SOF + RBV - Prof. Gamal Esmat

Report
New Treatment for HCV G4
Towards an End to HCV Epidemic in Egypt
Several potential innovative drug targets in HCV
NS2
c
E1
NS3/4A
A serine protease,
essential for posttranslational processing
of HCV polyproteins
Boceprevir1
Telaprevir1
ABT-450/r2
Sovaprevir3
Asunaprevir11
Simeprevir9
Faldaprevir12
Danoprevir12
GS-945113
MK-517214
ACH-806/GS-91321
NS3
IFN-lambda
NS5A NS5B
A type III interferon with a
restricted distribution of receptors
contributing to a favourable
adverse event profile7
E2
NS5A
NS5B
Multifunctional membraneAn HCV-specific, RNA-dependent
associated phosphoprotein,
RNA polymerase
essential component of the
HCV-RNA replication complex
Daclatasvir4
Ledipasvir4
ABT-2672
PPI-6686
AZ-6894
BMS-8243934
PPI-4614
Nucleos(t)ide
analogue
Sofosbuvir10
Mericitabine15
VX-13520
Non-nucleoside
analogue
BI-20712716
ABT-3332
ABT-07217
BMS-79132518
Tegobuvir12
Setrobuvir12
VX-22219
Filibuvir12
BMS-9141438
Cyclophilin A
Host protein involved in HCV
replication through interaction
with NS5A and the HCV
polymerase
Alisporivir5,*
SCY-6351
*On clinical hold, Novartis
press release
1. Rehman S, et al. Genet Vaccines Ther 2011;9:11. 2. http://clinicaltrials.gov/ct2/show/NCT01464827. 3. http://ir.achillion.com/releasedetail.cfm?releaseid=6989383. 4. Gish R
& Meanwell NA. Clin Liver Dis 2011;15:627–39. 5. Coelmont L, et al. PLoS One 2010;5:e13678. 6. http://clinicaltrials.gov/ct2/show/NCT01448200. 7. Miller DM, et al. Ann N Y
Acad Sci 2009;1182:807. 8. http://clinicaltrials.gov/show/NCT01309932. 9.Poordad F, et al. AASLD 2012, abstract 83. 10. Gane E, et al. EASL 2012, poster 1113.
11. http://clinicaltrials.gov/ct2/show/NCT01030432. 12 . Delang L, et al. Viruses 2010;2:826–66. 13. http://www.gilead.com/research. 14. http://clinicaltrials.gov/
ct2/show/NCT01353911. 15. Wedemeyer H, et al. Hepatology 2013 January 24. [Epub ahead of print]. doi: 10.1002/hep.26274. 16. http://www.pipelinereport.org/browse/hcvtreatment/bi-207127. 17. http://www.pipelinereport.org/browse/hcv-treatment/abt-072. 18. http://clinicaltrials.gov/show/NCT01193361. 19. http://www.vrtx.com/researchdevelopment/pipeline. 20. http://news.bms.com/press-release/financial-news/bristol-myers-squibbpresent-new-data-hepatitis-c-and-hepatitis-b-compo. [Accessed April 10, 2013].
Characteristics of DAA
DAA
PI 1st
generation
PI 2nd
generation
NS5A Inh. 1st
generation
NS5A Inh. 2nd
generation
NS5B
nucleos(t)ide
inh.
NS5B non
nucleos(t)ide
inh.
