Dr. John Dillion - Community Response

Report
HCV Disease Pathway
Acute infection
20-30%
Spontaneous cure
70-80%
??
Chronic Hepatitis
20-100%!!!
Cirrhosis
1- 4%/annum
Hepatocellular carcinoma
Modelled prevalent number of HCV infected IDUs in Scotland
according to stage of HCV disease, 1960-2030
Recovered from HCV
50
Cleared HCV from treatment
40
Mild disease
Moderate disease
30
2008
Living IDUs (thousands)
60
Cirrhosis
20
10
0
1960
1980
2000
Calendar year
2020
Hutchinson et al. Hepatology 2005
Modelled number of IDUs with cirrhosis in Scotland by
different uptake rates of HCV antiviral therapy, 2008-2030
2010
2020
2030
0
1,000
2,000
3,000
0
1,000
2,000
3,000
2,000
1,000
0
Living IDUs with cirrhosis
Uptake of therapy by
(up to) 2,000 IDUs per year
3,000
Uptake of therapy
by 1,000 IDUs per year
Uptake of therapy
by 225 IDUs per year
2010
2020
2030
2010
Cirrhosis prevented
Compensated
Decompensated
from antiviral therapy*
cirrhosis
cirrhosis
* Excludes those prevented from antiviral therapy prior to 2008
2020
2030
HCC
Hutchinson, SJ. et al 2008 J Hepatol. 48 (Suppl 2):S297
UPTAKE OF TREATMENT
In Scotland, 2002-2012: (a) the number of chronic HCV persons commencing a course
of therapy each year, and (b) the cumulative number of patients attaining SVR
Number treated.
800
3000
600
2000
400
1000
200
0
2002
Key points:
Cumulative SVR
4000
1000
2003
2004
2005
2006
2007
No persons
commencing
treatment
2008
2009
2010
2011
2012
Cumulative number of
known SVR
•1052 patients treated in 2012/13 (marginally below the national target of 1,150)
•In the last three years, more than 1,000 patients per year commencing treatment in
Scotland
•The number of persons known to have attained a SVR, now exceeds 3000
McDonald et al. J Viral Hep; in press
(1b) UPTAKE OF TREATMENT
(1a) ATTENDANCE AT SPECIALIST SERVICES
50
50
40
40
% Treated
% Attended
Proportion commencing treatment within 12 months of
attendance, by calendar period, in Scotland.
30
20
30
20
10
10
0
0
96-98
99-01
02-04
05-07
08-09
96-98
PERIOD OF DIAGNOSIS
99-01
02-04
05-07
08-09
PERIOD OF ATTENDANCE
Pre phase II
Phase II
McDonald et al. J Viral Hep; in press
(4) IMPACT OF SVR
(I) LIVER DEATHS
(II) FIRST-TIME ADMISSION FOR LIVER FAILURE
Number of admissions
Number of deaths
150
100
50
150
100
50
0
0
98
00
02
04
06
Year Death
08
10
98
00
02
04
06
08
10
Year Admission
McDonald et al. J Viral Hep; in press
Estimated uptake of HCV antiviral therapy, by selected
country
Estimated number
living with chronic
HCV
(N)
Annual number
initiated on HCV
therapy
(Rx)
Annual
treatment
uptake
(Rx/N)
38,000
1,052
2.8%
~500,000
~13,500
~2.7%
USA (2008-2012)2
~3,200,000
65,000
~2.6%
Australia (2006)3
202,400
2900
~1.4%
Scotland (2012)
France (2000-2005)1
1Lettmeier
2Volk
3Gidding
et al. J Hepatol. 2008;49(4)528-36
et al. Hepatology. 2009; 50:1750-1755
et al. J Gastroenterol Hepatol. 2009; 24(10)1648-54
Excess risk of a liver and an alcohol related hospital episode post
treatment (in SVR & non-SVR patients) AND post diagnosis (in
spontaneously resolved patients), compared to the general population
50.0
53.2
Excess risk*
26.8
Liver
10.5
10.0
5.0
5.9
4.5
2.0
1.0
7.4
Alcohol
1.3
0.5
Non-SVR
(N=638)
* Age, sex & year standardised
SVR
(N=560)
Non-cirrhotic Spontaneous
SVR
resolved
(N=503)
(N=3,690)
Innes et al. Hepatology, 2011.
