Post on 22-Sep-2020
1
WHAT’S NEW IN HCV TREATMENT
HIV Clinical Grand Rounds
AMC
Peter F Ells MD
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Evolving HCV Management in Harder-to-Treat Populations
Sofosbuvir +
ribavirin ±
pegIFN
Ledipasvir/
sofosbuvir
Simeprevir +
sofosbuvir
Ombitasvir/
paritaprevir/
ritonavir +
dasabuvir
2015
Agents
Sofosbuvir +
daclatasvir
2
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Evolving HCV Management in Harder-to-Treat Populations
Genotype 1 HCV Agents
Protease
Inhibitors
Polymerase Inhibitors NS5A
Inhibitors Other
Nucleotide Nonnucleoside
Simeprevir Sofosbuvir Ledipasvir Ribavirin
Paritaprevir/
ritonavir Dasabuvir Ombitasvir
Daclatasvir
www.hcvguidelines.org
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Evolving HCV Management in Harder-to-Treat Populations
Key Data for HCV decisions
HCV treatment history
– Interferon and ribavirin regimen?
– Protease inhibitor? Sofosbuvir?
Fibrosis stage?
– Options for fibrosis assessment
– If cirrhosis, is it decompensated?
Child Pugh B or C?
Transplant
evaluation?
http://www.hcvguidelines.
org
3
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Genotype 1 HCV: FDA-Approved
Regimens
Regimen Approval for Genotype 1
Simeprevir + peginterferon + ribavirin* 24-48 wks
Sofosbuvir + peginterferon + ribavirin 12 wks
Sofosbuvir + ribavirin Interferon ineligible, 24 wks;
HCC awaiting transplant, up to 48 wks
Ledipasvir/sofosbuvir 8-24 wks
Ombitasvir/paritaprevir/ritonavir, dasabuvir, ±
ribavirin 12-24 wks
Simeprevir + sofosbuvir 12-24 wks
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
*Screening pts with genotype 1a HCV infection for NS3 Q80K polymorphism strongly
recommended and alternative therapy should be considered if Q80K detected.
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Genotype 1 HCV: AASLD/IDSA-
Recommended Regimens
Regimen Genotype 1 Regimen Features
Simeprevir + peginterferon +
ribavirin
Not recommended
QD-QWK; multiple tablets +
injection
Sofosbuvir + peginterferon +
ribavirin Not recommended
QD-QWK; multiple tablets +
injection
Sofosbuvir + ribavirin Not recommended QD; multiple tablets
Ledipasvir/sofosbuvir Recommended QD; single-tablet regimen
Ombitasvir/paritaprevir/ritonavir,
dasabuvir, ± ribavirin Recommended QD-BID; multiple tablets
Simeprevir + sofosbuvir ± ribavirin Recommended QD; multiple tablets
http://www.hcvguidelines.
org
4
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Genotype 1 HCV Treatment Naive
AASLD-IDSA guidelines
– 3 regimens recommended
Ledipasvir/
Sofosbuvir*
Ombitasvir/
Paritaprevir/ Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV
Genotype 1a, cirrhosis 12 wks 24 wks + RBV 24 wks ± RBV
Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks
Genotype 1b, cirrhosis 12 wks 12 wks + RBV 24 wks
http://www.hcvguidelines.
org
*Ledipasvir/sofosbuvir for 8 wks can be considered in naive, noncirrhotic pts with baseline HCV
RNA < 6 million IU/mL.
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Genotype 1 HCV Treatment Naive
Noncirrhotic
Regimen Wks Study SVR
Ledipasvir/sofosbuvir
(HCV RNA < 6 M IU/mL) 8 ION-3[1,2] 119/123 (97%)
Ledipasvir/sofosbuvir 12 ION-3[1] 206/216 (95%)
Simeprevir + sofosbuvir* 8-12 OPTIMIST-1[3] 8 wks: 128/155 (83%)
12 wks: 150/155 (97%)
Ombitasvir/paritaprevir/ritonavir,
dasabuvir (GT1b) 12 PEARL III[4] 207/209 (99%)
Ombitasvir/paritaprevir/ritonavir,
dasabuvir, ribavirin (GT1a) 12 PEARL IV[4]
97/100 (97%)
Sofosbuvir + daclatasvir 12 AI444040[5] 41/41 (100%)
1. Kowdley K, et al. N Engl J Med. 2014;370:1879-1888. 2. Ledipasvir/sofosbuvir [package insert].
3. Kwo PY, et al. EASL 2015. Abstract LP14. 4. Ferenci P, et al. N Engl J Med. 2014;370:1983-1992.
5. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.
*GT1a + Q80K-8 wks: 36/49 (73%); GT1a + Q80K-12 wks: 44/46 (96%).
