Update Chronic Hepatitis C TreatmentUpdate Chronic Hepatitis C TreatmentUpdate Chronic Hepatitis C TreatmentUpdate Chronic Hepatitis C Treatment
DAADAADAADAA
2016.9.212016.9.212016.9.212016.9.21
ChienChienChienChien----Heng, ShenHeng, ShenHeng, ShenHeng, Shen
Department of HepatogastroenterologyDepartment of HepatogastroenterologyDepartment of HepatogastroenterologyDepartment of Hepatogastroenterology
Chang Gung Memorial HospitalChang Gung Memorial HospitalChang Gung Memorial HospitalChang Gung Memorial Hospital
Outline
� CHC epidemiology and treatment
� DAA
2
� DCV/ASV clinical trial : efficacy vs safety
� DCV/ASV real world data
CHCCHCCHCCHC Epidemiology Epidemiology Epidemiology Epidemiology and and and and TreatmentTreatmentTreatmentTreatment
HCV Structural and Nonstructural Proteins
E1 E2
NS2
NS4A
NS4B3' UTR
p7
5' UTRNS5B4
ACore E1 E2
NS
2
NS3 NS5A
Structural proteins Nonstructural proteins
IRES
ER lumen
SPP
4
C
Cytosol
NS2
NS3 NS5ANS5B
NS4B
• Single-stranded positive sense RNA genome
– 10 genes encoding structural & non-structural proteins
– Non-structural proteins essential for viral replication
UTR = untranslated region; IRES = internal ribosome entry site.
Moradpour and Penin. Curr Top Microbiol Immunol. 2013;369:113; Parfieniuk et al. World J Gastroenterol. 2007;13:5673.
SPP
p7
Natural History
5
Geographic variation and distribution of HCV genotypes
1a
3
4 5
Spain
12
3
4Germany
1a
1b1
23
4 5France
1a
1b
2a
2c3
6
China
1a
1b
2a
3a
Russia
1a
12
3a
3 4
UK1a
1b1
2
34
Canada
1a1b
2a
2b3 46
US
13
Egypt
1a
2a
2b 3
Japan1a1b
2a
3a
3b4
Pakistan
4 6
India
6
© John Wiley & Sons 2011. Reproduced with permission from Negro F, Alberti A. Liver Int 2011;31 Suppl 2:1–3
1a
1b
2b
3Brazil
1b2
3 1b
12
3Argentina 1
234
5
South Africa
13
41
234
Saudi Arabia
1b1
23
4 6
HCV genotypes 1 and 3 are the most prevalent genotypes globally
1a
12
3
4 6
Australia
1b
HCV genotype 1b is the major genotype in most countries in Asia Pacific
1a
1b2a
2c3 6
China1a
1b2a
3a
3b4
Pakistan
4 6
India
1a
1b2a
2b 3
Japan
1a
2a
2b
Korea
1b
7
© John Wiley & Sons 2011. Reproduced with permission from Sievert W et al. Liver Int 2011;31 Suppl 2:61–80
1a
12
3
4 6
Australia
1
23
4 6
1b
1a
2a2c3a
3b 6
Thailand1a
3a3b
6
Vietnam
1b
1b
1a
1b
2b
2
3aTaiwan
• Prevalence rate: 2~4% (0.4~0.8M), mainly >60 yrs
• GT Distribution: GT1b=54% and GT2=45%GT1a & GT3: rare
HCV genotype 1b patients are at increased risk of HCC
• REVEAL-HCV: Cumulative incidence of HCC by HCV subtype in Taiwan
HCV subtype 1b (n=270)
HCV subtypes 1a, 2a, 2b* (n=207)HCV RNA <1000 IU/mL (n=388)
Cum
ulat
ive
risk
of H
CC
(%
)
30
40
29.7%
0.3
0.4
P=0.0098
HCV Genotype 1, N=738, 29.4%
Cu
mu
lati
ve i
nci
den
ce Adjusted HR** P= 0.017
• 1,619 patients from LK-CGMH, KCGMH, KMUH• IFN-based therapy, n=1057; untreated, n=562; mean FU, 5.16 y (1-16 y)
Community Cohort Hospital Cohorts
8
* HCV genotype 3 is not a major HCV genotype in Taiwan.
Lee M-H et al. Int J Cancer 2014;135:1119–1126.