HCV treatment the state of the art Feb 2014
Interferon Based
Tailored to Genotype
Duration 24-48 weeks
Scotland Genotype 1&3
SVR G1 70%, G3 75%
Boceprevir dose must not be reduced or restarted once stopped
STOP
 Treatment-naïve without cirrhosis who achieve
undetectable HCV RNA at Weeks 8 and 24
PR
lead-in
BOC + PR
PR
BOC + PR*
 Non-cirrhotic treatment-naïve with detectable HCV
RNA at Week 8 but undetectable at Week 24*
 Non-cirrhotic relapsers and partial responders
HCV RNA
0
4
8
If ≥100 IU/mL
discontinue all
drugs
If detectable
discontinue all
drugs
12
24
28 28
BOC + PR
 Null responders
 Patients with cirrhosis
36
48
Weeks
*This regimen has only been tested in patients who have failed
previous therapy who were late responders
Boceprevir EU SmPC
Telaprevir dose must not be reduced orrestarted
stopped
Non-cirrhoticonce
naïves and
relapsers achieving undetectable
HCV RNA at Week 4 and 12 (eRVR)
STOP
Telaprevir
+ PR
PR
PR
 Non-cirrhotic naïves and relapsers without eRVR
 Partial and null responders
 Patients with cirrhosis
Weeks
0
HCV RNA
4
12
If >1000 IU/mL at Week 4 or 12:
discontinue all drugs
24
36
If detectable at Week 24 or 36:
discontinue PR
48
100
80
SVR (%)
63 *
66 *
60
38
40
20
0
n/N =
PR48
BOC RGT
BOC44/PR48
137/363
233/368
242/366
*p<0.001 for both boceprevir arms versus PR48
Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206
100
SVR (%)
80
72–75*
60
44
40
20
0
n/N =
*p<0.001 vs PR48 in ADVANCE (75% versus 44%)
PR48
T12PR
158/361
659/903
Sherman KE, et al. Hepatology 2010;52(Suppl.):401A
Jacobson IM, et al. N Engl J Med 2011;364:2405-16; Sherman KE, et al. CROI 2011. Abstract 957
Has changed drug
habit to get HCV
treatment
No
Contact/harm
reduction
Needle
exchange
On or off opiate
substitution therapy?
Methadone/
opiate
substitution
RCTs: randomized control trials
PWID: not a barrier to SVR in OST therapy
SVR achieved (%)
80
70
60
50
40
30
20
10
0
19/36 12/39 11/31
56/86 33/43* 33/43*
G1
Non-IDU
*ex-IDU vs active IDU; P=0.02
Non-G1
Ex-IDU
Active IDU
Jafferbhoy H, et al. J Viral Hepat. 2012:19(2):112–9
The Future
HCV Antivirals in Development
ANA773
PhI
Miglustat
Clemizole
AVL-181
RG 7348
NIM-811
MK-1220
Other HCV
Compounds
MK5172
CF-102
Golotimod (SCV 07) sc
NA-808
PRO 206
ITX 5061
VBY376
BI-201335
PhIII
GS 9256
TMC435350
ACH-1095
Taribavirin
Celgosivir
ITMN-191/R7227
Telaprevir
TaigGen Bio
ACH-1625
Boceprevir
IPH 1101
IMO-2125
PHX-1766
IDX-320
BIT-225
PF 4878691
IDX-136 and IDX-316
BMS-650032
Nitazoxanide
SCY-635
VX-985
MK-7009
GI-5005
CYT-107
ACH 2928
SCH 900518
Debio025
CB-5300
FGI 103723
Nov-205
PhIIb
BMS-791325
ATI-0180
PIs
VX-813
ABT 450
IDX-375
SPC-3649
BMS-824393
PhIIa
R7128
BMS 790052
PPI-461
EDP-239
Nuc
polymerases
PSI-7977
BMS
AZD-7295
Albuferon
IDX-184
NS5As
PSI-879
PSI-7851
HDV-IFN
(Hepasome)
Locteron CR
MK3281
AZD 2795
ITCA-638
ABT-072
ANA598
BI-207127
IFN-alpha-2b-medtronics
ABT-333
IFN-alpha-2b-XL
VCH-222+ Telaprevir
Interferon-alpha
(buccal lozenge, Amarillo)
RG7227+RG7128
VCH-222
VCH 916
GS9190+GS9256
IF's
Belerofon
