the role of new combination therapies without interferon for … · 2015. 5. 20. · the role of...
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The Role of New Combination
Therapies without Interferon
for Chronic HCV Infection
Wan-Long Chuang
Hepatobiliary Division
Department of Internal Medicine
Kaohsiung Medical University Hospital, TAIWAN
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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Adapted from Mohd Hanafiah et al., Hepatology 2013; 57: 1333
> 3.5%
1.5 – 3.5%
< 1.5%
Age-Specific HCV Worldwide Prevalence • 122 millions (2.3%) in 1990 185 millions (2.8%) in 2005
• > 111 million HCV-infected people reside in East, South, and South East Asia
East Asia
> 50 M
South Asia
> 50 M
HCV control is a critical issue in Asia
SE Asia
> 11 M Estimated data from Global Burden of Diseases, Injuries, and Risk Factors 2010 (GBD2010) Study, including data published up to 2007 in peer review and U.S. NHANES data up to 2010
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Hepatitis C Virus Prevalence in
Asian Pacific Region
Sievert et al, Liver Int 2011; 31 (Suppl 2): 61
1-1.9%
14.9% 3-5%
15.6%
4.4%
2-3%
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Distribution of HCV Genotypes in Asia Pacific Region
Yu & Chuang. J Gastroenterol Hepatol 2009;24:336
China
HCV-1: 69%
HCV-2: 13%
Else: 18%
Middle-East
HCV-1: 2%
HCV-4: 91%
Else: 7%
India
HCV-1: 14%
HCV-2: 6%
HCV-3: 67%
HCV-4: 3%
Else: 11%
Southeast Asia
HCV-1: 74%
HCV-2: 4%
HCV-3: 23%
Korea
HCV-1: 68%
HCV-2: 25%
Else: 8%
Japan
HCV-1: 67%
HCV-2: 30%
HCV-3: 1%
Else: 2%
Taiwan
HCV-1: 53%
HCV-2: 40%
Else: 8%
Macau, Vietnam,
Hong Kong
HCV-1: 50%
HCV-2: 8%
HCV-3: 7%
HCV-6: 30%
Else: 5%
Australia/ New Zealand
HCV-1: 52%
HCV-2: 9%
HCV-3: 32%
HCV-4: 6%
HCV-6: 2%
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Natural History of HCV Infection
Exposure (Acute phase)
Resolved Chronic
Cirrhosis Stable
Slowly
Progressive HCC
Transplant
Death
20%
20% 60-80%
25%
80%
75%
HIV and
Alcohol
Alter MJ. Semin Liver Dis 1995; 15: 5-14
Management of Hepatitis C: NIH Consensus Statement 1997
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Potential Benefits of
Sustained Virologic Response (SVR)
* Decreased infectivity
* Decreased risk for cirrhosis or decompensation
* Decreased risk for hepatocellular carcinoma
* Improved survival
* Improved quality of life
1. Serfaty et al. Hepatology 1998; 2. Mazella et al. J Hepatol 1996;
3. Niederau et al. Hepatology 1998; 4. McHutchinson et al. J Hepatol 2001
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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Standard IFN -2b as Initial Therapy for
Chronic Hepatitis C
McHutchison et al. NEJM 1998; 339: 1485
Poynard et al. Lancet 1998; 352: 1426
20%
40%
60%
80%
IFN 24 wk IFN 48 wk
6%
13% 19%
0%
US trial
International trial
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SVR to 24-Week IFN/Ribavirin Combination Therapy
and IFN Monotherapy in CHC Patients
0%
20%
40%
60%
80%
100%
ETR SVR
IFN/RBV
IFN
6 %
43 %
90 %
42 %
19/21
8/19 9/21
1/19
P = 0.002
P = 0.017
Lai et al. Gastroenterology 1996; 111: 1307