Age (years)
P for entire cohort: <0.001
Cum
ulat
ive
risk
of H
CC
(%
)
0
10
20
30 35 40 45 50 55 60 65 70 75 80
29.7%
19.2%
6.5%
0 2 4 6 8 10 12 14 160.0
0.1
0.2
P=0.0098
HCV Genotype non-1, N=881, 21.2%
year of follow-up
Cu
mu
lati
ve i
nci
den
ce Adjusted HR** 1.629 (1.09–2.42)
P= 0.017
Yu ML, et al., Antiviral Therapy, 2006;11:985-94.Yu ML, et al., Hepatology, 2006;44:1086-97.
**After adjustment for age, sex, hepatic fibrosis, achievement of SVR.
Urgency of Successful Treatment for Patients infected with HCV G1b!
Evolution of CHC treatment
9
D. A. A.D. A. A.D. A. A.D. A. A.(DDDDirect irect irect irect AAAActing cting cting cting AAAAntiviralsntiviralsntiviralsntivirals)
HCV Life Cycle and DAA Targets
Receptor bindingand endocytosis
Fusion and
uncoating
Transportand release
(+) RNATranslation and
polyprotein processing
Virionassembly
LDER lumen
LD
12
1. Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
processing
RNA replication
assembly
Membranousweb
ER lumen
LD
LD
NS3/4 protease inhibitors
NS5B polymerase inhibitors
• Nucleoside/nucleotide• Nonnucleoside
Block replication complex formation, assembly
NS5A inhibitors
RNA replicationBoceprevir
Telaprevir
Asunaprevir
Simeprevir
Paritaprevir
Grazoprevir
Sofosbuvir
Dasabuvir
Beclabuvir
Daclatasvir
Ledipasvir
Ombitasvir
Elbasvir
Daklinza/Sunvepra indication
13
Ref.: Taiwan Product Information
Daklinza/Sunvepra scientific data
Clinical Trial� 036 study including TW, CHINA, KR with 159 patients : 99% SVR
without RAV� Pooled analysis including 6 study 729 patients : 95% SVR without RAV
(high SVR irrespective of age and cirrhosis status )� 046 study : 99.7% durability
14
Real-world data� Clinical practice and real-world experience in Japan
– Overall SVR in general HCV GT1b patients– Elderly patients– Cirrhotic patients – Special population: CKD/Dialysis
� Korea RWD
DCV/ASV DCV/ASV DCV/ASV DCV/ASV Clinical TrialClinical TrialClinical TrialClinical Trial
Efficacy Efficacy Efficacy Efficacy vs vs vs vs SafetySafetySafetySafetyEfficacy Efficacy Efficacy Efficacy vs vs vs vs SafetySafetySafetySafety
DAA treatment outcome in IFN ineligible/intolerant patients - DCV/ASV phase III, open-label study in Asia(AI447-036)
Week 48
Primary
endpoint: SVR24
DCV + ASV
24 weeks
Follow-up
24 weeks
Week 0 Week 24
GT-1b
IFN-ineligible or
intolerant
N = 159
Week 36
Secondary
endpoint: SVR12
16
1. Wei et al. APASL 2016; Oral Presentation O-050.
2. Wei et al., J Gastroenterol Hepatol. 2016 Mar 22. doi: 10.1111/jgh.13379
Regimen
• DCV 60 mg QD + ASV 100 mg
BID
• 24 weeks of treatment
Patients, N = 159
• GT-1b infection
• Prior intolerance of IFN/RBV
or naive and ineligible for
IFN and/or RBV
• Compensated cirrhosis
permitted, capped at ~40%
Countries
• China (n = 127)
• Korea (n = 17)
• Taiwan (n = 15)
endpoint: SVR24endpoint: SVR12
DCV/ASV phase III study in Asia(AI447-036) - baseline demographics and disease characteristics
ParameterChina
N = 127
Korea
N = 17
Taiwan
N = 15
Total
N = 159
Age, median years (range)
≥ 65, n (%)
≥ 70, n (%)
54 (20–74)
14 (11)
3 (2)
59 (41–72)
5 (29)
3 (18)
66 (53–71)
9 (60)
1 (7)
56 (20–74)
28 (18)
7 (4)
Female, n (%) 82 (65) 10 (59) 12 (80) 104 (65)
HCV RNA, median log10 IU/mL (range) 6.75 (4.0–7.8) 6.58 (4.1–7.6) 6.70 (5.6–7.2) 6.71 (4.0–7.8)
17
GT, genotype; HCV, hepatitis C virus; IFN, interferon; IL28, interleukin 28
Majority were traditional difficult-to-treat population in IFN era
HCV RNA, median log10 IU/mL (range)
HCV RNA ≥ 800,000 IU/mL, n (%)
6.75 (4.0–7.8)
117 (92)
6.58 (4.1–7.6)
13 (76)
6.70 (5.6–7.2)
14 (93)
6.71 (4.0–7.8)
144 (91)
IL28B non-CC GT, n (%) 56 (44) 4 (24) 4 (27) 64 (40)
Cirrhotic, n (%) 42 (33) 6 (35) 4 (27) 52 (33)
IFN-ineligible, n (%)
IFN-intolerant, n (%)
Both, n (%)
46 (36)
97 (76)
16 (13)
10 (59)
9 (53)
2 (12)
6 (40)
11 (73)
2 (13)
62 (39)
117 (74)
20 (13)
