cirrhosis in Patients Receiving BOC + PegIFN/RBV
Subgroup Analysis of SPRINT-2[3]
PR48BOC RGTBOC/PR48
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217.
F3/4
100
80
60
40
20
0
SV
R (%
)
F0/1/2
38
67
213/319
n/N=
38
9/24
52
22/42
41
14/34
211/313
67
F3/4
100
80
60
40
20
0
SV
R (%
)
F0/1/2
23
66
77/117
132/15
68
21/31
44
14/32
81/119
68
Subgroup Analysis of RESPOND-2[4]
123/328
n/N=
14/61
BOC RGT
63/77
SVR in relation to IL28bSprint 2 Study
RVS (%
)
PR48
50/64n/N=
CC TT
BOC44/PR48
44/55
CT
PR48
33/116
BOC44/PR48
82/115
BOC RGT
67/103
PR48
10/37
BOC44/PR48
26/44
BOC RGT
23/42Samples were available for 653/1048 (62%) patients enrolled in SPRINT‐2; SVR was defined as undetectable HCV RNA at the last available value in
the period at or after follow‐up Week 24. If there was no such value, the follow‐up Week 12 value was carried forwardBoceprevir EU SmPC
IL28B Genotype Predicts Likelihood of Shortened Therapy With BOC or TVR
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
Eligibility fo
r Sho
rten
ed
Therap
y (%
)
118/132
158/304
CC CT/TT
89
52
Eligibility fo
r Sho
rten
ed
Therap
y (%
)
39/50
39/68
10/22
78
5745
SPRINT‐2: BOC + PR[1] ADVANCE*: T12PR[2]
*IL28B testing in ADVANCE was in white pts only.
80
60
40
20
0
n/N =
CC CT TT
100
80
60
40
20
0
n/N =
100
Predictors of Response to HCV Therapy
• On‐treatment predictors– Lead In–eRVR–Week 8 response– Week 12
Therapy with Boceprevir
SVR by Week 4 PR Lead-In Response
52
82 82
5
2939
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
Non-Black Patients Black Patients
≥1 log 10 HCV RNA decline from baseline
<1 log 10 HCV RNA decline from baseline
46
6761
0
2531
0
20
40
60
80
100
48 P/R BOC RGT BOC/PR48
SVR
(%)
SVR
(%)
121234
187228
178218
1226
1624 22
36
362
2173
3179
624
516
021
SVR in Poor IFN Responders Based on TW8 Response (Log Decline in VL Compared to BL
VL) (BOC Arms Combined)
0
38
21
50
91
09
33
48
79
0
16
30
49
83
0
20
40
60
80
100
% S
VR
RESPOND-2 SPRINT-2 CombinedStudies
<3 3-4 4-5 >5
016
38
628
1020
1011
028
223
2370
1531
2329
<3 3-4 4-5 >5 <3 3-4 4-5 >5
044
531
2998
2551
3340
Bacon BR, et al. AASLD 2011
Predictors of SVR when Lead‐in Response is Considered
RESPOND-2 (effect) Odds Ratio (95% CI) p-value
BOC/PR48 vs PR48 11.4 (4.6 to 28.0)
<.0001
BOC/RGT vs PR48 7.9 (3.3 to 18.9) <.0001
Previous Response: Relapser vsNonresponder
2.2 (1.2 to 4.3) 0.01
Log decline in HCV-RNA at TW 4 (continuous variable) 1.8 (1.3 to 2.4) <.0001
BMI: ≤25 kg/m2 vs >30 kg/m2 3.4 (1.4 to 8.2) 0.01
Only covariates remaining significant at α=0.05 after adjustment for the other variables were retained in the model as shown in the table. Factors entered but not retained in the model were IL28 polymorphism, HCV 1 subtype, race, gender, age, weight, platelets, fibrosis, steatosis, previous treatment (peginterferon alfa‐2a vs peginterferon alfa‐2b), ALT, baseline viral load, statinuse and region
80156
SPRINT-2: undetectable HCV RNA at Week 8 and Weeks 8 to 24
Patie
nts w
ith und
etectable
HCV
RNA (%
)
PR48
60/363
BOC44/PR48
204/366n/N=
Week 81 Weeks 8 to 242
BOC RGT
208/368
BOC44/PR48
161/366
BOC RGT
162/368
Patients eligible to receive 28 weeks of total treatment
1. Boceprevir EU SmPC2. Poordad F, et al. N Engl J Med 2011;364:1195–206
PR48
43/363
SPRINT‐2: SVR rates and treatment duration
96
72
15
96
75
0
20
40
60
80
100SV
R (%
)
Poordad F, et al. N Engl J Med 2011;364:1195–206 Bronowicki J‐P, et al. Hepatology 2010;52(Suppl.):881A
Undetectable Weeks 8–24
<28 wks18/124
–
48 wks59/82
SVR rates
+
28 wks156/162
+
48 wks155/161
–
48 wks55/73
BOC RGT BOC44/PR48
Response Guided Therapy with Telaprevir
No eRVR; PegIFN + RBV
Genotype 1 naïve PatientsRGT with Telaprevir + PegIFN/Ribavirin
TVR + PegIFN + RBV
Wks 480 24124
eRVR; stop at week 24, f/u 24 wksPegIFN + RBV
*Quantificacion HCV RNA LLD ≤ 25 IU/mL.Telaprevir [package insert]. May 2011.
