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How to use PIs in challenging patients - Virology Education

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How to use PI’s in challenging
patients
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
The challenging patients
•
•
•
•
•
•
•
Cirrhosis
Decompensated cirrhosis
Null responders, cirrhosis, 1a
Pre – transplant
Post – transplant
HIV-HCV coinfected
Renal failure
– Impaired renal function
– Dialysis
– Renal transplant patients
• IV drug users
•
•
•
•
•
•
•
– Methadone substitution
Thalassaemics
Children
Interferon contraindicated
Interferon intolerant
PI resistant patients
Those on “edge” of society
And.. the rest of the world
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
The several factors that influence
response
•
•
•
•
•
•
•
•
Ethnicity
Stage of fibrosis
IL28b inheritance
Viral load
Subtype 1a vs 1b
On treatment response.....
(Prior response)
GGT, LDH levels
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Fibrosis (Cirrhosis) matters
• Conundrum
– Patients most in need of treatment
– Treatment response not the same as those
without cirrhosis (except relapsers?)
– But better than seen with PEG IFN RBV alone
– Require longer course of treatment
– Higher incidence of anaemia and
thrombocytopaenia
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Cumulative incidence of liver related
complications: SVR vs no SVR in cirrhosis
Bruno Hepatology 45: 579 2007
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
SVR rates treatment naive in patients treated
with T12PR Cirrhosis vs Compensated cirrhosis
SVR rate
ADVANCE
100
90 92
92
79
80
SVR (%)
ILLUMINATE
71
eRVR–
60
60%*
22%
74
eRVR+*
66
61
50
n=322
46
n=118
40
51
38
20
0
All
Cirrhosis
T12PR
PR48
15/21
8/21
eRVR+
T12PR24
11/18
eRVR+
eRVR–
Overall
T12PR48 T12PR48 T12PR48
11/12
6/12
31/61
Kauffman et al hepdart 2011
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
SVR by Fibrosis score: Naive patients (Sprint 2)
Non Black Cohort
% SVR
PR
BOC RGT
70
70
BOC PR48
100
80
60
40
50
40
50
39
20
0
F0-F1-F2
Poordad F, et al. N Engl J Med 2011;364:1195–206
F3-F4
n = 9/23 13/26
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
18/36
BMS-790052 + BMS-650032: AI447011
Quad versus DAA combination
 In null-responders, BMS-790052 + BMS-650032 appear to require
PegIFN/RBV to prevent breakthrough and the occurrence of resistance
BMS-790052 + BMS-650032 + PR
7
7
6
6
Log10 HCV RNA
Log10 HCV RNA
BMS-790052 + BMS-650032
5
4
3
2
1
LOD
0
5
4
1
1
2
3
4
6
Week
8
10
12
initiation of PegIFN/RBV
(NS5a inhibitor and Protease inhibitor)
LOQ 25 IU/mL
LOD <10 IU/mL
3
2
LOQ
Quadruple regimen
*
LOQ
LOD
0
1
2
3
4
6
Week
8
10
12
Lok A, et al. AASLD 2010. Abstract LB-8
Lok A, et al. EASL 2011. Abstract 1356
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Treatment
DAA + DAA
PEG IFN RBV
DAA PEG IFN RBV
DAA DAA PEG IFN RBV
(Quad)
Cirrhosis
Success (SVR)
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Optimising SVR
In patients with cirrhosis:
• Quadruple therapy?
• Still require interferon
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Null responders
• (For 1b ... at least)
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
AI44-017: BMS-650032 (PI) + BMS-790052 (NS5A)
Daclatasvir (BMS-790052) +
Asunaprevir (BMS-650032)
(N=10)
Week 4
(RVR)


Week 12
(cEVR)
Follow-up x 24 weeks
Week 24
(EOT)
Post-treatment
Week 12 (SVR12)
Post-treatment
Week 24 (SVR24)
Non-cirrhotic Japanese adults with HCV genotype 1b infection, HCV RNA
>105 IU/mL and prior null response to PR
Dual oral treatment with daclatasvir and asunaprevir for 24 weeks
– Daclatasvir 60mg once daily
– Asunaprevir initially 600mg twice daily, subsequently reduced to 200mg twice daily
due to elevated transaminases at 600mg in a concurrent dose-ranging study
Chayama K, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-4
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
AI44-017 (BMS-650032/BMS-790052): virologic
response
Proportion of patients with
undetectable HCV RNA (%)
100
90
90
90
4/10
9/10
9/10
9/10
Week 4
Week 12
EOT
SVR24
80
60
40
40
20
0

One patient discontinued at Week 2; HCV RNA was undetectable after
24 weeks’ follow-up
Chayama K, et al. Hepatology 2011;54(Suppl. S1): Abstract LB-4
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Treatment of patients with severe liver disease
 SVR advanced fibrosis associated with decreased
incidence of clinical decompensation and HCC.