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Genotype 1 HCV PegIFN/RBV Treatment
Experienced
AASLD-IDSA guidelines
– 3 regimens recommended
Ledipasvir/
Sofosbuvir
Ombitasvir/
Paritaprevir/
Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir
Genotype 1a, no cirrhosis 12 wks 12 wks + RBV 12 wks ± RBV
Genotype 1a, cirrhosis 24 wks
12 wks + RBV
24 wks + RBV 24 wks ± RBV
Genotype 1b, no cirrhosis 12 wks 12 wks 12 wks ± RBV
Genotype 1b, cirrhosis 24 wks
12 wks + RBV
12 wks + RBV 24 wks ± RBV
http://www.hcvguidelines.
org
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Genotypes 2 and 3
AASLD-IDSA guidelines
Genotype 2 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin
+ Sofosbuvir
Treatment naive 12 wks
(16 wks for cirrhosis)
None
PegIFN/RBV nonresponders 12-16 wks 12 wks (alternative)
http://www.hcvguidelines.org
Genotype 3 Sofosbuvir + Ribavirin Peginterferon-α, Ribavirin
+ Sofosbuvir
Treatment naive 24 wks 12 wks (alternative)
PegIFN/RBV nonresponders 24 wks 12 wks (alternative)
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Management of HCV in
Patients With Genotype 3
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Evolving HCV Management in Harder-to-Treat Populations
Treatment Naive Treatment Experienced
BOSON: SVR12 With SOF-Based Regimens
in GT3 by Tx History and Cirrhosis Status
Foster GR, et al. EASL 2015. Abstract LO5.
58/
70
65/
72
68/
71 12/
21
18/
22
21/
23
26/
34
17/
36
30/
35
44/
54
49/
52
41/
54
No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
83 90
96
57
82 91
76 82
94
47
77 86 100
80
60
40
20
0
SV
R12
(%
)
SOF + RBV 16 wks SOF + RBV 24 wks SOF + PegIFN/RBV 12
wks
n/N =
7
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ALLY-3: SOF + DCV for 12 Wks in Pts With
GT3 HCV Infection
Of 16 pts with relapse, 11 had cirrhosis
1 of 16 relapses occurred between posttreatment Wks 4 and 12
Nelson DR, et al. Hepatology. 2015;61:1127-1135.
Treatment-Naive Pts
Treatment-Experienced Pts
Overall
No cirrhosis Cirrhosis
SV
R12 (
%)
96
63
97
58
94 69
105/ 109
20/ 32
73/ 75
11/ 19
32/ 34
9/ 13
100
80
60
40
20
0 n/N =
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Evolving HCV Management in Harder-to-Treat Populations
Daclastavir + Sofosbuvir in Tx-Naive and
Tx-Exp’d Pts With Genotype 3 HCV
ALLY-3[1]
Pts:
– Treatment naive and experienced
– Prior sofosbuvir and alisporivir included
– Prior NS5A inhibitors excluded
– Cirrhosis: 21%
Design
– 2 open-label cohorts
– Phase III
Regimen
– Daclatasvir + sofosbuvir once daily for 12 wks
EASL recommendations for DCV + SOF in GT3[2]
– No cirrhosis: DCV + SOF for 12 wks
– Compensated cirrhosis: DCV + SOF + RBV for 24 wks
1. Nelson DR, et al. Hepatology. 2015;61:1127-1135. 2. EASL HCV Guidelines. April 2015.
73
75 32
34
No Cirrhosis Cirrhosis
SV
R12 (
%)
Naive Experienced
97
58
94
69
0
100
80
60
40
20
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AASLD/IDSA Guidance for Treatment-
Naive or Treatment-Experienced GT3 Pts
Population Recommended Alternative
DCV + SOF SOF + RBV SOF + RBV
Naive, no cirrhosis 12 wks 12 wks + pegIFN 24 wks†
Naive, cirrhosis 24 wks ± RBV 12 wks + pegIFN 24 wks†
P/R failure, no cirrhosis 12 wks 12 wks + pegIFN Not recommended
P/R failure with cirrhosis,
or SOF/RBV failure 24 wks + RBV
† 12 wks + pegIFN
Not recommended
Decompensated cirrhosis‡ 12 wks +
low-dose RBV Up to 48 wks*
Not recommended
*RBV dosed 1000-1200 mg/day based on weight, with consideration for pt’s CrCl and hemoglobin. †For IFN-ineligible pts. ‡Pts with GT3 HCV decompensated cirrhosis should be referred to a medical
practitioner with expertise in that condition
AASLD/IDSA. HCV guidelines.
LDV/SOF or OMV/PTV/RTV + DSV not recommended for GT3
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Genotype 4 HCV Treatment Experienced
Regimen Wks FDA
Approved AASLD/IDSA Study SVR12
Sofosbuvir +
pegIFN/RBV 12 Yes Recommended NEUTRINO[1] 27/28*
(96%)
Sofosbuvir + ribavirin 24 No Recommended Ruane et al2] 13/15
(87%)
Ledipasvir/sofosbuvir 12 No Recommended Multiple[3,4]
19/20†[3];
20/22[4]
(91-95%)
Ombitasvir/paritaprevir/
ritonavir, ribavirin 12 No Recommended PEARL-I[5]
49/49
(100%)
1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Ruane PJ, et al. J Hepatol. 2015;62:1040-1046.