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Treatment with PegIFN Plus Ribavirin
is the Standard of Care
0
10
20
30
40
50
60
70
80
56% 54%
2002 2001
SV
R (
%)
n= 511 453
Fried2 Manns1
Manns M, et al. Lancet 2001; 358: 958
Fried M, et al. N Engl J Med 2002; 347: 975
All HCV genotypes
Peg-IFN-2b + RBV
Peg-IFN-2a + RBV
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Optimal Treatment Regimen Genotype-Guided Therapy
0
20
40
60
SV
R (
%)
80
100 24-LD
24-SD
48-LD
48-SD
LD = RBV 800 mg/day
SD = RBV 1000–1200 mg/day Hadziyannis et al. Ann Intern Med 2004; 140: 346
Peg-IFN-2a 180 mcg/w + RBV
84% 79%
81% 80%
Genotype 2/3
96 144 99 153
Genotype 1
29%
41% 42%
52%
n= 101 118 250 271
AASLD 2004 recommendation
48 weeks of PegIFN plus SD of RBV for HCV-1/4
24 weeks of PegIFN plus LD of RBV for HCV-2/3
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DAAs and HTAs in Clinical Development
Pawlotsky PM. Gastroenterology 2014; 146: 1176
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38–44%
17–21%
Treatment-naive patients
63–75%
59–66%
Treatment-experienced patients
ADVANCE/
SPRINT-2
RESPOND-2/
REALIZE
ADVANCE/SPRINT-2/
ILLUMINATE RESPOND-2/
REALIZE
SV
R (
%)
0
20
40
60
80
100
Triple therapy SOC
SV
R (
%)
0
20
40
60
80
100
Triple therapy SOC
30%
40%
SVR Rates with BOC and TVR in GT1 Treatment
Naïve and Experienced Patients
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Challenges of 1st Wave Protease Inhibitors
• Efficacy: - Very dependent on the IFN response (W4 VR) - only 30% for NR, 15% for prior NR/cirrhotic
• Resistance-associated Variants: especially for HCV-1a
• Tolerability: Additional AEs beyond pegIFN/RBV (SAE > 30% in LC)
• Regimens
– Complicated (lead-in, RGT, FDA/EU, TN/TE, futility)
– pill burden, treatment duration, adherence
• Drug-Drug Interactions
– Many with both agents to common drugs (Statin, SSRI, Sildenafil)
– > 50% FDA-approved drugs are either substrates or inhibitors of CYP3A4 (www.hep-druginteractions.org)
BOC = 12/d
RBV = 4-7/d TVR = 6/d
RBV = 4-7/d
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QUEST-1: Virologic Response to
Simeprevir + P/R Treatment
85% of pts in SMV arm met RGT criteria
Virologic Outcomes
24 Wks 48 Wks
210/
264
n/
N =
65/
130 203/224 6/28
202/
254
80
60
40
20
0
100
HC
V R
NA
Un
det
ecta
ble
(%
)
Wk 4 SVR12
80
12
80
50
SMV + P/R P/R
80
60
40
20
0
SV
R1
2 (
%)
100 91
21
SVR12 by RGT Group
SMV Arm: Total Duration of RGT
n/
N =
Jacobson et al. Lancet 2014; 384: 403
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NEUTRINO: SVR12 with Sofosbuvir + P/R According to Genotype & Fibrosis Level
SV
R1
2 (
%)
92
80
100
80
60
40
20
0 No
Cirrhosis
Cirrhosis
252/273 43/54
SVR12 According to
Fibrosis Level
SV
R1
2 (
%)
89 96
100 100
80
60
40
20
0 GT 1 GT 4 GT 5,6
261/292 27/28 7/7
SVR12 According to
Genotype
n/N =
Lawitz et al. N Engl J Med 2013; 368: 1878
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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24-Wk Daclatasvir (NS5AI) + Asunaprevir (PI) in
HCV-1 Null-responders, Ineligible/Intolerant Patients
AI447-011
Null-R Arm
A1
Daclatasvir 60mg/d +
Asunaprevir 600 mg BID
(n = 11)
Daclatasvir 60mg/d +
Asunaprevir 600 mg BID*
(n = 10)