 SVR rates pegylated IFN-a and ribavirin lower in patients
with advanced п¬Ѓbrosis or cirrhosis
 Rationale for:
 Triple therapies with protease inhibitors (genotype 1)
– Assiduous monitoring and management of side-effects
– Portal hypertension hypersplenism, leukocyte and platelet
counts at baseline low in cirrhotic patients.
– Hematological side effects frequent in cirrhotic than in noncirrhotic patients and may contraindicate therapy.
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Telaprevir in HCV-HIV coinfected patients
• Part A
– enrolled antiretroviral therapy (ART)-naive
– CD4 cell counts (> 500 cells/mm3)
– Not on antiretroviral treatment
• Part B enrolled CD4 > 300 cells/mm3
– on a stable ART regimen
– containing either efavirenz (Sustiva) or boosted
atazanavir (Reyataz)
• With tenofovir/emtricitabine
Sherman KE, et al. AASLD 2011. Abstract LB-8
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Patients with undetectable HCV RNA (%)
Telaprevir in HCV/HIV coinfected patients
Interim results
100
80
Undetectable HCV RNA at Week 24
86
75
67
75
71
60
50
40
55
33
20
0
T/PR
No ART
P/R
EFV
Three patients experienced HCV RNA breakthrough
(EFV, n=2; ATV/r, n=1)
No HIV RNA breakthroughs
ATV/r
Total
Sherman KE, et al. AASLD 2011. Abstract LB-8
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
% Patients With Undetectable
HCV RNA
HIV HCV Boceprevir Interim response
(% HCV RNA Undetectable)
3/34
3/64
5/34
24/64
8/32
35/62
11/32
43/61
Sulkowski M et al
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
HCV Infection in injection drug users
 Transmissions are frequent
 26% transmission among injection drug users who
have used needles for less than one year
 54% for those who had one to five years of use
 92% those with greater than five years of use
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Safety
• Anaemia notable
• Monitoring
• Management
• A marker of response
• Ribavirin dose reductions
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
SVR in Patients With Hgb <10 g/dL
by EPO and/or Ribavirin Dose Reduction
SPRINT-2
100
SVR (%)
80
78
71
RESPOND-2
83
74
68
95/129
30/44
48/67
Neither
Both
80
76
47/59
19/25
72
60
40
20
0
109/153
Both
29/37
RBV DR EPO
5/6
RBV DR EPO
Neither
BOC/PR
Full Analysis Set.
Note: BOC/PR includes patients pooled from Response-Guided Therapy and BOC/PR48 treatment group.
RBV=ribavirin; DR=dose reduction; EPO=erythropoietin.
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Poordad et al
Patient LG pre-telaprevir
Prior non responder with bridging fibrosis
Patient LG post telaprevir
SVR in REALIZE study
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Safety and efficacy of PegIFNО» compared with PegIFNО±-2a in
HCV-infected patients (G1/2/3) with compensated cirrhosis:
EMERGE Phase IIB efficacy and safety results through Wk 12
cEVR (% patients)
All О» versus О± doses in cirrhotics for
both G1 and G2/3
All О» doses
О±-2a 180 Ојg
Hematologic and laboratory
abnormalities (safety analysis set)
О»
Event, n (%)
120 Вµg
n=12
180 Вµg
n=10
О±-2a
240 Вµg
n=10
Total
n=32
180 Вµg
n=9
Hemoglobin
<10 g/dL*
0
Neutrophils
<1000/mm3
0
0
0
0
6 (66.6)
Platelets
<50,000/mm3
0
0
0
0
5 (55.6)
AST or ALT >5
x ULN
0
0
2 (20.0) 2 (6.3)
0
Direct bilirubin
>1.2 mg/dL
1 (8.3)
0
3 (30.0) 4 (12.5)
0
2 (20.0) 3 (30.0) 5 (15.6) 7 (77.8)
*and/or >3.5g decline from BL
• Very small study in cirrhosis
• No difference in efficacy between PegIFN λ and α-2a
• Marginal hematological benefit with λ
Rodriguez-Torres M, et al. AASLD 2011, San Francisco, #1344
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
PegIFNО» ameliorates RBV-induced anemia in HCV by maintaining
compensatory erythropoiesis:
EMERGE Phase IIb Wk 12 results
 Hb and reticulocyte analysis
 Little to no λ receptors on
 Hb decline similar 1st 2 wks
hematopoietic cells
 After 2 wks stabilized in PegIFNλ
 EMERGE randomized 526 naive
 Continued to decline in PegIFNɑ
 Those with significant anemia had higher
patients to:
reticulocyte count in О» vs Й‘ resulting in Hb
staying in normal range
 1st 12 wks RBV dose reductions
 ɑ 12.8%; λ 2.3,1.5 and 0.7%
 PegIFNλ 120,180 or 240 μg + RBV
vs PegIFNЙ‘ 180 Ојg + RBV
Reticulocytes Hb (g/L)
(%), mean
mean
160
140
Subjects with ≥2 g/dL Hb decline at Wk 2
All subjects
PegО» 120 Вµg
PegО» 180 Вµg
PegО» 240 Вµg
PegЙ‘
120
100
•
•
8
6
4
2
0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2
Study week
3 4 5 6 7 8 9 10 11 12
Broken lines
show upper and
lower limits of
normal
Paucity of IFNО» on hematopoietic cells allows bone marrow to respond to anemia
with reticulocytois and thus prevent significant anemia
IFNО» has a much more favorable hematopoietic profile than IFNЙ‘
Everson GT, et al. AASLD 2011, San Francisco, #1343
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Dealing with thrombocytopaenia
• Common in patients with cirrhosis
• Eltrombopag?