Efficacy
Resistance
profile
Pangenotypic
efficacy
Adverse
events
Drug-drug
interaction
Good profile
Average profile
Least favorable profile
Schinazi, et al. Liver Int 2014;34 Suppl 1:69-78
Many studies have looked at different ways of
combining these compounds
NS5A
Alfa
RBV
In different patient
types
• Different genotypes
• Treatment-naive
• Null-responders to
prior therapy
• Intolerant to previous
therapy
Alfa, peginterferon alfa-2a; lambda, peginterferon lambda-1a; RBV, ribavirin
This slide represents just a small selection of studies and regimens in current clinical development – other combinations are therefore possible
Sofo+RBV
Study
Patients
Regimen
Duration
Sofosbuvir and Ribavirin
for Hepatitis C Genotype
1 in Patients With
Unfavorable Treatment
Characteristics
Osinusi (2013)
JAMA
No: 60
treatment-naive patients
genotype 1
with bad predictors:
(African-American,
high BMI, low
frequency of
IL28B CC, viral load
and advanced fibrosis)
60 patients
Egyptians
G4
Treatment naive and experienced
A: 10 non cirrhotic
B: 50 All stages of
fibrosis:
25 (weight based RBV)
25 (low dose RBV: 600)
12 weeks
Sofosbuvir + RBV
12 weeks
Or 24 weeks
12 weeks SVR12 68%
24 weeks SVR12 93%:
G4 100 patients
Treatment naive and experienced
Sofosbuvir + RBV
12 weeks
Or 24 weeks
12 weeks SVR12 77%
24 weeks SVR12 90%
Sofosbuvir plus
ribavirin in the
treatment of chronic
HCV genotype 4
infection in Egyptian
patients
Ruane (2013)
Hepatology
Egyptian study
Response
SVR 24
Non cirrhotic: 90%
Wight based RBV: 68%
Low dose RBV: 48%
Sofo+IFN+RBV
Study
Patients
Regimen
Duration
Response
ATOMIC
316 naïve
Sofosbuvir with pegylated
genotype-1
interferon alfa-2a and ribavirin
for treatment-naive patients
with hepatitis C genotype-1
infection (ATOMIC): an openlabel, randomised, multicentre
phase 2 trial
Kowdley et al (2013)
Lancet
A (N:52): sofosbuvir
12 w
+P+R
24 weeks
B (N: 109, with 11 of
24 weeks (12 +12)
them genotype 4):
sofosbuvir +P+R
C (N: 155): 12 weeks of
sofosbuvir +P+R
followed by 12 weeks
of either sofosbuvir
monotherapy or
sofosbuvir +R
SVR 24
A: 89%
B: 89%
C: 87%
NEUTRINO
Sofosbuvir for previously
untreated chronic hepatitis C
infection
Lawitz (2013)
NEJM
Sofosbuvir + PegIFN
+ RBV
Total 90% (295/327)
G1a 92% (206/225)
G1b 82% (54/66)
G4 96% (27/28)
G5/6 100% (7/7)
Cirrhosis 80% (43/54)
G1, 4, 5, 6
Naïve
n = 327
(G1 79%)
12 weeks
Sofo and other DAA combination trials
Response
Duration
Regimen
Patients
Study
Cirrhotic TTT failure:
With RBV: 100% SVR12
Without RBV: 70% SVR 12
Non cirrhotic naïve:
6 weeks ttt: 68% SVR 12
8 weeks ttt; 100% SVR 12
8 weeks with RBV: 100%
8 weeks without RBV: 95%
12 without RBV: 95%
12 weeks
Sofosbuvir+ ledipasvir
With or without RBV
G1
prior null responders with
compensated cirrhosis
and in naive, noncirrhotic
patients
Electron
Once daily sofosbuvir/ledipasvir
fixed dose combination with or
without ribavirin
8 weeks
Sofosbuvir+ ledipasvir
With or without RBV
G1
treatment-naive,
noncirrhotic
SVR12 in prior null
responders with F0-F2
fibrosis were 93% (in both 12
and 24 weeks).
