HCV Treatment With New Therapies
in Patients With Cirrhosis
Paul Y. Kwo, MD
Professor of Medicine
Medical Director of Transplantation
Division of Medicine/Gastroenterology/
Hepatology
Indiana University School of Medicine
Indianapolis, Indiana
This activity is supported by educational grants from
Gilead Sciences and Janssen.
Estimated 1 Million HCV-Infected Persons in
the US Will Have Cirrhosis by 2020
 Projection based on multicohort natural history model
Acute hepatitis
Cirrhosis
Ever infected
Chronic HCV
5,000,000
4,000,000
3,000,000
2,000,000
Peak incidence
Davis GL, et al. Gastroenterology. 2010;138:513-521.
Yr
40 yrs
Peak cirrhosis
2030
2020
2010
2000
1990
1980
1970
0
1960
1,000,000
1950
Total Number of HCVInfected Persons
6,000,000
GBD 2010: HCV-Related Cirrhosis, Liver
Cancer, and Death in the United States
 Estimated 19,500 liver cancer and 49,500 cirrhosis deaths in US in 2010
 Total liver-related deaths increased from 45,000 to 70,000 over 20 yrs
Causes of CLD Death, US 2010
HBV
HCV
Causes of CLD Death, US
50
25,000
41
40 39
29
30
16
14
13
8
10
0
20,000
Deaths (n)
Deaths (%)
40
20
Liver cancer–HCV
Cirrhosis–HCV
Liver cancer–alcohol
Cirrhosis–alcohol
Liver cancer–HBV
Cirrhosis–HBV
Alcohol
Other
15,000
10,000
5000
0
Liver Cancer
Cirrhosis
1990 1995 2000 2005 2010
Yr
Cowie BC, et al. AASLD 2013. Abstract 23.
Birth Cohort Screening and DAA Tx
Could Greatly Reduce HCV-Related
Transplants
 Markov model[1] based on birth cohort developed to predict transplant rate[2]
 Assumptions in model: All stages of fibrosis treated at same rate; 90% response rate to new Tx; all pts
with decompensated cirrhosis or HCC within Milan criteria considered potential transplant candidates
Liver Transplants (n)
180,000
162,559
162,747
150,617
160,000
126,296
140,000
No treatment
120,000
91,310
100,000
25% treated
80,000
60,000
50% treated
49,013
75% treated
40,000
All treated
20,000
0
2013
18,193
2018
25,573
27,175
2023
2028
26,207
24,258
21,994
2033
2038
2043
Yr in Model
1. Davis GL, et al. Gastroenterology. 2010;138:513. 2. Desai AP, et al. AASLD 2013. Abstract 1427.
Fibrosis Assessment:
Important to Diagnose Cirrhosis
 AASLD/IDSA guidance
 An assessment of the degree of hepatic fibrosis, using
noninvasive testing or liver biopsy, is recommended (rating:
Class I, Level A)
 Fibrosis assessment used to determine treatment urgency if
limited resources prevent treatment of all cases of HCV
infection and need for additional screening
 Cirrhotic patients require regular screening for HCC,
varices, other complications
 Achieving SVR in cirrhotic HCV pts highly beneficial
AASLD/IDSA HCV Management Guidance. October 2014.
Options for Liver Fibrosis Assessment
Liver biopsy:
gold standard
Liver Biopsy
Serum markers
of fibrosis
Serum
Biomarkers
Elastography:
approved in
United States
Axial CT/MRI, US
can demonstrate
cirrhotic
morphology, portal
hypertension
Strategies for Noninvasive Fibrosis Assessment
 AASLD/IDSA guidance[1]
 Most efficient strategy combines direct serum biomarkers and
transient liver elastography[2]
 Consider biopsy for any patient with discordant results between
2 testing methods if the information will affect clinical decisions
 Persons with clinical evidence of cirrhosis do not require
further disease staging
1. AASLD/IDSA HCV Management Guidance. October 2014.
2. Boursier J, et al. Hepatology. 2012;55:58-67.
AASLD/IDSA: Patients With F3/F4 Fibrosis
Have Highest Priority for HCV Treatment
 Treatment recommended for all patients with chronic HCV
infection (rating: Class I, Level A)
 When constrained resources prevent treatment of all HCV
infection cases, highest priority should be given to patients
with advanced fibrosis (Metavir F3) or compensated cirrhosis
(Metavir F4), liver transplant recipients, and patients with
severe extrahepatic hepatitis C
 Based on available resources, treatment should be prioritized
as necessary so that patients at high risk for liver-related
complications and severe extrahepatic hepatitis C
complications are given high priority
AASLD/IDSA HCV Management Guidance. October 2014.