3. Kapoor R, et al. AASLD 2014. Abstract 240. 4. Abergel A, et al. EASL 2015. Abstract O056. 5. Hézode
C, et al. Lancet. 2015;[Epub ahead of print].
*Study included treatment-naive pts only. †Treatment-naive and treatment-experienced pts.
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Management of HCV in Pts With
Compensated Cirrhosis
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Evolving HCV Management in Harder-to-Treat Populations
AASLD/IDSA Guidance for GT1 HCV:
Treatment-Naive Pts
Population SMV + SOF LDV/SOF OMV/PTV/RTV
+ DSV
DCV + SOF
GT1a,
no cirrhosis 12 wks ± RBV 12 wks 12 wks + RBV 12 wks
GT1a,
compensated
cirrhosis
24 wks ± RBV
(without Q80K) 12 wks 24 wks + RBV 24 wks ± RBV
GT1b,
no cirrhosis 12 wks 12 wks 12 wks 12 wks
GT1b,
compensated
cirrhosis
24 wks ± RBV 12 wks 12 wks 24 wks ± RBV
AASLD/IDSA. HCV guidelines.
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Reddy KR, et al. Hepatology. 2015;62:79-86.
Pooled Data: Impact of Tx Duration and
RBV in Cirrhotic GT1 Pts (LDV/SOF) Pooled data (ONESTAR, ELECTRON, ELECTRON-2, 337-0113, ION-1, ION-2, SIRIUS)
No difference in SVR rate by HCV subtype
100
80
60
40
20
0 Total Treatment Naive
92 96 98 100
SV
R12 (
%)
118 204 133 58
96 98 97
47 45 33 36
100
Treatment
Experienced
90 96 98
71 159 100 22
100
12 wks of LDV/SOF
12 wks of LDV/SOF + RBV
24 wks of LDV/SOF
24 wks of LDV/SOF + RBV
n =
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SIRIUS: Impact of Tx Duration and RBV in
Cirrhotic, PI-Exp’d, GT1 Pts (LDV/SOF) 12 wks of LDV/SOF + RBV
100
80
60
40
20
0
N =
24 wks of LDV/SOF
SV
R12
(%
)
77
97 96
77
Bourlière M, et al. Lancet Infect Dis. 2015;15:397-404.
Pts with previous boceprevir, telaprevir, simeprevir, or faldaprevir
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Partial Null
OMV/PTV/RTV + DSV + RBV x 12 wks
SV
R12 (
%)
OMV/PTV/RTV + DSV + RBV x 24 wks
Tx Experienced
n/N = 22/
22
18/
18
25/
25
20/
20
6/
7
3/
3
14/
14
10/
10
59/
64
52/
56
14/
15
13/
13
11/
11
10/
10
40/
50
39/
42
TURQUOISE II: Impact of Tx Duration in
Cirrhotic GT1 Pts (OMV/PTV/RTV + DSV)
Poordad F, et al. N Engl J Med. 2014;370:1973-1982. Poordad F, et al. EASL 2014. Abstract O163.
GT1b GT1a
Tx Experienced
100 100 100 100 100 100 100 100 100
86
100
92 93 93
80
93
Naive Relapser Partial Null Naive Relapser
100
80
60
40
20
0
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Daclatasvir and Sofosbuvir ± RBV in Pts
With GT 1 HCV
Phase Regimen GT1 SVR, % GT1 Baseline Cirrhosis, %
III 12 wks DCV + SOF +
RBV (ALLY-1)[1]
82 (advanced cirrhosis)
95 (posttransplantation)
100
III 8-12 wks DCV + SOF
(ALLY-2)[2]
76 (8 wks; naive)
96 (12 wks; naive)
98 (12 wks; tx exp’d)
< 18
IIb 12-24 wks DCV +
SOF ± RBV[3]
98 (12 wks; naive)
100 (24 wks; naive)
98 (24 wks; tx exp’d)
16
1. Poordad F, et al. EASL 2015. Abstract LO8. 2. Wyles DL, et al. CROI 2015. Abstract 151LB.
3. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.