In cirrhotics: SVR 4: 100%
(in both null responders and
naïve) 24 weeks.
for 12 or
24 weeks
Sofosbuvir+simeprevir
with or without RBV
G1
Noncirrhotic and cirrhotic,
treatment-naıve and prior
null responder
LONESTAR (2)
Sofosbuvir and ledipasvir fixeddose combination with and without
ribavirin in treatment-naive and
previously treated patients with
genotype 1 hepatitis C virus
infection (LONESTAR): an openlabel, randomized, phase 2 trial
COSMOS (3)
SVR results of a oncedaily
regimen of simeprevir (TM435)
plus sofosbuvir (GS-7977) with of
without ribavirin in cirrhotic and
noncirrhotic HCV genotype 1
treatment naıve and prior null
responder patients
1)
(1)
Gane (2013), Hepatology 2) Lawitz (2013), Lance, 3) Jacobson (2013), Hepatology
SOF + RBV: In genotype 4
SVR12 (%)
This study done on 60 Egyptians (G4) living in USA
20% of them are cirrhotics.
21/31
12 Week
SOF + RBV
27/29
11/14
14/14
24 Week
SOF + RBV
12 Week
SOF + RBV
24 Week
SOF + RBV
All
Ruane PJ, et al. EASL 2014. P1243
Ruane PJ, et al. AASLD 2013. Abstract 1090
Treatment
naïve
10/17
12 Week
SOF + RBV
13/15
24 Week
SOF + RBV
Treatment
experienced
Ruane PJ, et al. EASL 2014. P1243
Sofosbuvir+ Ribavirin in G4 (Egypt)
Naïve
84%
Arm 1
(12 wks)
Overall
77%
Exper
70%
100 patients
(20% C, 3 centers)
Naïve
92%
Arm 2
(24 wks)
Overall
90%
Exper
89%
(Esmat, et al AASLD.2014)
• In 51 patients GT4, received SOF + RBV for 12
weeks, SVR in 39 (77%)
– Pts who were treatment naïve, Fibrosis
stage<F3, and baseline viremia <600,000 IU
were 9 pts. All showed SVR (100%)
– Pts who were either treatment experienced,
and/or fibrosis stage >F2 and viremia level
>600,000 IU showed SVR (71%) (12 pts of
whom 8 were treatment experienced)
– P value 0.01 (S)
0= naïve, Fibrosis <F3, viremial<600,000 IU
1= treatment experienced, and/or fibrosis ≥F3, viremial >600,000 IU
SOF STUDIES
100
96
100
87
90
79
80
84
89
70
70
SVR 12 %
92
59
60
50
40
30
20
10
0
OVERALL
NAÏVE
TE
SOF/PR1 NEUTRINO SOF/RBV2 12 WK
1. Lawitz et al. DDW 2013.
2. Ruane et al. EAS L2014. Poster 1242.
3. Esmat et al,AASLD. 2014
NAÏVE
TE
SOF/RBV2 24WK
NAÏVE
TE
SOF/RBV 12W
NAÏVE
TE
SOF/RBV 24WK
EGYPTIAN
Non invasive detection of hepatic fibrosis
Fib-4 Formula
http://gihep.com/calculators/hepatology/fibrosis-4-score/
Non invasive detection of hepatic fibrosis
Fibroscan
Non invasive diagnosis of Advanced hepatic fibrosis(>F2)
AUC
No of
patients
Best
cutoff
sensitivity
specificity
PPV
NPV
accuracy
LR+
LR-
*Fib-4
0.71
36841
1.45
0.69
0.63
0.28
0.90
0.63
1.9
0.49
♠Fibroscan
0.82
231
9.5
0.82
0.87
0.68
0.93
0.86
6.52 0.20
Fibroscan
Fib-4
≤1.45
>1.45
≤9.5
Do not treat
Wait or Do liver
biopsy
>9.5
Wait or Do liver
biopsy
Treat
*National Committee for control of viral hepatitis, NNTC data , Jan 2014
♠ Esmat et al, Arab Journal of Gastroenterology 14 (2013) 109–112
PEARL 1 INTERFERON-FREE REGIMENS
OF ABT-450/R + ABT-267 WITH OR WITHOUT
RIBAVIRIN
In 135 Ch HCV GENOTYPE 4 Patients
Current and future regimens containing the new DAAs for
genotype 4 patients
Phase III
Naive
Naive
Experienced
Phase IIb
Experienced
Naive
Naive
Experienced
Naive
Experienced
Naive
100
SVR (%)