Direct-Acting Antiviral Agents:
Key Characteristics
C
E1
E2
p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3/4A Protease Inhibitors (PI)
NS5B Nucleos(t)ide Inhibitors (NI)
High potency
Intermediate potency
Limited genotypic coverage
Pangenotypic coverage
Low barrier to resistance
High barrier to resistance
NS5A Inhibitors
NS5B Nonnucleoside Inhibitors (NNI)
High potency
Intermediate potency
Multigenotypic coverage
Limited genotypic coverage
Low barrier to resistance
Low barrier to resistance
Evolving Options for HCV Therapy
 New in 2013: beginning of all-oral therapy
 Sofosbuvir
 Simeprevir
 New in 2014 and early 2015: all-oral therapy options for all
 Sofosbuvir/ledipasvir
 Paritaprevir/ritonavir/ombitasvir + dasabuvir
 Daclatasvir
 Additional development of new therapies ongoing
Management of
Genotype 1 HCV With Cirrhosis
Current AASLD/IDSA Guidance: GT1,
Previous Nonresponders to pegIFN/RBV
 Note that guidelines do not yet reflect FDA approval of
sofosbuvir/ledipasvir or other agents that may be approved in coming
months
IFN Eligible
Preferred
Alternative
IFN Ineligible
Sofosbuvir 400 mg/day + simeprevir 150 mg/day ±
weight-based RBV 1000-1200 mg/day for 12 wks*
 Sofosbuvir 400 mg/day for 12 wks +
weight-based RBV 1000-1200 mg/day +
wkly pegIFN for 12-24 wks
 Simeprevir 150 mg/day for 12 wks +
weight-based RBV 1000-1200 mg/day +
wkly pegIFN for 48 wks*
 Sofosbuvir 400 mg/day + weight-based RBV
1000-1200 mg/day for 24 wks
*Pts with cirrhosis must have well compensated liver disease to receive simeprevir.
AASLD/IDSA HCV Management Guidance. October 2014.
Current AASLD/IDSA Guidance: GT1, TxNaive and Previous Relapsers
 Note that guidelines do not yet reflect FDA approval of sofosbuvir/ ledipasvir or other
agents that may be approved in coming months
 Recommendations for Tx-naive/previous relapse pts with compensated cirrhosis, including
those with HCC, same as for pts without cirrhosis
IFN Eligible
Preferred
 Sofosbuvir 400 mg/day + weightbased RBV 1000-1200 mg/day +
wkly pegIFN for 12 wks
Alternative
Simeprevir 150 mg/day for 12 wks +
weight-based RBV 1000-1200 mg/day
plus wkly pegIFN for 24 wks (GT1b or
1a without Q80K only)
IFN Ineligible
 Sofosbuvir 400 mg/day + simeprevir 150
mg/day ± weight-based RBV 1000-1200 mg/day
for 12 wks
 Sofosbuvir 400 mg/day + weight-based RBV
1000-1200 mg/day for 24 wks*
*Likely less effective than sofosbuvir + simeprevir, particularly among pts with cirrhosis.
AASLD/IDSA HCV Management Guidance. October 2014.
Sofosbuvir
 Oral, once-daily nucleotide NS5B polymerase inhibitor
 Potent antiviral activity; pangenotypic
 High barrier to resistance
 Pharmacology profile
 No significant drug interactions, including tacrolimus or cyclosporine
 Approved for combination treatment of HCV in following settings
 GT1-4 HCV
 HCC meeting Milan criteria; awaiting transplantation
 HIV coinfection
Sofosbuvir [package insert].
NEUTRINO: SVR12 With Sofosbuvir +
pegIFN/RBV in Tx-Naive GT1/4/5/6
 Open-label, single-arm, phase III study (N = 327): sofosbuvir 400 mg QD +
pegIFN/RBV for 12 wks
– 17% cirrhosis
100
SVR12 (%)
80
SVR12 by Biopsy Fibrosis Stage
F0
F1-F2
100
91
89
78
F3
100
40
40
20
20
124/137
34/38
32/41
0
Patel K, et al. AASLD 2013. Abstract 1093.