1. Wei et al. APASL 2016; Oral Presentation O-050.
2. Wei et al., J Gastroenterol Hepatol. 2016 Mar 22. doi: 10.1111/jgh.13379
SVR (sustained viral response) : cure in CHC
� SVR (sustained viral response) : undetected HCV RNA 12 weeks (SVR12) or 24 weeks (SVR 24) after treatment completion
18
� HCV is cured (does not relapsed) in > 99% of patients who achieve SVR
99% SVR24 achieved from DCV/ASV treatment in patients without baseline NS5A RAV (L31 or Y93)
40
60
80
100
Pa
tie
nts
wit
h S
VR
24
(%
)
44 42
9298 99
With baseline NS5A RAVs Without baseline NS5A RAVs
19
a114/116 (98%) from mainland China. Excludes patient who died on Day 25 (HCV RNA 29 IU/mL at Week 2); patient had no baseline NS5A-L31 or -Y93 RAVs.HCV, hepatitis C virus; NS3, non-structural protein 3; NS5A, non-structural protein 5A; RAV, resistance-associated variant; Included with permission Wei et al. APASL 2016; Oral Presentation O-050.
• 137/139 (99%)a patients without baseline NS5A RAVs achieved SVR24
• 43/44 (98%) with cirrhosis, 94/95 (99%) without cirrhosis
• Baseline NS5A RAVs(L31M or Y93H) present in 19 patients (12%)
• 8/19 (42%) achieved SVR24
0
20
L31M Y93H L31M or Y93H
Pa
tie
nts
wit
h S
VR
24
(%
)
8
19
8
18
145
157
137
140
137
139
0
1
DCV/ASV 036 study: on-treatment adverse events
Parameter, n (%)China
N = 127
Korea
N = 17
Taiwan
N = 15
Total
N = 159
AEs leading to discontinuation 2 (2)a 0 0 2 (1)
Serious AEs 3 (2)b,c 0 2 (13)d 5 (3)
Death 1 (1)b 0 0 1 (1)
AEs (any grade), > 5% 93 (73) 12 (71) 12 (80) 117 (74)
Upper respiratory tract infection 7 (6) 0 6 (40) 13 (8)
20
• No serious AEs were considered treatment-related
• One death (and preceding serious AEs), not considered treatment-related
Upper respiratory tract infection 7 (6) 0 6 (40) 13 (8)
Pruritus 6 (5) 2 (12) 1 (7) 9 (6)
aTreatment-related grade 3 bilirubin increase; LDH increase and anaemia.
bPatient with coronary artery disease with malignant arrhythmia and Adams–Stokes syndrome died Day 25 (did not receive
amiodarone).
cSudden hearing loss with arteriosclerosis of coronary artery; femoral neck fracture.
dHCC; pneumonia.
AEs, adverse events; HCC, hepatocellular carcinoma; LDH, lactate dehydrogenaseWei et al. APASL 2016; Oral Presentation O-050.
DCV/ASV 036 study summary
� 99% SVR24 in Asia patients without baseline NS5A RAVs from 036 study– majority patients with characteristic of traditional difficult-to-treat:
high viral load, IL28B non-CC, and cirrhosis.
� No treatment-related serious AEs or grade 4 laboratory
21
� No treatment-related serious AEs or grade 4 laboratory abnormalities
� Infrequent (1%) discontinuations due to AEs
� DCV+ASV is a highly efficacious and well-tolerated treatment for patients with HCV GT-1b infection, particularly those without baseline NS5A RAVs
Wei et al. APASL 2016; Oral Presentation O-050.