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Evolving HCV Management in Harder-to-Treat Populations
AASLD/IDSA Guidance for GT1 HCV:
Treatment-Experienced Pts Previous Treatment,
Cirrhosis Status
SMV + SOF LDV/SOF OMV/PTV/RTV +
DSV
DCV + SOF
PegIFN/RBV, no cirrhosis 12 wks 12 wks 12 wks + RBV (1a)
12 wks (1b) 12 wks
PegIFN/RBV, cirrhosis
24 wks ± RBV
(GT1a w/out Q80K
or GT1b)*
24 wks or
12 wks + RBV
24 wks + RBV (1a)
12 wks (1b) 24 wks ± RBV
SOF + RBV, no cirrhosis Not recommended 12 wks + RBV Not recommended Not recommended
SOF + RBV, cirrhosis Not recommended 24 wks + RBV Not recommended Not recommended
HCV PI, + PegIFN/RBV,
no cirrhosis Not recommended 12 wks Not recommended 12 wks
HCV PI + PegIFN/RBV,
cirrhosis Not recommended
24 wks or
12 wks + RBV Not recommended 24 wks ± RBV
SMV + SOF, no cirrhosis Not recommended 12 wks + RBV Not recommended 12 wks
SMV + SOF, cirrhosis Not recommended 24 wks + RBV Not recommended 24 wks ± RBV
*Not recommended if both GT1a and positive for Q80K.
AASLD/IDSA. HCV guidelines.
Management of HCV in GT1 Pts
With Decompensated Cirrhosis
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AASLD/IDSA Guidance for Pts With
Decompensated Cirrhosis
Refer to experienced HCV practitioner (ideally liver transplant center)
Avoid IFN, TVR, BOC, SMV, OMV/PTV/RTV + DSV, or monotherapy with RBV or DAA
AASLD/IDSA. HCV guidelines.
*Initial dose of 600 mg/day, increased as tolerated.
Population RBV Eligible RBV Ineligible
DCV + SOF LDV/SOF DCV + SOF
GT1/4 12 wks +
low-dose RBV*
12 wks +
low-dose RBV* 24 wks
GT1/4, SOF failure Not
recommended
24 wks +
low-dose RBV* Not
recommended
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Evolving HCV Management in Harder-to-Treat Populations
100
80
60
40
20
0
SV
R12 (
%)
CTP B CTP C CTP B CTP C
SOLAR-1 SOLAR-2
87 89 86 90 87 96
85 72
SOLAR-1 and -2: Impact of Tx Duration in
Decompensated Cirrhosis (LDV/SOF + RBV)
Error bars represent 90% CIs.
26/
30
3 relapses
1 death
24/
27
1 relapse
2 deaths
19/
22
1 relapse
1 death
1 LTFU
18/
20
1 relapse
1 death
26/
30
3 relapses
22/
23
1 relapse
17/
20
1 relapse
2 deaths
13/
18
1 relapse
3 deaths
1 w/d consent
Flamm SL, et al. AASLD 2014. Abstract 239. Manns M, et al. EASL 2015. Abstract P0774
LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks
n/N =
14
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ALLY-1: SOF + DCV + RBV for 12 Wks in
Pts With HCV and Cirrhosis
Treatment naive or treatment experienced
Poordad F, et al. EASL 2015. Abstract LO8.
SV
R12
(%
)
All Genotypes
100
60
80
40
20
0
37/45 39/41
82 95
Advanced Cirrhosis
Post-transplant
GT1
100
80
60
40
20
0 A B C
Child-Pugh Class
92 94
56
11/ 12
30/ 32
9/ 16
n/N = n/N =
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Evolving HCV Management in Harder-to-Treat Populations
SOF + NS5A Inhibitors ± RBV for 12 Wks
in GT1 Pts With Decompensated Cirrhosis
Foster GR, et al. EASL 2015. Abstract O002.
12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV
n =
100
80
60
40
20
0 All GT1
SV
R12
(%
; IT
T)
252 28 172 15 164 21 45 5
80
71 74 73
86 81 82
60
15
Management of HCV in
Patients With Renal Impairment
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Evolving HCV Management in Harder-to-Treat Populations
AASLD/IDSA Dosing Considerations for
Pts With Renal Impairment
eGFR/CrCl OMV/PTV/RTV +
DSV[1]
LDV/SOF[2] SMV + SOF,[3]
DCV + SOF[4]
RBV[5]
30-50 mL/min No adjustment
needed
No adjustment
needed
No adjustment needed Alternating
200 mg and
400 mg every
other day
15-30 mL/min No adjustment
needed
Safety and efficacy
not established
No adjustment needed
for SMV or DCV;
Safety and efficacy of
SOF not established
200 mg/day
< 15 mL/min or
hemodialysis
Safety and efficacy
not established
Safety and efficacy
not established
Safety and efficacy not
established
200 mg/day
1. OMV/PTV/RTV + DSV [package insert]. 2. LDV/SOF [package insert]. 3. AASLD/IDSA/IAS-USA.
Recommendations for testing, managing, and treating hepatitis C. 4. DCV [package insert]. 5. RBV
[package insert]. 6. AASLD/IDSA. HCV guidelines.