96
80
60
16/16
97
85
60
n/N =
SVR12 by FibroTest Stage
F4
76/78 101/105
0
46/54
79
68/86
Cirrhosis Predictive of Relapse With
Sofosbuvir + pegIFN/RBV in GT1
 Pooled multivariate regression analysis from NEUTRINO and
ATOMIC* studies[1]
Odds Ratio
P Value
Weight ≥ 75 kg
6.8
.01
IL28B non-CC
7.2
.009
Cirrhosis
3.2
.009
Factor
*ATOMIC: Open-label multicenter phase II study of sofosbuvir + pegIFN/RBV in noncirrhotic
treatment-naive patients; SVR rates 87% to 89% in GT1 HCV[2]
1. Foster GR, et al. EASL 2014. Abstract O66. 2. Kowdley KV, et al. Lancet. 2013;381:2100-2107.
Simeprevir
 Oral, once-daily NS3 PI for GT1 HCV
 Improved adverse effect profile vs previous PIs: no anemia
 Fewer drug–drug interactions vs previous PIs: no meaningful
drug–drug interactions with tacrolimus
 No data yet in CTP class B/C pts, but higher simeprevir
exposure in CTP class B/C individuals without HCV
infection makes dosing problematic
 Approved for combination treatment of GT1 HCV
 Screening for Q80K in GT1a pts recommended
Simeprevir [package insert].
COSMOS: Simeprevir + Sofosbuvir ±
RBV in GT1 HCV Patients
 Randomized phase IIa study
Wk 12
Patients With GT1 HCV
Cohort 1:
Previous null
responders, F0-F2
(N = 80)
Cohort 2:
Naives and previous null
responders, F3-F4
(N = 87)
Wk 24
Simeprevir + Sofosbuvir + RBV (n = 54)
Simeprevir + Sofosbuvir (n = 31)
Simeprevir + Sofosbuvir +
RBV (n = 54)
Simeprevir + Sofosbuvir
(n = 28)
Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV 1000-1200 mg/day.
Lawitz E, et al. Lancet. 2014;[Epub ahead of print].
COSMOS: SVR12 in Tx-Naive and Previous
Null Responders With F3-F4 Fibrosis
 Treatment-naive patients and previous null responders
100
100
93
93
94
16/16
25/27
13/14
82/87
SMV + SOF
SMV + SOF
+ RBV
SMV + SOF
SMV + SOF
+ RBV
93
SVR12 (%)
80
60
40
20
n/N =
0
28/30
SMV + SOF
+ RBV
24 Wks
Lawitz E, et al. Lancet. 2014;[Epub ahead of print].
12 Wks
Overall
HCV-TARGET: Adverse Events With
Sofosbuvir + Simeprevir ± RBV in GT1
 Longitudinal observational analysis of patients receiving DAA-based HCV therapy in North
America and Europe
 60% of patients with GT1 HCV initiated sofosbuvir + simeprevir ± RBV
 Most frequent adverse events: mild fatigue, headache, nausea
 Discontinuations for virologic failure or adverse event: n = 3
 Serious adverse events: 10 in 8 patients
 Deaths: n = 1 (hepatic decompensation)
Characteristic, %
Sofosbuvir + Simeprevir
(n = 347)
Sofosbuvir + Simeprevir + RBV
(n = 92)
Treatment experienced
49
42
Cirrhosis
50
63
GT1a/1b
61/30
78/12
10
10
Post liver transplant
Sulkowski MS, et al. AASLD 2014. Abstract 955. Note that these data were available in abstract form only
at the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.
Sofosbuvir + RBV in Pts With Cirrhosis and
Portal HTN ± Decompensation
 Interim results of an open-label phase II trial
Wk 24
Current analysis
HCV-infected
patients with
portal HTN ±
decompensated
liver disease*
(N = 50)
Wk 48
Wk 72
Sofosbuvir + Ribavirin (n = 25)
Observation (n = 25)
Sofosbuvir + Ribavirin (n = 25)
Sofosbuvir 400 mg once daily; RBV 1000-1200 mg/day divided twice daily.
*Among 25 patients allocated sofosbuvir + RBV, 10 had GT1a HCV, 9 had GT1b, 2 had GT2, 2 had GT3,
and 2 had GT4.
Afdhal N, et al. EASL 2014. Abstract O68.
Sofosbuvir + RBV in Pts With Cirrhosis and Portal
HTN: On-Tx Virologic Response
HCV RNA < LLOQ (%)
80
60
100
100
100
94*
100
100
94
93
75
56
44
CTP A
CTP B
40
20
n/N =
0
5/9
7/16
Wk 2
9/9 12/16
Wk 4
*1 patient with nonresponse at Wk 8.
Afdhal N, et al. EASL 2014. Abstract O68.