follow-up x 24 weeks
24-week treatment SVR12 SVR24
1. Lok AS et al N Engl J Med 2012; 366: 216-224
2. Chayama K, et al. Hepatology 2012; 55:742-8
3. Suzuki F, et al. EASL 2012. Oral 2344.
AI447-017 sentinel cohort
Null-R2
Daclatasvir 60mg/d +
Asunaprevir 600 mg BID* (Null-R n=21; ineligible/intolerant n=22)
AI447-017 Japanese G1b
cohort3 follow-up x 24 weeks
Null-G1a
22%
Null-G1b
90%
(ITT)
100%
(PP) Null-R 91%
Ineligible Intolerant
64%
*ASV initially 600 mg BID in sentinel cohort of 10 null responders, reduced to 200 mg BID during treatment • most patients with virologic failure had pre-existing NS5A-Y93H polymorphisms
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Pawlotsky PM. Gastroenterology 2014; 146: 1176
SVR12 Rates in HCV 2/3 Patients Treated with
Sofosbuvir & Ribavirin
(G2) (G2)
(G3 Naïve) (G3 Experienced)
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SVR12 Rates in HCV G1 Patients Treated
with Sofosbuvir and Ledipasvir FDC
Pawlotsky PM. Gastroenterology 2014; 146: 1176
(G1 Naïve) (G1 Experienced)
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SVR12 Rates in Taiwanese G1 & G2 CHC
Patients Treated with Sofosbuvir-based Therapy
Genotype 2: SOF + RBV 12 Weeks Genotype 1: LDV/SOF 12 Weeks
Pa
tie
nts
(%
)
83
85
42
42
41
43
74
76
9
9
87
87
43
43
44
44
74
74
13
13
Overall TN TE
Cirrhosis
No Yes
Treatment
Experience
Overall TN TE
Cirrhosis
No Yes
Treatment
Experience
Chuang et al. APASL 2015
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Sofosbuvir + Daclatasvir in Tx-Naive Pts and
PI Failures with GT1 HCV Infection
Sulkowski et al. N Engl J Med. 2014 ;370:211
GT1 HCV
TVR/BOC
Treatment Failures
(N = 41)
GT1 HCV
Treatment Naive
(N = 126)
SOF + DCV
SOF + DCV + RBV
SVR12, %
100 SOF n = 15
SOF + DCV n = 14 100
100 n = 15
SOF + DCV
SOF + DCV + RBV
n = 41
n = 41
100
95
SOF + DCV + RBV
SOF + DCV n = 21 100
95 n = 20
Wk 12 Wk 24 Wk 1
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COSMOS: Sofosbuvir + Simeprevir ± RBV in
Tx-Naive and Tx-Experienced GT1 Pts
No breakthrough on therapy, 6 relapses, 9 nonvirologic failures
Efficacy of 12 wks similar to 24 wks; RBV provided no additional benefit
Recently FDA approved: 12 wks in noncirhotics, 24 wks for cirrhotics; no RBV
Lawitz et al. Lancet 2014; 384: 1756
100
80
60
40
20
0
SV
R1
2 (
%)
Cohort 2: F3/4 Null Responders/Naives
19/24
S+S+R S+S
93
14/15
79
Cohort 1: F0-2 Null Responders
96 93
S+S+R S+S
26/27 13/14
12 Wks
93 93
S+S S+S+R
25/27 13/14
93
28/30
100
16/16
S+S S+S+R
24 Wks 12 Wks 24 Wks
n/N =
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SVR12 in HCV G1 Patients of SAPPHIRE-I, II, PEARL-
II, III, IV, and TURQUOISE-II Phase III Trials
(Combination Treatment with ABT-450/r, Ombitasvir, and
Dasabuvir, with or without Ribavirin)
Pawlotsky PM. Gastroenterology 2014; 146: 1176
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HALLMARK-DUAL: SVR12 with Daclatasvir +
Asunaprevir in GT1b HCV
Breakthrough: 9 (4%) treatment naive, 26 (13%) nonresponders, 20 (9%) IFN ineligible/intolerant
Relapse: 5 (3%) treatment naive, 7 (4%) nonresponders, 12 (6%) IFN ineligible/intolerant
28 of 73 patients with NS5A-L31 and/or Y93 variants at baseline achieved SVR12
SVR12, % (n/N) Daclatasvir + Asunaprevir
Treatment naive 90
(182/203)
Null responders 82
(98/119)
Partial responders 81
(68/84)
All IFN ineligible/intolerant 82
(192/235)
Advanced fibrosis/cirrhosis with thrombocytopenia 73
(56/77)
Manns et al. Lancet 2014; 384: 1597
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UNITY-1 and 2 Studies: Daclatasvir/ Asunaprevir/
Beclabuvir for non-Cirrhotic & Cirrhotic Patients
with GT 1 HCV Infection
Asselah T & Marcellin P. Liver Int 2015; 35 (Suppl. 1): 56
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C-WORTHY (Treatment-Naïve Cirrhotics and Null):
Efficacy for Cirrhotic Patients & Virologic Failure
Lawitz et al. EASL 49th Annual Meeting, 2014
94 94100 10099
94
0
20
40
60
80
100
All G1a All G1b TNCirrhotics
G1a
Nullcirrhotics
G1a
TNCirrhotics
G1b
Nullcirrhotics
G1b
Pati
ents
wit
h H
CV
RN
A <
25
IU/m
L (%
)
150/160 82/83 * 80/85 30/32** 33/33 14/14