In noncirrhotic pts for whom tx is urgent and renal transplant not an immediate option:
Recommended Recommended if RBV intolerant/ineligible, in consultation with expert[3]
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RUBY-1: OMV/PTV/RTV + DSV ± RBV in
Tx-Naive, Noncirrhotic GT1 Pts With CKD
SVR4: 10/10 pts reaching posttreatment Wk 4
– SVR12: 2/2 pts reaching posttreatment Wk 12
– No virologic failures observed as of time of reporting
Pockros PJ, et al. EASL 2015. Abstract L01.
Pt 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
GT 1a 1a 1a 1a 1b 1a 1a 1a 1a 1a 1b 1a 1a 1a 1b 1b 1b 1b 1b 1a
Renal Stage
4 4 5 5 5 5 5 4 5 5 5 5 4 4 5 4 5 5 5 5
BL (x 1000)
746 25300 17100 3520 2980 429 1730 43300 12600 6670 9820 292 6980 2570 3680 383 1230 6500 1850 4210
W1
W2
W4
W8
W12EOT
PTW4
PTW12
PTW24
HCV RNA: ≥ 25 IU/mL < 25 IU/mL Undetectable
Management of HCV in
HCV/HIV-Coinfected Patients
17
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Evolving HCV Management in Harder-to-Treat Populations
ION-4: LDV/SOF for 12 Wks in HCV/HIV-
Coinfected Pts GT1 or 4 HCV, 20% with compensated cirrhosis, 55% treatment
experienced
Naggie S, et al. CROI 2015. Abstract 152LB.
SV
R12
(%
)
96 95 97 96 94
Overall Naive Exp’d
321/
335
142/
150
100
179/
185
258/
268
63/
67
No
Cirrhosis
Cirrhosis
n/N =
80
60
40
20
0
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Evolving HCV Management in Harder-to-Treat Populations
ALLY-2: SOF + DCV in HCV/HIV-
Coinfected Pts
12 pts with relapse, 10 in 8-wk arm
Wyles DL, et al. CROI 2015. Abstract 151.
12-Wk
Naive
12-Wk
Exp’d
8-Wk
Naive
12-Wk
Naive
12-Wk
Exp’d
8-Wk
Naive
SV
R12 (
%)
96 98
76
97 98
80/83 43/44
0
20
40
60
80
100
31/41 98/101 51/52
76
38/50
GT1 GT1-4
n/N =
18
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Evolving HCV Management in Harder-to-Treat Populations
94
TURQUOISE-1: OMV/PTV/RTV + DSV + RBV
for 12 vs 24 Wks in GT1 HCV/HIV Coinfection
65% HCV treatment–naive pts in 12-wk arm, 69% in 24-wk arm
19% pts with METAVIR F4 fibrosis
Sulkowski M, et al. JAMA. 2015;313:1223-1231.
30/31 31/32 29/31 n/N =
100
80
60
40
20
0
97 97
EOTR SVR12
Pts
(%
) OMV/PTV/RTV +
DSV + RBV 12 wks
OMV/PTV/RTV +
DSV + RBV 24 wks
91
29/32
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Evolving HCV Management in Harder-to-Treat Populations
AASLD/IDSA Guidance for HCV/HIV
Coinfection
Same recommendations as in HCV-monoinfected pts, but consider drug–drug interactions
– Avoid combination of LDV and tenofovir DF if CrCl < 60 mL/min or if receiving tenofovir with RTV-boosted PIs
– When LDV/SOF and tenofovir DF are coadministered with antiretrovirals, monitor for nephrotoxicity
– Adjust/withhold RTV if receiving a boosted PI with OMV/PTV/RTV + DSV
– Adjust DCV with atazanavir/RTV, efavirenz, or etravirine
DCV + SOF ± RBV is recommended when ART regimen changes cannot be made to accommodate other DAAs
Other interactions at aidsinfo.nih.gov/guidelines, hiv-druginteractions.org, hep-druginteractions.org
AASLD/IDSA. HCV guidelines.
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Evolving HCV Management in Harder-to-Treat Populations
Sofosbuvir +
ribavirin
Sofosbuvir +
ledipasvir
Simeprevir +
sofosbuvir
Paritaprevir/
ritonavir +
dasabuvir +
ombitasvir
Sofosbuvir +
GS-5816
Sofosbuvir +
daclatasvir
Grazoprevir +
elbasvir
Daclatasvir +
asunaprevir +
beclabuvir
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Evolving HCV Management in Harder-to-Treat Populations
Investigational Agents
Population Regimen Trial Phase SVR12,
%
GT1 HCV + stage 4/5
CKD
12 wks of
grazoprevir/elbasvir C-SURFER[1] III 99
GT3 HCV (treatment-
naive, noncirrhotic or
cirrhotic)
8-12 wks
grazoprevir/elbasvir
+ SOF
C-SWIFT[2] II 91-100
GT1, 4, 6 HCV + HIV
coinfection
12 wks of
grazoprevir/elbasvir C-EDGE[3] III 96
GT3 HCV (treatment-
naive, noncirrhotic)