DCV/ASV Pooled-analyses data
High SVR With DCV + ASV in HCV GT 1b Mainland
Chinese, Koreans, and Taiwanese Without Baseline
Resistance-Associated NS5A Polymorphisms
McPhee F,1 Wei L,2 Xie Q,3 Suzuki Y,4 Toyota J,5 Karino Y,5 Chayama
K,6 Kawakami Y,6 Yu ML,7 Ahn SH,8 Zhou N,1 Kumada H.4
22
McPhee F, et al. APASL 2016; Poster P-0102.
K, Kawakami Y, Yu ML, Ahn SH, Zhou N, Kumada H.
1Bristol-Myers Squibb Research and Development, Wallingford, CT, USA; 2Peking University People’s
Hospital, Beijing, China; 3Shanghai Ruijin Hospital, Shanghai, China; 4Toranomon Hospital, Tokyo, Japan; 5Sapporo Kosei General Hospital, Sapporo, Japan; 6Hiroshima University, Hiroshima, Japan; 7Kaohsiung
Medical University Hospital, Kaohsiung, Taiwan; 8Yonsei University College of Medicine, Seoul, South
Korea.
The 25th Conference of the Asian Pacific Association for the Study of Liver
(APASL 2016) Tokyo, Japan, February 20–24, 2016
Studies included in the pooled analyses
StudyClinicalTrials
IDPhase Patients
Countries
included
Analyzed for
BL NS5A RAVs
No. in
SVR12
analyses
AI447-0171 NCT01051414 2Nonresponders or IFN/RBV
intolerant or ineligibleJapan 33 32
AI447-0262 NCT01497834 3Nonresponders or IFN/RBV
intolerant or ineligibleJapan 214 211
AI447-0283 NCT01581203 3Naive, nonresponders or
IFN/RBV intolerant or ineligible
Korea
Taiwan125 124
23
IFN/RBV intolerant or ineligible Taiwan
AI447-0314 NCT01718145 3 Naive and IFN-relapsers Japan 129 129
AI443-1175 NCT02123654 3 Naivea Japan 75 75
AI447-0366 NCT01995266 3 IFN/RBV intolerant or ineligible
China
Korea
Taiwan
159 158
• A total of 735 patients were included in the analysis of baseline NS5A polymorphisms at L31 and Y93H
• A total of 729 patients were included in the SVR12 analyses
a Only treatment-naive patients who received DCV + ASV in Study AI443-117 were included in
these analyses.
BL, baseline; IFN, interferon; No., number; RAV, resistance-associated variant; RBV, ribavirin; SVR,
sustained virologic response.
1. Suzuki Y, et al. J Hepatol 2013;58:655–662. 2. Kumada H, et al. Hepatol 2014;59:2083–2091.
3. Manns M, et al. Lancet 2014;384:1597–1605. 4. Kumada H, et al. J Gastroenterol Hepatol
2016;31:14–22. 5. Chayama K, et al. 25th APASL; Feb 20–24, 2016; Tokyo, Japan. Oral Presentation
O-7. 6. Wei L, et al. 66th AASLD; Nov 13–17, 2015; San Francisco, CA, USA. Poster LB-18.
McPhee F, et al. APASL 2016; Poster P-0102.
Baseline Characteristics
24
BL NS5A sequences were not available for 3 Korean, 9 Taiwanese, and 20 Japanese patients.
BL, baseline; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin.
McPhee F, et al. APASL 2016; Poster P-0102.
Result - Prevalence of baseline NS5A polymorphisms in GT-1b
Pro
po
rtio
n w
ith
NS
5A
po
lym
orp
his
m (
%)
12.5
13.8
15.6
18.2
16.0
18.8
10
12
14
16
18
20Mainland China (n=127)
Korea (n=80)
Taiwan (n=77)
Japan (n=451)
25
• The prevalence of NS5A-L31F/I/M/V or NS5A-Y93H was lowest among patients from mainland China and
highest in Taiwanese and Japanese patients
• NS5A-Y93H prevalence in mainland China was similar to that previously reported for patients from non-Asian countries (7.2%)1
GT, genotype.