Changed/additional info
Suspended / Discontinued
IDX-189
VCH 759
PEG-IL-29
P-1101
IDX-102
PF868554
sr-IFN-alpha
(LG Life Sciences)
IFN alpha, Medgenics
(Biopump SR)
PSI-938
GS 9190
BMS-790052 + BMS-650032
IDX184+IDX320
Sources: GBI Analysis (August 4, 2010), Pipeline Sources, Company Press Releases, Reuters Knowledge Analyst Reports
BI-201335+BI20127
Combination
Products
Non-nuc
polymerases
SOF Phase 3 Analysis in Patients with Traditional Negative Factors
‡
Virologic Response: SVR12 in NEUTRINO GT 1,4,5,6
Race
(Non-Black vs. Black)
Non-Black
SVR12 (%)
100
91
Obesity
(BMI < vs. ≥ 35 kg/m2)
< 35 kg/m2
Black
100
87
90
IL28B GT
(Non-TT vs. TT)
≥ 35 kg/m2
91
Non-TT
100
80
80
80
60
60
60
40
40
40
20
20
20
248/273
0
47/54
254/282
0
Mangia A, et al. AASLD 2013. Washington, DC. #1115
TT
91
251/276
41/45
86
44/51
0
22
NUC NS5B inhibitor sofosbuvir & Daclatasvir ±
Ribavirin (geno 1, n =45)
% undetectable HCV RNA
GS7977/daclatasvir
100%
80%
93%
79%
GS7977/daclatasvir/RBV
100%
93%
100%100%
100%100%
77%
67%
60%
40%
20%
0%
2 weeks
On Rx
4 weeks
On Rx
12 weeks 24 weeks 12 weeks
On Rx End of Rx post-Rx
Sulkowski M, et al. J Hepatol 2012; 56: S1422
QUEST-1: Phase 3 trial of Simeprevir + PR in
G1 treatment-naive patients
Response Guided Therapy
criteria met by 85%
SVR in 91% of RGT patients
No incremental rash/anemia
Hyperbilrubinemia
A NS3a PI a replacement for Boceprevir or telaprevir
Jacobson IM et al, EASL 2013, Amsterdam, #1425
24
AbbVie Phase III Clinical Program Results
fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) twice daily
Study
PEARL-II
(12 weeks)
PEARL-III
(12 weeks)
PEARL-IV
(12 weeks)
TURQUOISE-II
(12 & 24 weeks)
SAPPHIRE-I
(12 weeks)
SAPPHIRE-II
(12 weeks)
Patients
Treatment Regimen
AbbVie regimen + RBV
GT1b treatment(n=88)
experienced
AbbVie regimen only
(N=179)
(n=91)
AbbVie regimen + RBV
GT1b treatment-naive
(n=210)
(N=419)
AbbVie regimen only
(n=209)
AbbVie regimen + RBV
GT1a treatment-naive
(n=100)
(N=305)
AbbVie regimen only
(n=205)
GT1 treatment-naive
AbbVie regimen + RBV, 12
and treatment-experienced weeks (n=208)
with
AbbVie regimen + RBV, 24
compensated cirrhosis
weeks (n=172)
(N=380)
GT1 treatment-naive
AbbVie regimen + RBV
(N=631)
(n=473)
GT1 treatment-experienced AbbVie regimen + RBV
(N=394)
(n=297)
SVR12
97%
(85/88)
100%
(91/91)
99%
(209/210)
99%
(207/209)
97%
(97/100)
90%
(185/205)
92%
(191/208)
96%
(165/172)
96%
(455/473)
96%
(286/297)
• In developed country settings, people who inject drugs (PWID) contribute
to the majority (>80%) of HCV transmission
• Pooled UK evidence for impact of harm reduction on HCV incidence1
• Opiate substitution therapy (OST) or high coverage needle and syringe
programmes (NSP) alone reduces an individual’s HCV risk by ~50%
• In combination, reduces HCV risk by ~80%
• Modelling indicates OST and NSP likely important in preventing very high
HCV prevalences in UK, BUT insufficient to reduce HCV to very low levels2
[1] Turner K et al. Addiction 2011; 106:1978-88
[2] Vickerman P et al. Addiction 2012;107:1984-1995.
