thalassaemia Where are we now Telaprevir and boceprevir harbingers of important treatment advance Improved response rates observed naive and experienced patients SVR gt 70 ID: 320624
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Slide1
Treatment of Hepatitis C in patients with thalassaemia. Where are we now?
Telaprevir and boceprevir harbingers of important treatment advanceImproved response rates observed : naive and experienced patientsSVR > 70% have been reported in genotype 1 infection Efficacy in the treatment of genotype 2-6 has not been fully tested. Slide2
The natural history of fibrosis in chronic viral hepatitis
F0F2
F3
F4
Courtesy Pierre
Bedossa
Slide3
Telaprevir ADVANCE: SVR in naïve patients
Percent of patients with HCV RNA Undetectable
SVR
75
69
44
T12PR
T8PR
PR
P
<0.0001
P
<0.0001
271/363
250/364
158/361
n/N =
Jacobson IM, et al. N
Engl
J Med 2011;364:2405-16; 2.Slide4
Evidence for efficacy: boceprevir in
treatment-naïve, genotype 1 patients (SPRINT-2)BOC RGT
233/368
BOC44/PR48
242/366
PR48
137/363
n/N =
Boceprevir EU
SmPC
*
*
*
p
<0.001 for both boceprevir arms versus
PR48
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 forwardSlide5
The first generation protease inhibitors. Where are we now?
Response rates in patients with cirrhosis improved but suboptimalNaïve patients without severe fibrosis respond betterPrior null response and cirrhosis less likely to respond to retreatmentInherited IL28b haplotypes continue to influence response ratesResponse rates lower in subtype 1a vs 1b.
Side effects testing for patientsSlide6
REALIZE (telaprevir): SVR by baseline fibrosis stage and prior response to Peg-IFN/RBV
SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was usedPol S, et al. Hepatology 2011;54(Suppl. S1):374A
53/62
n/N=
2/15
12/38
145/167
10/18
0/5
3/17
36/47
16/38
0/9
1/5
11/32
No, minimal
or portal
fibrosis
Cirrhosis
Stage
Pbo/PR48
Pooled T12/PR48
SVR (%)
48/57
1/15
1/18
24/59
1/10
7/50
Bridging
fibrosis
No, minimal
or portal
fibrosis
Cirrhosis
Bridging
fibrosis
No, minimal
or portal
fibrosis
Cirrhosis
Bridging
fibrosis
Prior
relapsers
Prior partial
responders
Prior null
respondersSlide7
BOC
RGTBoceprevir (SPRINT-2): SVR rates by
IL28B genotype
Samples 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
forward
Boceprevir
EU
SmPC
SVR (%)
PR48
n/N=
CC
TT
BOC44/
PR48
CT
PR48
BOC44/
PR48
BOC
RGT
PR48
BOC44/
PR48
BOC
RGT
63/77
50/64
44/55
33/116
82/115
67/103
10/37
26/44
23/42Slide8
Telaprevir (ADVANCE): SVR rates by IL28B genotype
Samples were available for 454/1088 (42%) patients (Caucasian) enrolled in ADVANCESVR: sustained virologic response, defined as undetectable HCV RNA 24 weeks after last planned doseJacobson IM, et al. J Hepatol 2011;54(Suppl.):S542
T8/PR
PR
T12/PR
PR
T12/PR
T8/PR
PR
T12/PR
T8/PR
n/N=
38/45
35/55
45/50
20/80
48/68
43/76
6/26
16/22
19/32
SVR (%)
CC
TT
CTSlide9
Interim results: Royal Free Cohort
Undetectable VL at TW4 n
(%)Met stopping rule at TW4
n (%)
Met stopping rule week
TRW12
n
(%)
1a
21 (70)
4 (13)
9 (30)*
1b
16 (84)
0
0
rs860 Non CC
31 (76)
4 (10)
8 (20)
rs860 CC
8 (89
)
0
0
rs916 Non TT
19 (70)
4 (15)
6 (23)
rs917 TT
20 (87)
0
2 (9)
VL> 800,000
29 (73)
4 (10)
8 (21)
VL <800,000
12 (92)
0
1 (8)
At triple therapy week 4 and 12Slide10
The paradox of progressAdvances have brought higher rates of cure
but more complexity to treatment of hepatitis C- a paradox of progressDo not make treatment more straightforwardComplex process of decision making is required to assess Side effects?Resistance in patients who fail treatment Slide11
Managing adverse events:Rashesvarying
grades of severity and duration have been reported in 55% telaprevirMost drug related dermatitis moderate severityUnpredictably progress5 % of patients experienced severe rashDrug Rash with Eosinophilia and Systemic Symptoms (DRESS) occurred in 0.4% and Stevens-Johnson syndrome in 0.1% in clinical trials.AnaemiaParticular relevance in patients with thalassaemiaSlide12
Boceprevir: similar SVR when RBV dose modification and EPO are used to manage anemiaTreatment-naive G1 patients (n=687) received BOC-based therapy. Overall, 500 patients developed anemia (
Hb ≤10g/dL or were expected to reach that nadir before next visit) and were randomized to have anemia managed with either EPO (40,000 units/wk subcutaneously), or RBV dose reduction (by 200–400mg/day). Transfusion in patients with Hb ≤8.5 g/dL was allowed to prevent study discontinuation. Poordad F, et al. EASL 2012. Abstract 1419. Poster presented on Thursday 19th April
178
249
178
251Slide13
Still stuck with IFNThe requisite backbone of PEG IFN:other
problems associated with PEG IFN and RBV useIncluding depression, psychiatric symptoms worsening of liver function and severe infectionsrender a large group intolerant of PEG IFN ineligible for treatment. Slide14