1. McPhee F, et al. Adv Ther 2015;32:637–649.25
1/127 1/80
2
77
16
449
9
127
10
80
12
77
72
449
10
127
11
80
14
77
85
449Pro
po
rtio
n w
ith
NS
5A
po
lym
orp
his
m (
%)
0.8
7.17.9
1.3
2.63.5
0
2
4
6
8
10
L31F/I/M/V Y93H L31F/I/M/V or Y93H
1/127 1/80
2
77
16
451
9
127
10
80
12
77
72
451
10
127
11
80
14
77
85
451
McPhee F, et al. APASL 2016; Poster P-0102.
95.6% SVR in patients without RAVS
VR
12
(%
)
87.7
94.3 95.6
50
60
70
80
90
100With L31F/I/M/V and/or Y93H Without L31F/I/M/V and/or Y93H
26
• SVR12 to DCV + ASV treatment was 96% in the absence of baseline L31F/I/M/V and/or Y93H
• The SVR12 rate was ≈ 40% where either or both these polymorphisms were present at baseline
8
20
622
707
40
102
590
625
48
119
582
608
8
20
620
707
39
102
589
625
47
119
581
608
SV
R1
2 (
%)
40.0 38.2 39.5
0
10
20
30
40
50
L31F/I/M/V Y93H L31F/I/M/V or Y93H
8
20
622
709
39
102
591
627
47
119
583
610
McPhee F, et al. APASL 2016; Poster P-0102.
Higher and Similar SVR12 Rates in the Absence of Baseline L31F/I/M/V and/or Y93H in Irrespective of Age or Cirrhosis status
SV
R12
(%
)
Mainland China (n = 126) Taiwan (n = 76)
SV
R12
(%
)
27
• In the absence of baseline L31/F/I/M/V and/or Y93H,
SVR12 rates were high and similar across national groups irrespective of age or cirrhosis status.
All
Korea (n = 80) Japan (n = 447)
< 65 years ≥ 65 years LC w/o LC All < 65 years ≥ 65 years LC w/o LC
All
SV
R12
(%
)
< 65 years ≥ 65 years LC w/o LCAll
SV
R12
(%
)
< 65 years ≥ 65 years LC w/o LC
McPhee F, et al. APASL 2016; Poster P-0102.
Conclusions from Pooled-analyses data
� The all-oral, RBV-free regimen of DCV + ASV was highly efficacious for treatment of GT-1b without baseline NS5A-L31 or NS5A-Y93H resistance-associated polymorphisms– SVR12 rates of up to 100% across subgroups including the elderly (>
65 years of age) and patients with cirrhosis– Pre-therapy screening for NS5A polymorphisms at L31 and Y93H may
be beneficial
28
be beneficial
� These findings are consistent with earlier data in Japanese and non-Asian patients and in a smaller pooled group of Korean and Taiwanese patients1
ASV, asunaprevir; DCV, daclatasvir; GT, genotype; RBV, ribavirin; SVR, sustained virologic
response.
1. McPhee F, et al. Adv Ther 2015;32:637–649.
McPhee F, et al. APASL 2016; Poster P-0102.
Durability of SVR from DAA treatment:prospective, observational follow-up study of patients who participated in DCV or DCV/ASV clinical trials (AI444-046)
24 14448
Previous participants in
DCV and/or ASV trials
(N = 1850)
Observational study
Week 0 1209672
Primary endpoint: durability of SVR through follow-up
Minimum five study visits (in bold)
29Reddy. AASLD 2014; Poster 1965.
Regimen
• observational study
• 3-year follow-up after
treatment in parent
studies
Patients
• Estimated 1850
• GT-1, -2, -3, -4
• SVR or non-SVR
Countries
USA, Argentina , Australia, Brazil,
Canada, Denmark, France,
Germany, Ireland, Italy, Japan,
Mexico, Poland, Puerto Rico, S
Korea, Spain, Sweden, Taiwan, UK
Assessments include virologic and disease parameters
• HCV RNA levels: durability of SVR achieved in parent study
• Persistence of RAVs in patients with virologic failure (non-SVR) in parent study
99.7 100 100 98.7 97.6
40
60
80
100
Pa
tie
nts
(%
)
SVR maintained to last follow-up visit Relapse between SVR12 and post-treatment Week 24 Relapse after SVR24
Durability of SVR12 from DCV or DCV/ASV treatment (046 study) : <1% relapse rate
DCV based, IFN-free regimen: 0.2% relapse (1/525) DCV/PR regimen: 2% relapse (8/405)
w39 w73<w24<w24
30
1.3 2.00.3a0.4b
0
20
Pa
tie
nts
(%
)
DCV + ASV DCV + ASV +
BCV ± RBV
DCV + SOF
± RBV
DCV + ASV +
pegIFN/RBV
DCV +
pegIFN/RBV
345346
1346
108108
7171
154156
243249
2156
5249
1249
• Overall 9 of 930 patients(<1%) with SVR12 in the parent studies experienced relapse after SVR12
– 8 relapses occurred in patients receiving pegIFN/RBV-containing regimens; all were IL28B-CT
– 7 occurred between post-treatment Weeks 12 and 24 during parent treatment study
– 2 occurred after SVR24
aRelapsed post-treatment Week 39. bRelapsed post-treatment Week 73.