8 wks of
SOF + GS-5816
± RBV
ELECTRON-
2[4] II 88-100
1. Roth D, et al. EASL 2015. Abstract LP02. 2. Poordad F, et al. EASL 2015. Abstract O006.
3. Rockstroh JK, et al. EASL 2015. Abstract P0887. 4. Gane EJ, et al. AASLD 2014. Abstract 79.
20
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Evolving HCV Management in Harder-to-Treat Populations
Future HCV Treatment: Shorter Duration
With Triple-Drug Regimens
Pts
– Treatment naive, genotype 1 (N = 60)
Design
– Single-center, open-label, phase IIA trial
Regimens
– 12 wks of SOF + LDV
– 6 wks of SOF, LDV, GS-9669
– 6 wks of SOF, LDV, GS-9451
Kohli A, et al. Lancet. 2015;385:1107-1113.
20/20 19/20 19/20 n/N =
SOF + LDV
20/20 19/20 19/20
100 95 95 100
80
60
40
20
0
SV
R12 (
%)
SOF + LDV
+ GS-9669
SOF + LDV
+ GS-9451
12 wks 6 wks 6 wks
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Evolving HCV Management in Harder-to-Treat Populations
Tx Naive,
No Cirrhosis Txt Naive,
Cirrhosis Txt Exp’d,
+/- Cirrhosis
Tx Naive,
No Cirrhosis
Short-Duration Sofosbuvir/GS-5816 +
GS-9857: Efficacy Results
All pts who did not achieve SVR12 relapsed
SVR12 rates for treatment-experienced pts: no cirrhosis, 68% (17/25 pts); cirrhosis, 60% (3/5 pts)
Gane EJ, et al. EASL 2015. Abstract LP03.
6 Wks
100
80
60
40
20
0
SV
R12 (
%)
93 87
67
14/15 13/15 20/30 n/N =
4 Wks
27
4/15
21
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Evolving HCV Management in Harder-to-Treat Populations
UNITY-1: Efficacy of 12-Wk DCV/ASV/BCV
in Noncirrhotic GT1 by Treatment Experience
Treatment-Naive Pts Treatment-Experienced Pts
100
80
60
40
20
0
SV
R1
2 (
%)
All GT1a GT1b
92 90 98
287/ 312
206/ 229
81/ 83
All GT1a GT1b
92/ 103
64/ 75
28/ 28
89 85
100
Poordad F, et al. JAMA. 2015;313:1728-1735.
n/N =
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Evolving HCV Management in Harder-to-Treat Populations
C-SWIFT: Short-Duration GZR/EBV + SOF
in GT1 or 3 HCV Infection Pts: treatment-naive, genotype 1 (n = 102) or genotype 3 (n = 41)
Design: multicenter, open-label, phase II trial
Regimen: grazoprevir/elbasvir FDC + sofosbuvir
– GT1 noncirrhotic: 4 vs 6 wks; cirrhotic: 6 vs 8 wks
– GT3 noncirrhotic: 8 vs 12 wks; cirrhotic: 12 wks
Poordad F, et al. EASL 2015. Abstract O006.
SV
R12 (
%)
100
80
60
40
20
0 4 Wks 6 Wks 6 Wks 8 Wks 8 Wks 12 Wks 12 Wks
Genotype 1 Genotype 3
33
26/ 30
16/ 20
17/ 18
14/ 15
14/ 14
10/ 11*
87 80
94 93 100 91
10/ 30*
*Excluded pts who discontinued due to reasons other than virologic failure.
Noncirrhotic Cirrhotic
n/N =
22
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Evolving HCV Management in Harder-to-Treat Populations