100
Experienced
No data
for
DCV/PR
27/28
SOF/PR1
NEUTRINO
11/14
10/17
SOF/RBV2
12 wk
1. Lawitz et al. DDW 2013.
2. Ruane et al. EAS L2014. Poster 1242.
3. Moreno et al. EASL 2014. Poster 1319.
4.Hézode et al.EASL2014.
4. Hézode et al. AASLD 2012. Poster 755.
14/14
13/15
SOF/RBV2
24 wk
29/35
41/72
SMV/PR*3
RESTORE
42/42
37/37
ABT-450/r +
Ombitasvir
+RBV*4
PEARL-I
(SVR4 only in
experienced)
12/12
12/12
DCV 60
mg/PR*5
COMMAND-1
EASL Guidelines: Treatment of HCV GT 4 infection
Treatment
Options
Recommendation status: Regimen
Comments by authors
Option 1
B1: PR + SOF 12 wks
„appears the most efficacious and the
easiest to use “
Evaluated in TN Neutrino SVR 96% 27/28
No data in TE
Option 2
B1: PR+ SMV 12 wks + additional PR for either
12 or 36 wks
TN: SVR 89% 31/35
Prior Relapsers: SVR 86% 19/22
Non Responders 57% 41/72
(12 wks SMV + PR; 24 wks total duration for TN & relapsers
including cirrhosis and 48 wks for Prior partials and nulls
including those with cirrhosis)
Option 3
B1: PR + DAC 60mg 24 wks
B2: 12 wks TT + additional PR for either 12 or
36 wks: (24 wks total duration for TN & relapsers including
Theoretically effective, few data available
SVR 100% in 12/12 COMMAND 1 trial
cirrhosis and 48 wks for Prior partials and nulls including those
with cirrhosis)
Option 4
C2:R + SOF 24 wks
„only preliminary data is available in
Egyptian pts“
TN 12 wks treatment: SVR 79% 11/14
TN 24 wks treatment: SVR 100% 14/14
TE 12 wks treatment: SVR 59% 10/17
TE 24 wks treatment: SVR 93% 14/15
B2: SOF+SMV 12 wks
„no data with this combination- it is likely that
data from Cosmos can be extrapolated“
IFN intolerant or
ineligible
Option 5
Consider adding RBV in patients with predictors of poor response or
in pts with cirrhosis
Option 6
B2: SOF +DAC (60mg) 12 wks TN or 24wks TE
Consider adding RBV in patients with predictors of poor
„no data with this combination- it is likely that
data can be extrapolated“
COST EFFECTIVENESS CHART
120,000 L.E
SVR %
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
COST/PT
P/R 48
12,000 L.E
P/R/SOF 12 WK
9600 L.E
*NAÏVE, NON CIRRHOTIC, LOW VIREMIA,
R/SOF 24 WK
12,600 L.E
*R/SOF 12 WK
6600 L.E
Eradication of HCV in Egypt
Overcoming the Barriers
Number of Patients with Hepatitis C in Egypt
Current Incidence (2.5/1000)
16,000,000
12,000,000
8,000,000
4,000,000
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
0
Current therapy 50% Efficacy, 50,000/yr
DAA, 90% Efficacy, 250,000/yr
Current therapy 50% Efficacy, 100,000/yr
Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Number of Patients with Hepatitis C in Egypt
90% Reduction in Incidence (0.25/1000)
16,000,000
12,000,000
8,000,000
4,000,000
2013
2014
2015
2016
2017
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
2052
2053
2054
0
Current therapy 50% Efficacy, 50,000/yr
DAA, 90% Efficacy, 250,000/yr
Current therapy 50% Efficacy, 100,000/yr
Annual mortality assumed at: 50/100,000 Or 5/1000 for HCV positive patients
Overcome the Barriers
•Ideal drug
•Decrease incidence
•Mass treatment
Ideal Drug
It is important for patients treatment
but more important for control and
eradication of any infectious
disease
Decrease incidence
•Blood safety.