* One G1b failure was null-cirrhotic ** One failure was a motor vehicle accident Excludes patients who have not yet reached FU or who are neither G1a or G1b TN: treatment-naïve
Nine of 253 (3.6%) treated patients experienced virologic failure:
•7 patients: relapsed (6 GT1a and 1 GT1b)
•2 patients: breakthrough (1 GT1a and 1 GT1b)
Virologic failure Cirrhosis + RBV (n = 129) No RBV (n = 127)
Viral breakthrough Yes 1
No 1
Viral relapse Yes 2 3
No 2
• 5/5 (100%) patients with baseline NS3 R155K or
D168A RAVs by population sequencing achieved
SVR4/8
• 27/33 (82%) patients with baseline NS5A 30, 31, and
93 RAVs by population sequencing achieved SVR4/8
• Signature RAVs detected by population sequencing
at failure
NS3: Y56H, D168A, 156A/G/V
NS5A: Q30R/Q
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C-SWIFT Study: MK-5172 + MK-8742 + SOF in
Treatment-Naïve Patients with HCV GT1
Asselah T & Marcellin P. Liver Int 2015; 35 (Suppl. 1): 56
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Safety and DDIs with SOF/LDV
Safety/tolerability[1]
– Treatment-related AEs: 45% SOF/LDV vs 71% SOF/LDV + RBV
– Without RBV:
– < 1% d/c due to AEs
– < 1% serious AEs
– Headache, fatigue: ~ 20%
– Nausea, diarrhea:
~ 8% to 10%
– Almost no anemia
DDIs[2]
– St John’s wort
– Rifampin
– Acid reducing agents: high pH reduces LDV absorption
– Statins: coadministration with rosuvastatin not recommended
– Seizure meds: almost all contraindicated
– Digoxin: be careful—may increase levels
– ARVs: most okay; careful with TDF and check them all
1. Alqahtani et al. AASLD 2014. Abstract 1944
2. Sofosbuvir/ledipasvir [package insert]. October 2014
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Event, % 3 DAAs + RBV 3 DAAs P Value
Any AE 84 75 < .05
Serious AE 2 1 NS
Headache 25 26 NS
Fatigue 29 29 NS
Diarrhea 7 11 NS
Nausea 14 9 < .05
Pruritus 11 6 < .05
Hemoglobin < 10 g/dL 7 0 < .05
Bilirubin > 3 x ULN 5 0.5 NS
Safety and DDIs with 3 DAAs ± RBV
Ferenci et al. N Engl J Med 2014; 370: 1983
DDIs: relatively similar to first-generation PIs (CYP3A) check the label and other
resources (e.g., University of Liverpool Web site)
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Treatment Options for GT4 HCV
1. Lawitz et al. N Engl J Med 2013; 368: 1878. 2. Moreno et al. EASL 2014. Abstract P1319.
3. Esmat et al. AASLD 2014. Abstract 959.
100
80
60
40
20
0
SV
R1
2 (
%)
96
27/
28
12 Wks
SOF + P/R
in Tx-Naive Pts[1]
Other options: SOF + SMV; no data but should work
n/N =
100
80
60
40
20
0
65
70/
107
12 Wks S + 12-24 P/R
SMV + P/R in
Tx-Naive and Tx-Exp’d Pts[2]
12 Wks 24 Wks
100
80
60
40
20
0
77
40/
52
90
46/
51
SOF + RBV in
Tx-Naive and Tx-Exp’d Pts[3]
All-Oral Therapy IFN-Based Therapy
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1. Kapoor et al. AASLD 2014. Abstract 240. 2. Pol et al. AASLD 2014. Abstract 1928.
PEARL-I: Paritaprevir/RTV/Ombitasvir
± RBV x 12 Wks[2]
2 DAAs
100
80
60
40
20
0
91
40/
44
100
42/
42
2 DAAs +
RBV
100
49/
49
2 DAAs +
RBV
Naive Pts P/R Failure
n/N =
SYNERGY: SOF/LDV x 12 Wks[1]
100
80
60
40
20
0
95 95
SVR4 SVR12
< L
LO
Q (
%)
SV
R1
2 (
%)
20/21 19/20
Treatment Options for GT4 HCV
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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Perfectovir(s) ?
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Requirements for HCV Therapy
SVR > 90%
Toxicity
Tolerability
Must haves
Short duration
One size fits all: pangenotypic
High barrier to resistance Helpful
No drug–drug interactions
Low pill burden
Nice
bonus
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Perfectovir(s) ?
Nearly!
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For DAAs Affordable or
Generic Drugs Available Countries
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Recommended Regimens for Treatment-Naive
GT1 HCV Pts
Subtype
Noncirrhotic Compensated Cirrhotic
Regimen Duration,
Wks Regimen
Duration,
Wks
GT1a
or 1b LDV/SOF 12* LDV/SOF 12
GT1a OMV/PTV/RTV + DSV + RBV 12 OMV/PTV/RTV + DSV + RBV 24
GT1b OMV/PTV/RTV + DSV 12 OMV/PTV/RTV + DSV + RBV 12
GT1a SMV + SOF ± RBV 12 SMV + SOF ± RBV 24
GT1b SMV + SOF 12 SMV + SOF 24
* Shorter course can be considered in pts with pretreatment HCV RNA < 6 million IU/mL
at provider’s discretion but should be done with caution.