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
ENABLE 1 AASLD 2011 – Abstract #: LB-3
Virologic Responses (ITT)
Placebo
Eltrombopag
100
90
∆=16.7%
95% CI:9.2–24.1
Patients (%)
80
70
P<0.0001
66
60
50
50
40
∆=14.8%
95% CI:8.6–21.1
10
0
P=0.0080
P<0.0001
42
30
20
∆=10.7%
95% CI:3.3–18.1
48
37
∆=7.9%
95% CI: 2.4–13.4
26
P=0.7495
17 16
RVR
P=0.0064
14
EVR
cEVR
ETR
23
SVR
Virologic Response
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
27
Afdhal et al AASLD
ENABLE 1 AASLD 2011 – Abstract #: LB-3
Median Platelet Counts (ITT)
Median Platelet Count (x103/ВµL)
95% of patients from Part 1 entered Part 2
160
140
120
Placebo
Eltrombopag
Part 2
Part 1
Follow-Up
100
80
60
40
Threshold for dose reduction
20
OLB
//
//
0
2
AVB
1
2
4
6
8
12
16
20
24
28
32
36
40
44
4
12
24
Time Since Randomization (Weeks)
Pbo
Epag
712
426
208
387
227 227 218 197 189 165 141 135 89
73
69 68
64
65 205 196 193
443 438 430 423 414 404 377 363 248 202 183 173 169 168 400 396 391
AVB, antiviral baseline; OLB, open-label baseline.
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
28
Afdhal et al AASLD
Subtype, response and resistance
• Frequency of resistance will vary
–based on interferon response
–and HCV subtype
–(adherence and effectiveness)
• Relevance?
• May or may not be detrimental
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
The lead in paradigm
• TW4 response:
– Strong predictive value for SVR
– Defines interferon sensitivity
– (in “real time”, but over 4 weeks)
• Decision making?
– delay DAA? Delay treatment?
– Subdivide treatment into
– [DAA+PEG IFN +RBV] or [PEG IFN + RBV only]?
• Prioritization patients
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
MK-5172 activity against 1st generation PI mutations
 Pan-genotypic
 Effective against 1st generation
mutations
 Once daily
1A
6.8
120
80
40
34
1B 2A 3A 4A 5A
HCV NS3 genotype
0.039
0
6A
WT
V36A
V36M
F43S
T54A
T54S
Y56H
Q80K
R155K
R155T
A156S
A156T
A156V
D168A
D168E
D168G
D168V
D168Y
V36M/R155K
0.01
0.006
0.1
0.013
1
0.908
3.0
2.9
0.077
10
43
0.068
100
75
G1a
G1b
IC50 (nM)
MK-5172
TMC435
2750
100
IC50 (nM)
160
MK-5172 and TMC435 activity against
NS3 enzymes from different genotypes
0.074
10,000
* **
200
 Features of 2nd generation PIs
*MK-5172 mean IC50 of A156T is 458 nM and 412 nM in a
G1a and G1b background, respectively
**MK-5172 mean IC50 of A156V is 841 nM and 533 nM in a
G1a and G1b background, respectively
• True 2nd generation PI
• Reduced effectiveness in G3 but covers most mutations except A156 T/V
Graham D, et al. AASLD 2011, San Francisco, #370
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
Summary: small molecule inhibitors HCV
 HCV therapy has and will change:
– addition of protease inhibitors improves response rates
– Still require interferon and ribavirin.
 Separate development programmes
– for treatment-naïve and non-responding patients, 1a 1b
– IFN sparing and IFN free a reality
– Need to adapt to changing and evolving therapy
 Limited information in patients with cirrhosis, decompensated cirrhosis
and null responders and transplant patients
 Will response rates for challenging patients be improved?
– Via a different mechanisms of HCV clearance, or still require innate immune
response
– (IFN sensitivity , RBV sensitivity = innate determinants of clearance)
1st Global Workshop on HCV Therapy Advances // 9-10 December 2011, Madrid, Spain
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