8/8
15/16
Wk 8
8/8 15/16
Wk 12
7/7 14/15
Wk 24
Sofosbuvir + RBV in Pts With Cirrhosis/
Portal HTN: Disease Marker Changes
SOF + RBV (n = 25)
20
15
10
5
0
-5
-10
-15
Platelets (103/µL)
P = .003
17
P = NS
Albumin (g/dL)
P = .001
1
-1
-9
CTP A
Observation 24 wks (n = 25)
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
CTP B
P = .001
0.5
0.4
13
20
0
0
-20
-40
0
-0.1
CTP A
-60
-80
-72
CTP B
Ascites
Clinical Events, n
ALT (U/L)
-75
CTP B
CTP A
Hepatic Encephalopathy
SOF + RBV
(n = 25)
Observation
(n = 25)
SOF + RBV
(n = 25)
Observation
(n = 25)
Baseline
6
9
5
2
Wk 12
5
8
3
3
Wk 24
0
7
0
4
Afdhal N, et al. EASL 2014. Abstract O68.
Sofosbuvir/Ledipasvir
 Oral, once-daily fixed-dose combination of nucleotide NS5B polymerase
inhibitor and NS5A inhibitor
 Sofosbuvir: potent antiviral activity; pangenotypic
 Ledipasvir: potent antiviral activity against GT1a, 1b, 4a, 5a, 6a
 Combination has high barrier to resistance
 Pharmacology profile
 Clinically significant drug interactions include with P-gp inducers
 No clinically significant drug interactions with tacrolimus or cyclosporine
 Approved for treatment of GT1 HCV
Sofosbuvir/ledipasvir [package insert].
Sofosbuvir/Ledipasvir 400/90 mg:
Prescribing Information for GT1 HCV
Patient Population
Recommended Treatment
Duration, Wks
Treatment naive with or without cirrhosis
12*
Treatment experienced† without cirrhosis
12
Treatment experienced† with cirrhosis
24
*8-wk duration can be considered in treatment-naive patients without cirrhosis who have pretreatment HCV
RNA < 6 million IU/mL.
†Treatment-experienced patients who have experienced treatment failure with either pegIFN/RBV or an HCV
PI plus pegIFN/RBV.
Sofosbuvir/ledipasvir [package insert].
ION-1: SOF/LDV FDC ± RBV for 12 or 24
Wks in Treatment-Naive GT1 Patients
 Open-label phase III trial[1,2]
 15% to 17% of participants had cirrhosis
 No upper age or BMI limit; platelet count ≥ 50,000/mm3, no neutrophil min
Wk 12
Stratified by HCV subtype (1a vs
1b) and cirrhosis
Wk 24
SOF/LDV (n = 214)
Treatment-naive pts
with GT1 HCV
(N = 865)
SOF/LDV + RBV (n = 217)
SOF/LDV (n = 217)
SOF/LDV + RBV (n = 217)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.
ION-1: SVR12 According to Cirrhosis Status
100
100
97
100
100
99.5 96.9
100
100
SVR12 (%)
80
No cirrhosis
Cirrhosis
60
40
20
n/N =
0
179/
179
32/
33
SOF/LDV
178/
178
33/
33
SOF/LDV + RBV
12 Wks
181/
182
31/
32
SOF/LDV
179/
179
36/
36
SOF/LDV + RBV
24 Wks
 SVR12 rates did not differ by GT1a vs GT1b in any treatment arm
Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.
ION-2: SOF/LDV FDC ± RBV for 12 or 24
Wks in Tx-Experienced GT1 Pts
 Open-label phase III trial
 20% of participants had cirrhosis, 41% to 46% were previous nonresponders, and 46% to 61%
had experienced PI failure
 No upper age or BMI limit; platelet count ≥ 50,000/mm3, no neutrophil min
Stratified by HCV subtype (1a vs 1b),
cirrhosis, and previous Tx response
Wk 12
Wk 24
SOF/LDV (n = 109)
Tx-experienced pts
with GT1 HCV
(N = 440)
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
SOF/LDV + RBV (n = 111)
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
ION-2: SVR12 According to Cirrhosis Status
100
95
86
100
82
99
100
99
100
SVR12 (%)
80
60
No cirrhosis
Cirrhosis
40
20
n/N =
0
83/
87
19/
22
SOF/LDV
89/
89
18/
22
SOF/LDV + RBV
12 Wks
86/
87
22/
22
SOF/LDV
88/
89
22/
22
SOF/LDV + RBV
24 Wks
 Absence of cirrhosis was significantly associated with SVR12 in multivariate
exact logistic regression model (OR: 5.1; P = .012)
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
Pooled Efficacy/Safety Analysis of
Sofosbuvir/Ledipasvir in Cirrhosis
 Pooled analysis of GT1 HCV–infected pts with cirrhosis from phase II and III
trials of sofosbuvir/ledipasvir ± RBV for 12-24 wks
Baseline Characteristic, n (%)
GT1, Cirrhosis (N = 514)
Tx experienced
353 (69)
HCV subgenotype 1a
307 (60)
Non-CC
 IL28B
Safety similar to that observed in pts without cirrhosis
405 (79)
Initiated Tx with albumin < 3.5 g/dL
59 (11)
3
Initiated Tx with
platelet
< 90,000
91 (18)observed
AEs
morecount
frequent
in ptscells/mm
treated with RBV; no other AE or SAE trends
 SVR12 rate in 284 pts with available data: 95%
Bourlière M, et al. AASLD 2014. Abstract 82. Note that these data were available in abstract form only at
the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.