AASLD/IDSA HCV Guidelines
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Population
Noncirrhotic Compensated Cirrhotic
Regimen Duration,
Wks Regimen
Duration,
Wks
Prior PegIFN/RBV
GT1a or 1b LDV/SOF 12 LDV/SOF 24
GT1a or 1b LDV/SOF + RBV 12
GT1a OMV/PTV/RTV + DSV + RBV 12 OMV/PTV/RTV + DSV + RBV 24
GT1b OMV/PTV/RTV + DSV 12 OMV/PTV/RTV + DSV + RBV 12
GT1a or 1b SMV + SOF ± RBV 12 SMV + SOF ± RBV 24
Prior SOF
GT1a or 1b Defer therapy LDV/SOF ± RBV 24
Prior PI
GT1a or 1b LDV/SOF 12 LDV/SOF 24
GT1a or 1b LDV/SOF + RBV 12
Recommended Regimens for Treatment-
Experienced GT1 HCV Pts
AASLD/IDSA HCV Guidelines
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Recommended Regimens for GT4
Recognizing that data are limited, AASLD/IDSA guidance makes these recommendations
– LDV/SOF for 12 wks
– OMV/PTV/RTV + RBV for 12 wks
– SOF + RBV for 24 wks
– Recommended in treatment-experienced and as alternative for treatment-naive pts: SOF + RBV + pegIFN for 12 wks
– Alternative for treatment-naive pts: SOF + SMV ± RBV for 12 wks
AASLD/IDSA HCV Guidelines
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2014 AASLD-IDSA HCV Guidelines - HCV-2, 3 -
Genotyp
e
Recommended Alternative NOT Recommended
Treatment naive
2 SOF + RBV x 12wk None
•PEG + RBV
•TVR, BOC, SMV
•Any single DAA
3 SOF + RBV x 24wk SOF + PEG/RBV x 12wk
•PEG + RBV
•TVR, BOC, SMV
•Any single DAA
Failed to prior PegIFN/RBV
2 SOF + RBV x 12wk SOF + PEG/RBV x 12wk
•PEG + RBV
•TVR, BOC, SMV
•Any single DAA
3 SOF + RBV x 24wk SOF + PEG/RBV x 12wk
http://www.hcvguidelines.org/
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One Strategy for All Countries ?
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Standard of Care
Available
Acceptable
Accessible
Affordable
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US
Boceprevir
Boceprevir, 2011
Telaprevir
TVR, 2011
SMV, 2013
DCV/ASV, 2014
The data of DAAs for Asian CHC patients are limited
Taiwan, 2014 Boceprevir
Telaprevir
Simeprevir, 2013
Sofosbuvir
SOF & Ledipasvir
(FDC), 2014
3D Regimen, 2014
Simeprevir, 2014
Sofosbuvir,
Daclatasvir Boceprevir, 2011
Telaprevir
China 2018 Simeprevir
Sofosbuvir
DAAs for CHC Therapy not yet Widely Available in Asia
Europe
Japan
Malaysia
Singapore
Philippines
HK
2012/13
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Costs for FDA-Approved DAAs
Boceprevir (Victrelis): $ 26,400 24 weeks,
$35,200 for 32 weeks, and $ 48,400 for 44 weeks
Telaprevir (Incivek): $ 49,200 for 12 weeks
Simeprevir (Olysio): $ 66,360 for 12 weeks
Sofosbuvir (Sovaldi): $ 84,000 for 12 weeks
SOF & Ledipasvir (Harvoni): $ 94,500 for 12 weeks
Daclatasvir & Asunaprevir: $ 27,000 for 24 weeks
3D Regimen (Viekira pak ): $ 83,319 for 12 weeks
* The costs do not include the other medications for combination
therapy
* The cost for a 48-week course of pegylated interferon and
ribavirin is approximately $ 10,000 in Taiwan (reimbursed by
national health insurance).
http://www.hepatitisc.uw.edu/page/treatment/drugs
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For DAAs Unaffordable and
Generic Drugs Unavailable Countries
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Combination therapy with PegIFN and
Ribavirin is still the SOC
for treatment of CHC
(the situation in most of Asian countries)
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For the Countries
DAAs Available
but only with Limited Resources
(Generic Drugs not Available)
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12. In chronic HCV genotype 1 infection, the following apply: (I)
Treatment with peginterferon and ribavirin for 48 weeks is
recommended.
In patients who achieve an RVR at week 4, treatment can be
discontinued after 24 weeks if the HCV RNA at baseline is <400,000
IU/mL.
In patients who achieve a complete EVR at week 12, treatment should
be continued up to 48 weeks.