ASV, asunaprevir; BCV, beclabuvir; DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; pegIFN, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained
virologic response; SVR12/24, sustained virologic response at post-treatment follow-up Week 12/24.
Reddy et al. AASLD 2014; Poster 1965.
046 study: Sustained SVR were achieved in >99% patients receiving DCV-based regimen
� Durability of RNA undetectable was achieved in patents with SVR12 after 3-years follow-up– >99% of patients (921/930) maintain the durability
– Only 2 patients experienced relapse after post-treatment Week 24
– Long term benefit could be expected to reverse disease progression, to regress fibrosis/cirrhosis, and to reduce HCC risk.
31
to regress fibrosis/cirrhosis, and to reduce HCC risk.
� For patients who failed with DCV-containing regimen– Pre-existing NS5A RAVs was observed and persist in most
treatment failure patients.
– Exclusion of baseline NS5A RAV can ensure high SVR and durability.
Reddy et al. AASLD 2014; Poster 1965.
DCV/ASV DCV/ASV DCV/ASV DCV/ASV Real World DataReal World DataReal World DataReal World Data
DCV/ASV Japan Real World Data
1st presented by Kazuaki Chayama, Hiroshima University
2016 APASL STC on HCV satellite symposium, Kaohsiung, Taiwan
Japan RWD: in ~500 patients data, SVR 97% was achieved in patients with <25% RAV
Overall
SVR
100
(%)
80
60
97%
(385/396)
97%
(29/30)
67%
(8/12)
100%
(26/26)
Overall ETR: 96.7% (491/508)
50%
(6/12)
80%
(24/30)
SVR for RAV <25%:
97% (407/422)
ETR SVROverall SVR: 94.1% (478/508)
SVR for RAV >25%:
71% (30/42)
34
NS5A-L31/Y93 RAVs
0
40
60
20
<1% 25-75% 75-100%1-25%
(6/12)
<1% 1-25% 75-99%25-75%
Kazuaki Chayama et al., 1st presented at APASL STC 2016 TW
� genotype 1b: 508� Male 262 / Female 246� Age: median 74 years (23-90)� Simeprevir+PegIFN/RBV failure 13 cases
Elderly: patients ≥75 years shows 97.1% SVRElderly
ETR SVR
100
(%)
80
60
Fre
qu
en
cy94.1%
(160/170)
98.6%
(138/140) 92.4%
(157/170)
97.1%
(136/140)
n.s.n.s.
35
0
40
60
20
Fre
qu
en
cy
Younger
<75 years
Older
≥75 years
Younger
<75 years
Older
≥75 years
Kazuaki Chayama et al., 1st presented at APASL STC 2016 TW
Liver cirrhosis: patients with cirrhosis shows 92.6% SVR
Cirrhosis
ETR SVR
100
(%)
80
95.1%
(156/164)
94.7%
(90/95)
93.9%
(154/164)
92.6%
(88/95)
p = 0.891 p = 0.691
36Kazuaki Chayama et al., 1st presented at APASL STC 2016 TW
0
40
80
60
20
cirrhosischronichepatitis cirrhosischronic
hepatitis
>95% SVR in renal impairment patient groupCKD
60
80
100
Dis
ap
pe
ara
nce
of
seru
m H
CV
RN
A(%
)
95.995.1
100� 226 patients underwent DCV and ASV
therapy Sep. 2014-May 2015
37Kazuaki Chayama et al., 1st presented at APASL STC 2016 TW
eGFR: >60 eGFR: 45-60 eGFR: <45
0
20
40
60
�2W �4W �8W �12W �EOT �SVR4 �SVR12
Dis
ap
pe
ara
nce
of
seru
m H
CV
RN
A
2W 4W 8W 12W EOT PT4(SVR4)
PT12(SVR12)
Weeks after treatment initiation
eGFR (ml/min/1.73m2)
Hemodialysis: patients with dialysis show 100% SVR
Dialysis
• Design: DCV/ASV 24 weeks for HCV-1 patients on hemodialysis (n = 28), with propensity score-matched 56 patients without renal dysfunction