What threat does resistance pose?HCV does not replicate via DNA intermediate
HCV genome does not integrate into the human genome there is no stable genetic reservoirDrug selection pressure discontinuedadvantage is lost: RAV’s outgrown by more fit, wild-type virusTheoretical possibility of restoration of drug susceptibilitySlide15
EXTEND (telaprevir): resistant variants no longer detected in 85% of patients by last visit
Median follow-up time from treatment-failure: 29 months (range 7–49)Clonal sequencing performed in representative Phase 2 samples (n=20 patients) indicated that HCV populations returned to pre-treatment state*Variant categories are not mutually exclusive*Zeuzem S, et al. Hepatology 2010;52(Suppl):227ASherman KE, et al. Hepatology
2011;54 (Suppl. S1):485A
Variants at HCV NS3
position
Overall
36
54
155
156
168
36+155
variants
Population
Sequencing
0
20
40
60
80
100
49/60 patients
107/126
20/21
74/81
11/11
69/82
n/N =
91
84
82
85
Percent of patients with no detectable variants
95
100
0
0/1Slide16
Boceprevir resistance analysis: detectability of most common RAVs* declines during follow-up
Barnard RJO, et al. Hepatology 2011;54 (Suppl. S1): Abstract 164
*In non-SVR patients with detectable RAVs at treatment failure in SPRINT-2 and RESPOND-2.As of latest follow-up time point (range 6–14 months)
Patients with RAVs no longer detected by population sequencing (%)Slide17
Viral kinetics in patients who met the >1000 IU/mL HCV RNA Week 4 stopping rule with telaprevir
Adda N, et al. HepDART 2011. Abstract 45Treatment-naïve patients
Treatment-experienced patients
10
8
10
7
10
6
10
5
10
4
10
3
10
2
10
0
4
6
8
12
10
2
Weeks
HCV RNA (
IU/mL
)
0
4
6
8
12
10
2
Weeks
HCV RNA (
IU/mL
)
10
8
10
7
10
6
10
5
10
4
10
3
10
2
10Slide18
SVR12 not yet reported for the
24 week groupsATOMIC study: GS7977 + IFN + RBV 12 weeksInterferon sparing: a new threshold
Kowdley
KV,
et al.
EASL 2012, Barcelona, #1Slide19
BMS-790052 + BMS-650032: AI447011
In null-responders, BMS-790052 + BMS-650032 appear to require PegIFN/RBV to prevent breakthrough and the occurrence of resistance
BMS-790052 + BMS-650032
Lok A, et
al NEJM
Log
10
HCV RNA
7
6
5
4
3
2
1
Week
0 1 2 3 4 6 8 10 12
*
LOQ 25 IU/mL
LOD <10 IU/mL
LOD
LOQ
LOD
LOQ
Log
10
HCV RNA
7
6
5
4
3
2
1
Week
0 1 2 3 4 6 8 10 12
initiation of PegIFN/RBV
BMS-790052 + BMS-650032 + PR
Quadruple regimen
Quad versus DAA combination
(NS5a inhibitor and Protease inhibitor)Slide20
ASPIRE (TMC435): SVR24 by prior response and Metavir score
Patients with SVR24 (%)
TMC435
100mg*
PR48
48 29 10
TMC435
150mg*
PR48
52 26 15
TMC435
100mg*
PR48
30 20 11
TMC435
150mg*
PR48
48 21 11
TMC435
100mg*
PR48
38 29 13
PR48
16 10 6
PR48
12 10 2
PR48
13 3 2
TMC435
150mg*
PR48
29 21 13
Relapsers
Partial responders
Null responders
Zeuzem S, et al. J Hepatol 2012;56 (Suppl 2):S1
n=
*All TMC435 duration pooledSlide21
Will we have better, more tolerable interferons?Lambda interferon
No haematological toxicitySlide22
Daclatasvir and GS-7977 across HCV genotypes 1–3
Sulkowski
M,
et al.
EASL 2012, Barcelona, #1422
100
100
100
100
100
100
87
86
93
100
100
100
94
100
86
88
100
86
%
<LOD
%
<LLOQ
G1a/b
G2/3
mITT
*
*Bars <100% after 4 weeks reflect missing valuesSlide23
All oral regimens: a realistic dream?Therapeutic landscape is undoubtedly forever changed for the better
High barrier to resistance and pan-genotypic effects. Do not yet know whether RBV remains important, or the appropriate dose of RBV in these regimensNull responders to PEG IFN and RBV are null responders to both agents?Multiple DAAs without RBV? Costs will escalateSlide24
DAA + IFN (IFN freer) or IFN free?
12 weeksSlide25
Next priorities for all oralMore data in patients with
CirrhosisDecompensated cirrhosisPost transplant recurrent hepatitis CHIV and HCV coinfected patientsPatients with haemoglobinopathiesPatients with renal impairment or post renal transplant patientsChildrenSurely the next group of patients requiring attention will be those resistance to first generation PI’s?Slide26
Overcoming null responseMay be nullified in patients treated with potent regimens given for
sufficient time to effect clearance of HCV from the liver and perhaps extrahepatic sites. An inverse correlation between the influence of the innate response and potency of DAA agents. Difficult to develop an experimental model Slide27
Who should be treated now and who should wait?
Whoever wants treatmentWhoever is fit for treatmentFit for the regimenNo contraindicationsMotivated to have treatmentUnderstands : likelihood of responseRisks and benefits of treatment
Understands what is coming down the lineAgrees it is an opportune timeReimbursed
Indicated
Introduce thinking and evidence
27