In patients who do not achieve an EVR at week 12, but show a
significant reduction in HCV RNA levels (partial EVR) and negativity
of HCV RNA at week 24 (late virological response, LVR), treatment
may be continued up to 72 weeks.
APASL 2012 Consensus Statements Treatment of HCV Infection
Omata et al. Hepatol Int 2012; 6: 409
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SVR Rates with 48-week PegIFN Plus Ribavirin in Genotype 1 (~50%)
1. Manns et al. Lancet 2001; 358: 958; 2. Fried et al. N Engl J Med 2002; 347: 975;
3. Hadziyannis et al. Ann Intern Med 2004; 140: 346; 4. Ferenci et al. J Hepatol 2006; 44: 275;
5. Zeuzem et al. J Hepatol 2005; 43: 250
60%
2005
Zeuzem5
0
10
20
30
40
50
60
70
80
46%
52%
2002 2004
SV
R (
%)
n= 348 298 271 95 90
Fried2 Hadziyannis3
52%
42%
2001
Manns1
2006
Ferenci4
Peg-IFN-2b + RBV
Peg-IFN-2a + RBV
48-week treatment duration
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RVR is a Strong Predictor of SVR in HCV-1
0
20
40
60
SV
R (
%)
80
89
73
Patients with
an RVR at week 4
88 91 100
16
35
23
44
Patients without
an RVR at week 4
n= 81 84 208 210 18 33 40 55
24-LD
24-SD
48-LD
48-SD
LD = RBV 800 mg/day; SD = RBV 1000–1200 mg/day;
RVR = HCV RNA <50 IU/mL at week 4 Jensen et al. Hepatology 2006; 43: 954
PEGASYS® 180 g plus COPEGUS®
Post hoc/retrospective analysis
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69
94%
Liu2
HCV-1 patients with an LVL and RVR
Equal Efficacy with 24-week PegIFN/RBV
1. Yu ML, et al., Hepatology 2008;47:1884-93. 3. PEGASYS EU SPC, revised 2007. (based on: Jensen D, et al. Hepatology 2006; 43: 954)
2. Liu CH, et al. Clin Infet Diseas 2008; 47:1260-9. 4. Zeuzem S, et al. J Hepatol 2006; 44: 97. 5. Berg A, et al. Hepatology. 2009;50:369-77.
RVR = HCV RNA <50 IU/mL at wk 4; LVL (low viral load) = 1≤400,000; 4 ≤600,000; 2,3 ≤800,000 IU/mL
28
96%
Yu1 0
20
40
60
SV
R (
%)
80
100
10
30
50
70
90
n=
PegIFNα-2a/RBV
PegIFNα-2b/RBV
24 weeks 48 weeks
Asian
57
100%
24
100%
Liu2 Yu1
Asian
110
89%
27
93%
Jens.3 Zeuz.4 Berg5
19
85%
Caucasian
13
85%
Zeuz.4
27
96%
Jens.3
13
95%
Berg5
Caucasian
Data from 5 studies in East & West population
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High SVR Rates with 24-Wk PegIFN Plus Ribavirin in Genotype 2/3 (~83%)
1. Hadziyannis et al. Ann Intern Med 2004; 140: 346; 2. Von Wagner et al. Gastroenterology 2005; 129: 522
3. Zeuzem et al. J Hepatol 2005; 43: 250; 4. Zeuzem et al. J Hepatol 2004; 40: 993
5. Mangia et al. N Engl J Med 2005; 352: 2609
0
10
20
30
40
50
60
70
100
SV
R (
%)
90
80
n= 96 71 19 224 70
2004 2005
Mangia5 Zeuzem4 Von
Wagner2
2004
84%
95%
81%
2004
Hadziyannis1
76% 80%
Zeuzem3
2005
24-week treatment duration Peg-IFN-2b + RBV
Peg-IFN-2a + RBV
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Equal Efficacy between 16 and 24-Wk Groups – HCV-2
Intention-to-treat analysis
16 weeks 24 weeks
86% 87%
98% 100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100% RVR (<50 IU/mL at week 4)
EOT (<50 IU/mL at end of treatment)
94% 95%
SVR (<50 IU/mL at end of follow up)
6% 3%
Relapse rate
Yu, Chuang, et al, Gut 2007; 56: 553
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Racial Difference of SVR Rates in HCV-1/4
PegIFN + SD RBV for 48 weeks
White
HCV-1/4
0
10
20
30
40
50
60
70
80
50%
SV
R (
%)
100
90
Muir AJ et al. N Engl J Med 2004; 350: 2265
Rodriguez-Torres et al. N Engl J Med 2009; 360: 257
Yu & Chuang. J Gastroenterol Hepatol 2009
78%
Taiwan
HCV-1
70%
Korea
HCV-1
61%
Japan
HCV-1
52%
HK
HCV-1
68%
Kuwait
HCV-4
Some data from individual studies, not all direct head-to-head comparison
AA
HCV-1
19%
Hispanic
HCV-1
34%
West East
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Percentage of SVR by Genotypes of rs12979860
C/C vs. T/T OR: 2.0 (95%C.I 1.8-2.3) OR: 3 .0 (95%C.I:1.9-4.7) OR: 2.1 (95% C.I: 1.4-3.2)
Ge et al, Nature 2009; 461: 399
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83
65
54
33
1726
18
86
13
92
0
20
40
60
80
100
IL-28B SNP & RVR on SVR in HCV-1
Thompson et al.