HD (n =
28)
No renal
dysfunction
(n = 56)
p value
Age, y 65.5 ± 9.5 65.9 ± 11.6 0.6314
Gender, M/F16/12
(57.1/42.9)
29/27
(51.8/48.2)0.6422
Cirrhosis 11 (39.3) 22 39.3) 1.000
HC
V R
NA
< L
LOQ
(%
)
38
Hb, g/dL 11.8 ± 1.1 13.7 ± 1.6 < 0.0001
PLT, 103/μL 148 ±51 146 ± 67 0.5853
Cre, mg/dL 7.16 ± 1.90 0.73 ± 0.40 < 0.0001
eGFR,
ml/min/1.73
m2
6.9 ± 2.4 80.9 ± 24.5 < 0.0001
ALT, IU/L 19.1 ± 9.5 54.5 ± 24.5 < 0.0001
HCV RNA,
log10 IU/mL5.89 ± 0.91 6.01 ± 0.60 0.9507
HCV NS3
D168 mutant0 (0) 1 (1.8) 0.4808
IL28B
rs8099917 GG5 (17.9) 14 (25.0) 0.4607
* One patient discontinued treatment at week 12 due to ALT to 187 IU/L
Toyoda H, et al. J Gastroenterol 2016 [Epub ahead of print]
Selected baseline characteristics Haemodialysis
patients
(N = 21)
Age, median years (range) 63 (50–79)
Compensated cirrhosis, n (%) 4 (19.0)
HCV RNA,
median (range), log10 IU/mL5.7 (2.9–6.8)
ALT (IU/L), median (range) 18 (9–55)
N = 21 patients with GT-1b, n = 1 with GT-1a
and n = 1 unknown received DCV + ASV at
Hokkaido University Hospital and associated
hospitals, Hokkaido, Japan
(Jan–Nov 2015)
• 15/21 (71%) male
Virologic outcome
Hemodialysis: patients with dialysis show 95.5% SVR
Dialysis
39
Previous treatment history, n (%)
Naive
Relapse
15 (71.4)
2 (9.5)
HD duration, years (range) 7 (1.5–33)
Baseline NS5A RAVs (Y93H), n (%) 3 (14)
85.795.5 95.5
4.5
0
20
40
60
80
100
RVR SVR4 SVR12 Relapse
Pa
tie
nts
(%
)
Safety
• Grade 3–4 abnormalities (elevated ALT and platelets) were detected in
one patient who achieved SVR12, but discontinued treatment at 12
weeks after treatment
• One serious AE (HCC) was detected at the end of therapy in one patient
with previous history of HCC
• Other common AEs: anaemia, nasopharyngitis and increased ALT
18
2120
21
20
21
• 95% patients achieved SVR12, including those
with cirrhosis and NS5A RAV
• One patient experienced virologic relapse 4
weeks post-treatment
Virologic outcome
Adapted from Suda et al. J Gastroenterol. 2016: DOI:10.1007/s00535-016-1162-8.
2016 JSH Guideline Recommendation by CKD stage
eGFR
(mL/min/1.73m2)
1 2 3 4 5 5D
≧≧≧≧90
(Normal)
60~~~~89
(Mild)
30~~~~59
(Moderate)
15~~~~29
(Severe)
<15
(Kidney failure)
(Dialysis)
GT1
NS5A
RAV(+) SOF/LDV SOF/LDV SOF/LDV (No Recommendation available)
1.SOF/LDV 1.SOF/LDV1.SOF/LDV
CKDStage
40
GT1
GT2
NS5A
RAV(-)
SOF/RBV (SOF/RBV)
DCV/ASV DCV/ASV DCV/ASV1.SOF/LDV
OBV/PTV/r
2.DCV/ASV
1.SOF/LDV
(OBV/PTV/r)
2.DCV/ASV
1.SOF/LDV
OBV/PTV/r
2.DCV/ASV
Japan society of Hepatology,Guideline of the Management of Hepatitis C Virus Infection May 2016 (Ver.5)
Japanese MLHW* 2016 Treatment Guidelines for Dialysis Patients with HCV Infection
Dialysis patients with HCV Genotype 1
Initial treatment, Daclatasvir + asunaprevir 24 weeks
(ombitasvir/ paritaprevir/ ritonavir 12 weeks)Re-treatment
41*MLHW: Ministry of Labor Health and Welfare
� For dialysis patients with HCV infection, daclatasvir + asunaprevir therapy is the first-line
treatment at present based on actual clinical evidence.