Relative prevalence reduction (%)
at 15 years (2027)
100
90
80
Annually
70
No scale-up
60
Scale-up to 10/1,000 PWID
50
Scale-up to 20/1,000 PWID
40
Scale-up to 40/1,000 PWID
30
Scale-up to 80/1,000 PWID
20
10
0
Edinburgh
25% baseline
chronic
prevalence
Melbourne
50% baseline
chronic
prevalence
Vancouver
65% baseline
chronic
prevalence
Bars indicate the mean relative prevalence reductions; whiskers represent the 95% credibility interval for the simualtions
Martin NK, et al. J Hepatol 2011;54:1137–44
DYNAMIC HCV TRANSMISSION MODEL
Non-SVR
infected PWID
Allow for
re-infection
New
PWID
Antiviral
treatment
Uninfected
PWID
Spontaneous
clearance
Cease/die
Infection
Acutely infected
PWID
Chronically infected
PWID
ADDITIONAL RISK HETEROGENEITY
High risk,
Off OST
High risk,
On OST
Low risk,
Off OST
• PWID cycle through various
risk and intervention states,
associated with different
risks of HCV acquisition
• Allows for examination of
targeting strategies
Low risk,
On OST
Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster
GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention
among people who inject drugs: modeling treatment scale-up in the age of direct
acting antivirals. Hepatology 2013
RESULTS: EDINBURGH
IFN-free DAAs
Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster
GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention
among people who inject drugs: modeling treatment scale-up in the age of direct
acting antivirals. Hepatology 2013
SENSITIVITY ANALYSIS
• Delaying initiation of IFN-free DAA scale-up by 4 yrs reduces
impact by over 20%
• Less impact seen with shorter injecting duration
• Impact not sensitive to changes in assumptions regarding
population heterogeneity and treatment targeting (low risk or
on OST) because of movement/cycling between risk states
Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster
GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention
among people who inject drugs: modeling treatment scale-up in the age of direct
acting antivirals. Hepatology 2013
Effect Estimates
AOR1
95% CI
>100%NSP
0.48
0.3
0.9
OST
0.41
0.2
0.8
OST and >100%NSP
0.21
0.1
0.5
1 adjusted for: gender, crack, homeless, injecting duration
100%NSP is defined as exchanging more syringes than you inject
Turner K et al. Addiction 2011; 106:1978-88
NECESSARY DAA TREATMENT RATES TO HALVE CHRONIC
PREVALENCE IN 10 YRS WITH HARM REDUCTION
Martin NK, et al..
CID 2013
Tayside
NESI: Needle Exchange Surveillance Initiative
6 months into project
Success of HCV Therapy
Triple Rx
100%
Protease inhibitor
+ PEG/RBV
24 weeks
Cure rate
75%
50%
HCV a disease that need not
75%
kill anyone
HCV a disease we can kill in our
life time
PEG/RBV
48 weeks
IFN/RBV
48 weeks
25%
0%
Combo DAA
Nuc
+ 2nd DAA
12 wks
No IFN
No RGT
IFN-α
24 weeks
4%
1985
IFN-α
48 weeks
45%
27%
9%
20yrs
2004
2011 2013
95-100%

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