Gastroenterol 2010
IDEAL Caucasians
N=1171
P<0.001
Allele % SVR RVR SVR if RVR SVR if no RVR
Allele % SVR RVR SVR if RVR SVR if no RVR
CC CT TT rs12979860
TT GT/GG rs8099917
P<0.001 P<0.001
Huang, Chuang, Yu, et al.
J Hepatol 2012
Taiwan HCV-1,
Tx for 24 wks
N= 226
P<0.001 P<0.001
P<0.001
86 85
46
73
14
42
19
80
33
100
0
20
40
60
80
100
Allele % SVR RVR SVR if RVR SVR if no RVR
Huang, Chuang, Yu, et al.
Antiviral Res 2012
Taiwan HCV-1,
Tx for 48 wks
N= 182
P=0.001 P<0.001
P=0.01
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Treatment-experienced HCV patients
Retreatment with PegIFN/RBV in Taiwan
13
76
0
20
40
60
80
HCV-11
4 51 0
79
HCV-2/32
SV
R (
%)
N =
15 55
Previous null responders Previous relapsers
48w PegIFN/RBV for HCV-1; 24w PegIFN/RBV for HCV-2/3
15
78
HCV-11
20 50
Non-TT or NR
Relapser and TT
IL-28B rs8099917 genotype
1. Huang, Chuang, Yu, et al. J Gastroenterol Hepatol 2013; 28: 1515
2. Huang, Chuang, Yu, et al. PLoS ONE 2013; 8: e58882.
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Treatment-experienced HCV-2 patients
Retreatment with PegIFN/RBV in Asia
4 51 0
79
0
20
40
60
80
HCV-2/3 (> 90% HCV-2)
SV
R (
%)
.
N =
Previous null responders
Previous relapsers
Regimens of retreatment:
24w PegIFN/RBV for HCV-2/3
Retreatment with SOC for previous relapsers is encouraged
Huang, Chuang, Yu, et al. PLoS ONE 2013; 8: e58882.
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HCV Practice Recommendation for IFN-eligible Naïve
Patients in Asia-Pacific Countries with DAA Available
HCV, hepatitis C virus; DAA, direct acting antivirals; BL, baseline; W, treatment week; LVL, low HCV viral loads; HVL, high HCV viral loads; RVR, rapid virologic response, HCV RNA undetectable at week 4; P or PegIFN, peginterferon; R or RBV, ribavirin.
Dot line indicated option of choice, based on cost-effectiveness of available DAA regimens
Treatment-naïve
HCV patients
HCV Genotype
1 or 4 or 6
HCV Genotype
2 or 3
LVL and
IL28B CC Cirrhosis No cirrhosis
PegIFN/RBV for
24-48 weeks
LVL/non-CC
or HVL/CC
RVR
BL
W4
(+)
HVL and
IL28B non-CC
(-)
Cost
effectiveness
Cost
effectiveness
RVR (-) RVR (+) in G2
PegIFN/RBV for
24 weeks
PegIFN/RBV
for 16 weeks
Cost
effectiveness
DAA-based
regimens
*
* For areas with only boceprevir/PR, telaprevir/PR, simeprevir/PR or daclatasvir/PR available.
Yu & Chuang. Clinical Liver Disease, 5: 17–21. doi:10.1002/cld.442
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HCV Practice Recommendation for IFN-experienced
Patients in Asia-Pacific Countries with DAA Available
Treatment-
experienced
HCV patients
HCV Genotype
1 or 4 or 6
HCV Genotype
2 or 3
Relapser and
IL28B CC
Partial/null
responders or
cirrhosis
Relapser and
non-cirrhotic
PegIFN/RBV for
48 weeks
EVR
BL
W12
(+)
Partial/null
responders or
IL28B non-CC
(-)
DAA-containing regimens
EVR
PegIFN/RBV for
24 weeks
W4
(+)
(-) HCV RNA
decline > 1 log
(+)
(-)
Cost
effectiveness
Cost
effectiveness
Dot line indicated option of choice, based on cost-effectiveness of available DAA regimens
HCV, hepatitis C virus; DAA, direct acting antivirals; BL, baseline; W, treatment week; IL28B CC, interleukin-28B CC genotype; EVR, early virologic response, HCV RNA decline > 2 logs at week 12; PegIFN, peginterferon; RBV, ribavirin.
