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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.


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.


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


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


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


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.


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


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(%).


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


Conclusion

� DCV/ASV is efficacious and safe treatment of CHC from clinical trial and real world data

47

Thank You for Your Attention !Your Attention !

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