Opportunities and Challenges With Current
Therapies in GT1 Cirrhosis
 Higher SVR rates in GT1 HCV with compensated cirrhosis
with just 12 wks of therapy with sofosbuvir + pegIFN/RBV
than with first-generation protease inhibitors
 No adjustment of sofosbuvir required
 Adverse effects of pegIFN/RBV still problematic in cirrhotics
 All oral therapy now available for patients with GT1 HCV
with 2 different regimens
 Sofosbuvir/ledipasvir
 Sofosbuvir + simprevir ± RBV
 Based on limited data in F3/F4 disease (39 patients)
 Viral suppression associated with clinical improvement
Current AASLD/IDSA Guidance:
Genotype 2/3
Genotype 2
Genotype 3
Recommended
 Sofosbuvir 400 mg/day + weight-  Sofosbuvir 400 mg/day + weightbased RBV 1000-1200 mg/day
based RBV 1000-1200 mg/day for
for 12 wks*
24 wks
Alternative
(if IFN eligible)
 Previous nonresponders only:
 Sofosbuvir 400 mg/day + weightSofosbuvir 400 mg/day + weightbased RBV 1000-1200 mg/day +
based RBV 1000-1200 mg/day +
wkly pegIFN for 12 wks
wkly pegIFN for 12 wks
*Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks.
AASLD/IDSA HCV Management Guidance. October 2014.
FISSION: Sofosbuvir + RBV vs pegIFN/ RBV
in Tx-Naive GT2/3 HCV Patients
 Randomized, controlled, open-label phase III noninferiority trial
– 20% to 21% had cirrhosis; 71% to 72% had GT3 HCV
Stratified by HCV GT (2 vs 3),
HCV RNA (< vs ≥ 106 IU/mL),
cirrhosis (yes vs no)
Treatment-naive
patients with
GT2/3 HCV
(N = 499)
Wk 12
Sofosbuvir 400 mg/day
+ RBV 1000-1200 mg/day
(n = 256)
PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day
(n = 243)
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
Wk 24
FISSION: SVR12 According to
Genotype and Fibrosis Level
Sofosbuvir + RBV
100
PegIFN + RBV
98
91
82
SVR12 (%)
80
71
62
61
60
40
34
30
20
n/N =
0
58/59
44/54
No cirrhosis
10/11
Cirrhosis
Genotype 2
Gane E, et al. EASL 2013. Abstract 5.
8/13
89/145
99/139
No cirrhosis
13/38
11/37
Cirrhosis
Genotype 3
FUSION: Sofosbuvir + RBV for 12 or 16 Wks
in Tx-Experienced GT 2/3 HCV Pts
 Randomized, double-blind, placebo-controlled phase III trial
– 62% to 64% had GT3 HCV, 33% to 35% had cirrhosis, 74% to 76% were previous relapsers
Stratified by
HCV GT (2 vs 3),
cirrhosis (yes vs no)
Tx-experienced pts
with GT2/3 HCV
(N = 201)
Wk 12
Sofosbuvir 400 mg/day +
RBV 1000-1200 mg/day
(n = 103)
Placebo
Sofosbuvir 400 mg/day +
RBV 1000-1200 mg/day
(n = 98)
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Wk 16
FUSION: SVR12 According to
Genotype and Fibrosis Level
Sofosbuvir + RBV 12 wks
96
100
100
100
78
60
60
80
SVR12 (%)
SVR12 (%)
80
40
63
n/N =
25/
26
23/
23
6/10
40
7/9
No cirrhosis
Cirrhosis
Genotype 2
61
60
37
19
20
20
0
Sofosbuvir + RBV 16 wks
0
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
14/
38
25/
40
5/26
14/
23
No cirrhosis
Cirrhosis
Genotype 3
VALENCE: Sofosbuvir + RBV for 12 or 24
Wks in Naive and Exp’d GT2/3 HCV Pts
 Phase III study in Europe
 21% had cirrhosis, 58% previously treated with IFN-based therapy
 Original protocol amended to lengthen treatment for all GT3 pts when emerging data
suggested benefit of additional treatment for this group*
Wk 12
GT2
HCV-infected
Tx-naive or
exp’d pts
(N = 323)
GT3
Wk 24
Sofosbuvir 400 mg/day +
RBV 1000 mg or 1200 mg/day
(n = 73)
Sofosbuvir 400 mg/day +
RBV 1000 mg or 1200 mg/day
(n = 250)
*Small number of GT3 pts (n = 11) who had already completed 12 wks at time of protocol amendment
were included in safety analysis with GT2 but analyzed separately for efficacy. Pts randomized to placebo
in original protocol offered alternative treatment protocol.
Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
VALENCE: SVR12
GT2 12-Wk Treatment
(n = 73)
100
97
100
100
94
78
60
40
92
87
62
60
40
20
20
n/N =
0
95
80
SVR12 (%)
80
SVR12 (%)
GT3 24-Wk Treatment
(n = 250)
29/30
2/2
30/32
7/9
Naive,
Naive,
Exp’d
Exp’d,
Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic
n/N =
0
87/92
Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
85/98
29/47
Naive,
Naive,
Exp’d
Exp’d,
Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic
 No increase in AEs seen with longer duration treatment
 AEs consistent with RBV
12/13
LONESTAR-2: Sofosbuvir + P/R for 12 Wks
in Treatment-Exp’d GT2/3 HCV Pts
 Single-arm trial of pts with treatment failure on P/R
 Approximately 50% with compensated cirrhosis
No cirrhosis
100
93
100
Wk 12
Sofosbuvir 400 mg/day +
PegIFN 180 µg once wkly +
RBV 1000 mg or 1200 mg/day
83
10/
12
10/
12
60
40
20
n/N =
0
Lawitz E, et al. AASLD 2013. Abstract LB-4.
83
80
SVR12 (%)
Pts with GT2 or
GT3 HCV and
previous
treatment failure
with P/R
(N = 47)
Cirrhosis
9/
9
GT2
13/
14
GT3
Anticipated Changes in HCV Therapy
 All-oral regimens will be the standard of care by end of 2014
for all genotypes
 Excellent efficacy in pts with compensated cirrhosis
 More data required in pts with decompensated cirrhosis
On-Treatment Monitoring:
GT1 With Cirrhosis
 Safety data from phase II/III studies suggest no difference in monitoring required for
patients with CTP class A cirrhosis
 Assessments for drug-related adverse events should be conducted more frequently if
clinically indicated (eg, CBC count for patients receiving RBV)
Treatment Wk
4
8
12/EOT
16*
20*
24*
CBC
X
X
X
X
X
X
Creatinine
X
X
X
X
X
X
Calculated GFR
X
X
X
X
X
X
Hepatic fxn panel
X
X
X
X
X
X
TSH (with IFN)
HCV RNA
X
X
X
X
X
*If using a 24-wk treatment option.
AASLD/IDSA HCV Management Guidance. October 2014.
SVR 12
X
On-Treatment Monitoring:
GT2 With Cirrhosis
 Safety data from phase II/III studies suggest no difference in monitoring required for
patients with CTP class A cirrhosis
 Assessments for drug-related adverse events should be conducted more frequently if
clinically indicated (eg, CBC count for patients receiving RBV)
Treatment Wk
4
8
12/EOT
16*
CBC
X
X
X
X
Creatinine
X
X
X
X
Calculated GFR
X
X
X
X
Hepatic fxn panel
X
X
X
X
TSH (with IFN)
HCV RNA
SVR 12
X
X
X
*Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending
treatment to 16 wks.
AASLD/IDSA HCV Management Guidance. October 2014.
X
On-Treatment Monitoring:
GT3 With Cirrhosis
 Safety data from phase II/III studies suggest no difference in monitoring required for
patients with CTP class A cirrhosis
 Assessments for drug-related adverse events should be conducted more frequently if
clinically indicated (eg, CBC count for patients receiving RBV)
Treatment Wk
4
8
12
16
20
24/EOT
CBC
X
X
X
X
X
X
Creatinine
X
X
X
X
X
X
Calculated GFR
X
X
X
X
X
X
Hepatic fxn panel
X
X
X
X
X
X
TSH (with IFN)
HCV RNA
X
X
X
X
X
AASLD/IDSA HCV Management Guidance. October 2014.