•Avoid unneeded injection.
•Auto destructive syringes.
•Infection control.
•Media awareness.
•Case detection and treatment by Ideal drug
HCV in EGYPT
from Control to Eradication
To decrease HCV prevalence to< 2 % in Egypt
in 10 years(Mathematical modeling)
Effective treatment SVR > 90%
Annual treatment of 250.000 to 300.000 patients
Decrease incidence by prioritize treatment to
most frequent injectors
J.viral hepatitis,2014
HCV Treatment guidelines
(Draft)
• Priority for treatment will be directed towards
patients with F3 and F4.
• No differentiation in treatment priority will be
established based on the previous treatment
experience.
• Assessment of fibrosis stage will be performed by
using a combination of both Fibroscan results and
FIB 4 score. F3-4 stage will be considered if both
Fibroscan result is more than 9.5 and FIB4 score is
more than 1.45. If both results are below these
cut-off values, patient will not be assigned as a
treatment priority . If one of these two methods
is above the cut-off value while the other is
below, performing liver biopsy or re-assessment
after one year is recommended to rule out the
fibrosis stage of the patient.
• Upper GI endoscopy is mandatory in the
following circumstances:
a. Histological evidence of cirrhosis by liver biopsy
b. Fibroscan > 19.2 K.Pa
c. Platelet count < 100,000
• Patients who are eligible to receive Interferon
(according to the currently used
inclusion/exclusion criteria for combined IFN/RBV
treatment)will be treated with daily Sofosbuvir
(400 mg) and weight-based RBV (1000 mg [<75
kg] to 1200 mg [>75 kg]) plus weekly PEG for 12
weeks.
• Recommended regimen for patients who are not
eligible to receive IFN is daily Sofosbuvir (400 mg)
plus weight-based RBV (1000 mg [<75 kg] to 1200
mg [>75 kg]) for 24 weeks
• Inclusion criteria for treatment will be expanded
to adapt for more advanced liver fibrosis patients
(who will be treated with Interferon free
regimen) as defined with the presence of one or
more of the following;
–
–
–
–
–
–
Child score up to 8
Total bilirubin ≤ 3
Albumin ≥ 2.5
Platelet count ≥ 50,000
Prtothrombin concentration ≥ 50%
Hemoglobin concentration ≥ 10 mg
• Otherwise, waiting for new DAAs combination is
advised.
• Patients with more decompensated liver disease
will be excluded from treatment until enough
data will be available and this will be applied to:
– Child C patients with scores ≥ 9
– Presence of ascites (except after control)
– Patients with HCC except after successful radical
curative intervention (4 months after resection or
successful local ablation) evident by triphasic CT.
– Presence of large risky esophageal varices (except
after prophylactic management)
• Age limits for treatment legibility will be
above 18 years and below 70 years for all
patients while BMI will be accepted up to 35.
• The same rules will be applied for all patients
regardless the source of payment and there
will be no role for patients' preferences in
deciding the treatment regimen.
• For special population groups; priority for
treatment will be offered for post liver
transplantation, post kidney transplantation
patients and combined HCV/HBV infection
regardless the fibrosis stage
• . Other groups like Pediatric age group and kidney
disease patients will be kept for discussion after
the availability of enough data.
• Patients with documented extra-hepatic
manifestations will be prioritized for
treatment according to the same guidelines.
• Treatment experienced patients should not
start evaluation for new treatment regimens
except after 6 months from cessation of
interferon therapy.

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