HCV-RNA TVR + PegIFN/RBV
PegIFN/RBV Total Duration
Undetectable * wks 4 and 12 12 weeks 12 additionalweeks
24 wks
Detectable (but ≤ 1000 IU/mL) wks 4 and/or 12
12 weeks 36 Additionalweeks
48 wks
F/u 24 wks
Response‐Guided Approach With TVR in Tx‐Naive Patients Supported by 2 Studies
• 65% of patients eligible for shortened therapy[1]
92 88
ILLUMINATE: Response-Guided TVR + PegIFN/RBV in
Treatment-Naive Genotype 1
T12PR24 T12PR48
SVR
in P
ts A
chie
ving
eR
VR (%
)
100
80
60
40
20
0
149/162
140/160
n/N=
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.
ADVANCE: TVR + PegIFN/RBV in Treatment-Naive Genotype 1
• 58% of patients eligible for shortened therapy[2]
8997
T12PR24 PR
SVR
in P
ts A
chie
ving
eR
VR (%
)
100
80
60
40
20
0
189/212
28/29
n/N=
Stopping rules during boceprevir dosing period
0 48Weeks 284 8 24 3612
If ≥100 IU/mLat Week 12
If detectable at Week 24
Stop all drugs
Boceprevir EU SmPC
Stopping rules during telaprevir dosing period
Telaprevir EU SmPC
0Weeks 4 8 12
If >1000 IU/mL at Week 4 or 12:stop all drugs*
*In prior null responders, consideration should be given to conduct an additional HCV RNA test between Weeks 4 and 12. If the HCV RNA concentration is >1000 IU/mL, telaprevir and PR should be discontinued
Optimize Study
Less frequent dosing
+ food + food + food
+ food + food
24/48
PRT + PR
120
Weeks
Response Guided Therapyat week 4
74 73
0
20
40
60
80
100
OPTIMIZE SVR rates: telaprevir bid was non-inferior to q8h
Full analysis populationCI: confidence interval Buti M, et al. Poster presented at AASLD 2012:LB-8
SVR
12(%
)
270/371274/369
T12(q8h)/PRT12(bid)/PR
Difference 1.5% (95% CI: –4.9%, 12.0%)
OPTIMIZE: a similar proportion of patients achieved RVR
At Week 4, RVR determined total treatment duration– For patients achieving RVR, total treatment duration was 24 weeks, otherwise
total treatment duration was 48 weeks
RVR: rapid virologic response, undetectable HCV RNA at Week 4 Buti M, et al. Poster presented at AASLD 2012:LB-8
69
86
67
85
0
20
40
60
80
100
RVR SVR in RVR+ SVR in RVR+RVR
Patie
nts
(%)
T12(bid)/PR (N=369) T12(q8h)/PR (N=371)
77
51
78
54
77
49
0
20
40
60
80
100
246/321
491/636
29/54
24/49
245/315
53/103
CirrhosisNo cirrhosis
OPTIMIZE: SVR12 by cirrhosis status
One patient did not have a baseline fibrosis assessment and was excluded from this analysis Horsmans Y, et al. EASL 2013; Abstract 826
TVR bid
Allpatients
TVR q8h
TVR bid
All patients
TVR q8h
SVR
12(%
)
6979
0
20
40
60
80
100
<95% ≥95%
Patie
nts
with
SVR
(%)
TVR adherence*
OPTIMIZE: TVR adherence and SVR12
*determined by pill count (both TVR dosing regimens combined) Sievert W, et al. Poster to be presented at EASL 2013. Abstract 905
OR (95% CI): 1.86 (1.29–2.69)
e-diary (Observed)>95% adherent (%)>85% adherent (%)
TVP BID7490
TVP 8h6487
CONCISE study: 12 weeks of Treatmenyresults of interim analysis*
*128 patients were followed for 16 or more weeks; 66% (N=85) were randomized at Week 12, respectively: 57 in T12PR12 and 28 in T12PR24 armsRVR: Week 4 HCV RNA< 25 IU/mL, target not detected. PR: Peg-IFN alfa-2a (180 µg/week) and ribavirin (1000–1200 mg/day) Nelson DR et al. EASL 2013; Abstract 881
PR
Randomization 2:1in patients with RVR who continued
all study drugs through Week 12
T (1125 mg BID) + PR
weeks0 124 24
Follow-up
IL28B CC non F4:
Naïves
Relapsers
N=128 SVR4: 96% (47/49)SVR12: 89% (16/18)
IL28B CC
F0-F2
CC F3-4 TripleTherapy: Peg-RBV + TVP o BOC
Peg-RBV
24 wksRVR
VL < 400.000 y F0-F1
48 wksVL > 400.00 o F2
No RVR
Stop (*)
48 wks
< 1 log10
> 1 log10
* An IP (F2) could be added but it seems better to wait for new drugs
Spanish Management of Hepatitis C Genotype 1 in naive patients
IL28B CT/TT
≥ F2: Triple Therapy: Peg-RBV + TVP o BOC
Document treball SCD (M Bruguera, R Esteban, X Forns, R Planas, J Quer, R Solà, M Vergara)
IL28B CT/TT
F0-F1Wait for new treatments
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