SVR 12
X
Triple DAA Therapy With Paritaprevir/
Ritonavir/Ombitasvir + Dasabuvir + RBV
 Paritaprevir is a potent NS3/4A protease inhibitor
 Ritonavir boosting of paritaprevir increases the peak, trough,
and overall drug exposures of paritaprevir to enable once-daily
dosing
 Ombitasvir is a potent NS5A inhibitor
 Dasabuvir is a nonnucleoside NS5B polymerase inhibitor
TURQUOISE II: Paritaprevir/RTV/Ombitasvir +
Dasabuvir + RBV in Cirrhotic GT1 Pts
 Open-label phase III trial
 Inclusion criteria: GT1, compensated cirrhosis (CTP class A), DAA naive, radiographic ascites
and varices permitted, serum albumin ≥ 2.8 g/dL,
total bilirubin < 3 mg/dL, serum AFP ≤ 100 ng/mL, INR ≤ 2.3, platelets
≥ 60,000 cells/mL
Wk 12
DAA-naive cirrhotic
pts with GT1 HCV
(N = 380)
Paritaprevir/RTV/Ombitasvir
+ Dasabuvir + RBV
(n = 208)
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV
(n = 172)
Paritaprevir/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily;
RBV 1000-1200 mg/day.
Poordad F, et al . N Engl J Med. 2014;370:1973-1982.
Wk 24
TURQUOISE-II: ITT SVR12
P = .09
100
92
96
SVR12 (%)
 Noninferiority threshold: 43%[1]
 High SVR12 rates regardless of sex, age,
80
BMI, or baseline HCV RNA in
subgroup analyses[2]
60
 Pts with platelet counts
40
20
n/N =
0
 Superiority threshold: 54%[1]
191/208
165/172
12 wks
24 wks
< 100,000/mm3: 89% to 97%
 Pts with serum albumin
< 3.5 g/dL: 84% to 89%
Paritaprevir/RTV/Ombitasvir +
Dasabuvir + RBV
1. Poordad F, et al. N Engl J Med. 2014;370:1973-1982. 2. Fried MW, et al. AASLD 2014. Abstract 81.
Note that these data were available in abstract form only at the time of drafting this slideset and are subject
to change at the AASLD 2014 presentation.
TURQUOISE II: SVR12 According to GT1 HCV
Subtype and Treatment Experience
GT1a
SVR12 (%)
100
100 100
92.9
80.0
12 wks
24 wks 100
80
80
60
60
40
40
20
20
n/N =
0

92.2 92.9
93.3100
59/ 52/
64 56
14/ 13/
15 13
11/ 10/
11 10
40/ 39/
50 42
Naive
Relapse
PR
Null
Response
0
GT1b
100 100
100 100
85.7100
100 100
22/ 18/
22 18
25/ 20/
25 20
6/7 3/3
14/ 10/
14 10
Naive
Relapse
PR
Null
Response
Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt),
7/12 relapsers by posttreatment Wk 12 were GT1a null responders
Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
TURQUOISE-II: Laboratory Abnormalities
Event
12-Wk Arm
(n = 208)
24-Wk Arm
(n = 172)
ALT > 5 x ULN, %
2.9
0
Total bilirubin > 3 x ULN, %
13.5
5.2
 < 10 g/dL
7.2
11.0
 < 8.0 g/dL
1.4
0.6
Hemoglobin, %
 ALT elevation
– Asymptomatic, transient, and improved or resolved with ongoing study drug dosing

Bilirubin elevation
– Transient, predominantly indirect, no discontinuations due to hyperbilirubinemia
 Hemoglobin decrease
– Managed with reduction of ribavirin dose in 34 pts (8.9%)
Poordad F, et al. EASL 2014. Abstract O163. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
GT1 HCV SVR Summary: Treatment-Naive
Patients With Cirrhosis
100
100
COSMOS[1]
100
100
ION-1[2]
100
97
TURQUOISE-II[3]
100
97
94
95
80
67
SVR (%)
60
40
20
n/N =
0
2/3
6/6
6/6
3/3
32/33
33/33
31/32
36/36
81/86
70/74
SOF +
SMV
12 Wks
SOF +
SMV +
RBV
12 Wks
SOF +
SMV
24 Wks
SOF +
SMV +
RBV
24 Wks
SOF/
LDV
12 Wks
SOF/
LDV +
RBV
12 Wks
SOF/
LDV
24 Wks
SOF/
LDV +
RBV
24 Wks
3DAA +
RBV
12 Wks
3DAA +
RBV
24 Wks
1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:18891898. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