C-EDGE: Grazoprevir/Elbasvir for Tx-Naive
and Tx-Experienced Pts
1. Zeuzem Z, et al. EASL 2015. Abstract G07. 2. Kwo P, et al. EASL 2015. Abstract P0886.
Tx-Naive: Grazoprevir/Elbasvir for 12 Wks in GT1, 4, or 6 HCV[1]
SV
R12 (
%)
All Pts GT1a GT1b GT4 GT6
95 92
99 100
80
299/ 316
144/ 157
129/ 131
18/ 18
8/ 10 n/N =
100
80
60
40
20
0
Tx-Exp’d: Grazoprevir/Elbasvir ± RBV for 12 or 16 Wks in GT1, 4, or 6 HCV[2]
0
100
80
60
40
20
GZR/ EBV
GZR/EBV + RBV
GZR/EBV + RBV
GZR/EBV
92
97/ 105
98/ 104
97/ 105
103/ 106
94 97 92
12 Wks 16 Wks
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Evolving HCV Management in Harder-to-Treat Populations
Sofosbuvir +
ribavirin
Sofosbuvir +
ledipasvir Simeprevir +
sofosbuvir
Paritaprevir/
ritonavir +
dasabuvir +
ombitasvir
Sofosbuvir +
GS-5816
Sofosbuvir +
daclatasvir
Grazoprevir +
elbasvir
Daclatasvir +
asunaprevir +
beclabuvir
Many other DAA combinations
currently under investigation
23
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Evolving HCV Management in Harder-to-Treat Populations
Summary
All-oral HCV therapy has significantly improved tolerability and efficacy, but challenging populations remain
Cirrhotics may require addition of RBV or longer duration with current therapy to achieve SVR rates comparable to noncirrhotics
GT3 pts remain a challenging population although the recent availability of DCV introduces a new, IFN-free option in this population
HIV-coinfected individuals can now achieve SVR rates comparable to monoinfected, but drug–drug interactions must be carefully considered
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Evolving HCV Management in Harder-to-Treat Populations
Genotype 1 HCV Previous PI Failure
AASLD-IDSA guidelines
– 1 regimen recommended
Ledipasvir/
Sofosbuvir
Ombitasvir/
Paritaprevir/
Ritonavir +
Dasabuvir
Simeprevir +
Sofosbuvir ±
Ribavirin
Genotype 1a, no cirrhosis 12 wks None None
Genotype 1a, cirrhosis 24 wks
12 wks + RBV
None
None
Genotype 1b, no cirrhosis 12 wks None None
Genotype 1b, cirrhosis 24 wks
12 wks + RBV
None None
http://www.hcvguidelines.
org
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Evolving HCV Management in Harder-to-Treat Populations
Genotype 1 HCV Previous PI Failure
Regimen Cirrhosis Wks Study SVR
Ledipasvir/sofosbuvir No 12 ION-2[1] 50/52 (96%)
Ledipasvir/sofosbuvir Yes 24 ION-2[1] 14/14 (100%)
Ledipasvir/sofosbuvir Yes 24 SIRIUS[2] 75/77 (97%)
Ledipasvir/sofosbuvir, ribavirin Yes 12 SIRIUS[2] 74/77 (96%)
Sofosbuvir + daclatasvir Mix 24 AI444040[3] 21/21 (100%)
Sofosbuvir, daclatasvir, ribavirin Mix 24 AI444040[3] 19/20 (95%)
1. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 2. Bourlière M, et al. Lancet Infect Dis.
2015;15:397-404. 3. Sulkowski M, et al. N Engl J Med. 2014;370:211-221.
25
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Evolving HCV Management in Harder-to-Treat Populations
TURQUOISE II: OBV/PTV/RTV + DSV +
RBV in Cirrhotic Pts With GT1 HCV
Pts (N = 380):
– Treatment-naive and experienced pts
– All compensated cirrhosis
Design
– Open-label phase III
Regimen
– Paritaprevir/ritonavir, dasabuvir, ombitasvir, ribavirin
– Duration: 12 vs 24 wks
Safety
Outcome
12 Wks
(n = 208)
24 Wks
(n = 172)
SAE, n (%) 13 (6.2) 8 (4.7)
AE leading to
d/c, n (%)
4 (1.9) 4 (2.3)
Fatigue, % 32.7 46.5
Headache, % 27.9 30.8
Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
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Evolving HCV Management in Harder-to-Treat Populations
SIRIUS: LDV/SOF in Pts With GT1 HCV and
Previous PegIFN/RBV ± PI Failure Pts:
– Treatment-experienced, failure of both pegIFN/RBV and PI + pegIFN/RBV regimens
– Compensated cirrhosis
Design
– Randomized, double-blinded
Regimens
– Placebo 12 weeks followed by LDV/SOF + RBV for 12 wks
– LDV/SOF + Placebo for 24 wks
2 AEs higher with LDV/SOF vs placebo during first 12 wks
– Headache: 35% vs 21%
– Fatigue: 17% vs 4%
75
77
Safety
Outcome,
%
Placebo 12 wks
Then LDV/SOF +
RBV 12 wks
(n = 78)
LDV/SOF
24 wks
(n = 77)
SAE 5 10
AE leading
to d/c
1 0
Headache 27 40
Fatigue 9 19
Bourlière M, et al. Lancet Infect Dis. 2015;15:397-404.
26
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Evolving HCV Management in Harder-to-Treat Populations
LDV/SOF + RBV in Pts With Genotype 1
HCV and Previous Sofosbuvir Failure Pts
– GT1 treatment-experienced pts who experienced failure of prior SOF regimens (n = 51)
– SOF + pegIFN/RBV: 49%
– SOF + RBV: 39%
– SOF placebo + pegIFN/RBV: 10%
– GS-0938 monotherapy: 2%
– 16% black
– 59% GT1a
– 27% cirrhosis
Design
– Open-label cohort
Regimen
– Ledipasivr/sofosbuvir + RBV for 12 wks
1 pt relapsed: genotype 3a
Wyles D, et al. Hepatology. 2015;[Epub ahead of print]. Wyles DL, et al. AASLD 2014. Abstract 235.