� Prior to therapy, the absence of resistance mutations in the NS5A region (Y93 and L31) should be
confirmed.
� Dialysis patients are often on multiple medications; thus, it is important to review drug
interactions beforehand.
� In dialysis patients, serum ALT levels are reported to be lower than usual.
� If liver injury occurred during therapy, the patient should be carefully monitored, and a dose
reduction or discontinuation should be considered.
Japanese MLHW. Guidelines for the Treatment of Chronic Hepatitis C and Cirrhosis for Fiscal Year 2016
The real-life data of daclatasvir and asunaprevir treatment in Korean patients with hepatitis C
genotype 1b infection
Hye Won Lee1, Beom Kyung Kim1-3, Seung Up Kim1-3, Jun Yong Park1-3
Do Young Kim1-3, Sang Hoon Ahn1-3, and Kwang-Hyub Han1-3
1Department of Internal Medicine, 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; 3Yonsei Liver Center, Yonsei University Health System, Seoul, Korea
� The use of DCV+ASV was approved by Korean health insurance 2015 August.
� Between August 2015 and March 2016, a total of 161 patients with chronic hepatitis C (CHC) who finished treatment with DCV+ASV at Severance hospital were analyzed.
Methods
� The patients received DCV (60mg once daily) plus ASV (100mg twice daily) for 24 weeks.
� End of Treatment Response (ETR) and Sustained Virological Response at post-treatment week 12 (SVR12) and safety outcomes were evaluated.
Ref: The Liver Week 2016, Free paper O-039
Week 4Week 4Week 4Week 4 Week 12Week 12Week 12Week 12 EOTEOTEOTEOT PostPostPostPost----Week 12Week 12Week 12Week 12
Severance hospital data
278 218 188 161 48
Number of DCV/ASV treated patients at Yonsei Liver Center till 10Jun 2016
278 218 188 161 48
DCV + ASV for 24 weeks
Week240 36
DCV 60 mg once-daily
ASV 100 mg twice-daily
Treatment Treatment Treatment Treatment
12-week f/u
Ref: The Liver Week 2016, Free paper O-039
THE FIRST AND THE BEST
THE FIRST AND THE BESTsince 1885since 1885
Baseline characteristics
Variables Values (n=161)
Age, years 66.0 (27-86)
<65 years 74 (46.0)
≥ 65 years 87 (54.0)
Male 59 (36.6)
Prior HCV therapy
Treatment-naïve 90 (55.9)
Non-responders 25 (15.5)
IFN/RBV ineligible/intolerant 29 (18.0)
Relapsers 17 (10.6)Relapsers 17 (10.6)
HCV RNA, log10 IU/ml 6.1 (2.3-7.3)
AST (IU/L) 47.5 (17-281)
ALT (IU/L) 33 (5-193)
Liver stiffness values (kPa) 8.2 (3-75)
Cirrhosis 51 (31.7)
Hepatocellular carcinoma 20 (12.4)
Baseline NS5A polymorphism (n=150)
Y93H only 17 (11.3)
L31F/I//M/V only 5 (3.3)
Values are expressed as median (range) or n(%).
Ref: The Liver Week 2016, Free paper O-039
THE FIRST AND THE BEST
THE FIRST AND THE BESTsince 1885since 1885ETR and SVR12 rates according to
Baseline NS5A RAVS
100.0 95.2
82.4
97.0
86.4
96.9
66.7
92.7
83.3
92.1
77.8
94.3
60
80
100
ETR (n=150) SVR12 (n=44)
%
55/58 42/45
67/70 19/23 17/18
0
20
40
■ With L31F/M/V or Y93H
■ Without L31F/M/V or Y93H
L31F/M/V Y93H L31F/M/V
or Y93HL31F/M/V or Y93HL31F/M/V Y93H
5
5
138
145
14
17129
133
19
22
124
128
2
3
38
415
6
35
387
9
33
35
Ref: The Liver Week 2016, Free paper O-039
Conclusion
� DCV/ASV is efficacious and safe treatment of CHC from clinical trial and real world data
47
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