Yu & Chuang. Clinical Liver Disease, 5: 17–21. doi:10.1002/cld.442
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WHO HCV Guidelines 2014: Recommendations on HCV Treatment
All adults and children with chronic HCV infection, including people who inject
drugs, should be assessed for antiviral treatment (strong recommendation; moderate
quality of evidence)
PegIFN + RBV recommended rather than standard nonpegylated IFN with RBV (strong
recommendation; moderate quality of evidence)
TVR or BOC, in combination with pegIFN/RBV, suggested for GT1 chronic HCV
infection rather than pegIFN/RBV alone (conditional recommendation; moderate quality
of evidence)
Sofosbuvir, in combination with RBV with or without pegIFN (depending on HCV
genotype), recommended for GT1-4 HCV infection rather than pegIFN/RBV alone (and
rather than no treatment for persons who cannot tolerate IFN) (strong recommendation;
high quality of evidence)
Simeprevir, in combination with pegIFN/RBV, recommended for GT1b HCV infection
and genotype 1a HCV infection without the Q80K polymorphism, rather than
pegIFN/RBV alone (strong recommendation; high quality of evidence)
WHO 2014. Guidelines for the screening, care and treatment of persons with hepatitis C infection
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Introduction
Interferon-based Therapy
New Combination Therapies without Interferon
The Role of New Combination Therapies
Summary
Outline
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The new combination therapies without Interferon for
chronic hepatitis C have the characteristics of high SVR
rates, low toxicity, good tolerability, short duration, high
barrier to resistance, and low drug-drug interactions.
The new IFN-free DAAs therapy will become the standard
of care for chronic hepatitis C in the Asian Pacific countries
in the near future.
However, combination therapy with pegIFN and ribavirin is
still the SOC for treatment of CHC in most of Asian
countries.
The role of new combination therapies without interferon
for chronic hepatitis C needs further elucidation under
considering the issue of cost-effectiveness.
Summary
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The new combination therapies without Interferon for
chronic hepatitis C have the characteristics of high SVR
rates, low toxicity, good tolerability, short duration, high
barrier to resistance, and low drug-drug interactions.
The new IFN-free DAAs therapy will become the standard
of care for chronic hepatitis C in the Asian Pacific countries
in the near future.
However, combination therapy with pegIFN and ribavirin is
still the SOC for treatment of CHC in most of Asian
countries.
The role of new combination therapies without interferon
for chronic hepatitis C needs further elucidation under
considering the issue of cost-effectiveness.
Summary
![Page 68: The Role of New Combination Therapies without Interferon for … · 2015. 5. 20. · The Role of New Combination Therapies without Interferon for Chronic HCV Infection Wan-Long Chuang](https://reader036.vdocuments.us/reader036/viewer/2022071506/6126a85188724529410868bc/html5/thumbnails/68.jpg)
The new combination therapies without Interferon for
chronic hepatitis C have the characteristics of high SVR
rates, low toxicity, good tolerability, short duration, high
barrier to resistance, and low drug-drug interactions.
The new IFN-free DAAs therapy will become the standard
of care for chronic hepatitis C in the Asian Pacific countries
in the near future.
However, combination therapy with pegIFN and ribavirin is
still the SOC for treatment of CHC in most of Asian
countries.
The role of new combination therapies without interferon
for chronic hepatitis C needs further elucidation under
considering the issue of cost-effectiveness.
Summary
![Page 69: The Role of New Combination Therapies without Interferon for … · 2015. 5. 20. · The Role of New Combination Therapies without Interferon for Chronic HCV Infection Wan-Long Chuang](https://reader036.vdocuments.us/reader036/viewer/2022071506/6126a85188724529410868bc/html5/thumbnails/69.jpg)
The new combination therapies without Interferon for
chronic hepatitis C have the characteristics of high SVR
rates, low toxicity, good tolerability, short duration, high
barrier to resistance, and low drug-drug interactions.
The new IFN-free DAAs therapy will become the standard
of care for chronic hepatitis C in the Asian Pacific countries
in the near future.
However, combination therapy with pegIFN and ribavirin is
still the SOC for treatment of CHC in most of Asian
countries.
The role of new combination therapies without interferon
for chronic hepatitis C needs further elucidation under
considering the issue of cost-effectiveness.
Summary
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Thank You for Your Attention !
Kaohsiung
KMU