Prior Regimen SVR12, n/N (%)
PegIFN/RBV/
SOF 25/25 (100)
SOF/RBV 19/20 (95)
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Evolving HCV Management in Harder-to-Treat Populations
Treatment Naive Treatment Experienced
BOSON: Is SOF + PegIFN/RBV for 12 Wks
Superior to SOF + RBV for 24 Wks in GT3?
Foster GR, et al. EASL 2015. Abstract LO5.
65/
72
68/
71
18/
22
21/
23
26/
34
30/
35
44/
54
49/
52
No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
90 96
82 91
82
94
77 86 100
80
60
40
20
0
SV
R12
(%
)
SOF + RBV 24 wks SOF + pegIFN/RBV 12 wks
n/N =
27
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Evolving HCV Management in Harder-to-Treat Populations
Sofosbuvir + PegIFN/RBV or RBV in Pts
With GT3 HCV and Previous SOF Failure Pts
– SOF + RBV treatment failures from FISSION, POSITRON, FUSION
– Cirrhosis included
Design
– Open-label cohorts
– Pt/investigator selected regimen
Regimen
– Sofosbuvir + ribavirin for 24 wks
– PegIFN/RBV + sofosbuvir for 12 wks
Esteban R, et al. EASL 2014. Abstract O8.
n/N =
100
80
60
40
20
0
91
63
20/
22
24/
38
SV
R12 (
%)
SOF + PegIFN/
RBV
SOF + RBV
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Evolving HCV Management in Harder-to-Treat Populations
0
LDV/SOF + RBV in Treatment-Experienced
Pts With Genotype 3 HCV
Ledipasvir/sofosbuvir?
– No data in sofosbuvir failure
Pts:
– Treatment naive and experienced
– With and without cirrhosis
Design
– Open-label cohorts
Regimen
– Ledipasvir/sofosbuvir + RBV for 12 wks
Gane E, et al. EASL 2014. Abstract O6. Gane E, et al. AASLD 2014. Abstract LB-11.
n/N =
100
80
60
40
20
Naive No
Cirrhosis
Cirrhosis
100
89
73
26/
26
25/
28
16/
22
SV
R12 (
%)
28
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Evolving HCV Management in Harder-to-Treat Populations
AASLD/IDSA Guidance for GT1 HCV:
Previous Treatment With NS5A Inhibitor
If minimal liver disease, defer treatment, pending further data
If cirrhotic or treatment otherwise urgent, resistance testing for RAVs that confer decreased susceptibility to NS3 PIs, NS5As recommended
– If both NS5A and NS3 RAVs detected, treatment within clinical trial recommended
AASLD/IDSA. HCV guidelines.
Previous
Treatment,
Cirrhosis Status
DCV + SOF LDV/SOF OMV/PTV/RTV
+ DSV
SMV + SOF
NS5A, cirrhosis or
urgent treatment
required
Not
recommended
If no NS5A RAVs:
24 wks + RBV
Not
recommended
If NS5A RAVs but no
NS3 RAVs:
24 wks + RBV
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Evolving HCV Management in Harder-to-Treat Populations
AASLD Guidance on HCV/HIV Drug–Drug
Interactions SMV SOF LDV DCV OMV/PTV/RTV + DSV
ATV/RTV No data No data LDV↑; ATV↑ DCV↑
PTV↑; ATV↑
DRV/RTV SMV↑; DRV↔
SOF↑; DRV↔
LDV↑; DRV↔
DCV↑; DRV↔
PTV ↓/↑; DRV↓
LPV/RTV No data No data No data DCV↑; LPV↔
PTV↑; LPV↔
Tipranavir/RTV No data No data No data No data No data
EFV SMV↓; EFV↔
SOF↔; EFV↔
LDV↓; EFV↓ DCV↓ No PK data
RPV SMV↔; RPV↔
SOF↔; RPV↔
LDV↔; RPV↔ No data
PTV↑; RPV↑
Etravirine No data No data No data DCV↓ No data
RAL SMV↔; RAL↔
SOF↔; RAL↔
LDV↔; RAL↔ No data
OMV/PTV/RTV + DSV↔; ↑RAL
EVG/COBI No data COBI↑; SOF↑
COBI↑;
LDV↑ No data No data
DTG No data No data LDV↔; DTG↔
DCV↔; DTG↑
PTV↓ DTG↑
Maraviroc No data No data No data No data No data
TDF SMV↔; TDF↔
SOF↔; TDF↔
LDV↔; TDF↑
DCV↔; TDF↔
OMV/PTV/RTV + DSV↔; TDF↔
AASLD/IDSA. HCV guidelines.