GT1 HCV SVR Summary: TreatmentExperienced Patients With Cirrhosis
100
COSMOS[1]
100
90
100
ION-2[2]
86
80
TURQUOISE-II[3]
100
100
97
90
82
SVR (%)
80
60
40
20
n/N =
0
4/4
4/5
4/4
SOF +
SMV
12 Wks
SOF +
SMV +
RBV
12 Wks
SOF +
SMV
24 Wks
9/
10
SOF +
SMV +
RBV
24 Wks
19/
22
SOF/
LDV
12 Wks
18/
22
SOF/
LDV +
RBV
12 Wks
22/
22
22/
22
110/
122
95/
98
SOF/
LDV
24 Wks
SOF/
LDV +
RBV
24 Wks
3DAA +
RBV
12 Wks
3DAA +
RBV
24 Wks
1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:14831493. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
ELECTRON 2: SOF/LDV FDC ± RBV in
Diverse Hard-to-Treat Patients
 Partially randomized, open-label phase II trial
Wk 12
GT1 and CTP class B
cirrhosis
(N = 20)
SOF/LDV FDC (n = 20)
SVR12: 65% (13/20);
7 relapses
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day
Laboratory Parameter
GT1, CTP Class B
Median total bilirubin, mg/dL (range)
1.5 (0.7-3.7)
Median serum albumin, g/dL (range)
3.1 (2.3-3.8)
Median INR (range)
1.2 (1.0-3.0)
Ascites, n (%)
4 (20)
Hepatic encephalopathy, n (%)
6 (20)
Median platelet count, 103/µL (range)
Gane EJ, et al. EASL 2014. Abstract O6.
84 (44-162)
Sofosbuvir/Ledipasvir + RBV in Patients
With Decompensated Cirrhosis
 Study population: GT 1 or 4 HCV infection, Tx naive or experienced, CTP B (n
= 55) or C (n = 53) decompensated cirrhosis
 Treatment: 12 or 24 wks of sofosbuvir/ledipasvir plus RBV (escalating doses
beginning at 600 mg/day)
 Tx-emergent SAEs occurred in 28 patients (26%)
 4 SAEs in 4 pts deemed related to study treatment: anemia, decreased hemoglobin,
hepatic encephalopathy, peritoneal hemorrhage
 Most common AEs: fatigue, nausea, headache
 SVR4 rates among patients with available data
 CTP B: 89% with 12 wks, 92% with 24 wks
 CTP C: 91% with 12 wks, 33% with 24 wks (based on 3 pts)
Flamm SL, et al. AASLD 2014. Abstract 239. Note that these data were available in abstract form only at
the time of drafting this slideset and are subject to change at the AASLD 2014 presentation.
AI444-040: Sofosbuvir + Daclatasvir ± RBV
for GT3 HCV Pts
 Randomized, open-label phase IIa study
 14% of patients with GT2/3 HCV had cirrhosis (specific number for GT3 not
reported)
Wk 24
Tx-naive pts
with GT3 HCV
(N = 18)
Daclatasvir 60 mg QD +
Sofosbuvir 400 mg QD*
(n = 13)
Daclatasvir 60 mg QD +
Sofosbuvir 400 mg QD +
RBV 1000 mg or 1200 mg/day
(n = 5)
*7 patients received 4-week lead-in with sofosbuvir 400 mg QD alone before addition of daclatasvir.
Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.
AI444-040: SVR12 in GT3 by Treatment Arm
100
100
Daclatasvir + sofosbuvir
Daclatasvir + sofosbuvir + RBV
85
SVR12 (%)
80
60
40
20
n/N =
11/13
5/5
0
All GT3 Pts (Including Pts
With Cirrhosis)
 A potential option for cirrhotic GT3 pts, more data required in
cirrhotic nonresponders
Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.
Management of HCV With Cirrhosis: Summary
 All oral therapies for patients with GT1 HCV infection
approved in 2014
 > 90% SVR rate, 12- to 24-wk duration
 Cirrhosis: some treatment-experienced patients require
24 wks of treatment
 Interferon not required
 RBV-free therapies now available
 More data needed in decompensated liver disease
 GT2: High SVR rates regardless of cirrhosis
 GT3: High SVR rates in treatment-naive patients
 Additional strategies needed for cirrhotic nonresponders