paul y. kwo, md professor of medicine medical director of transplantation division of...
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Paul Y. Kwo, MD Professor of Medicine
Medical Director of TransplantationDivision of
Medicine/Gastroenterology/ Hepatology
Indiana University School of Medicine
Indianapolis, Indiana
HCV Treatment With New Therapiesin Patients With Cirrhosis
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
Davis GL, et al. Gastroenterology. 2010;138:513-521.
6,000,000
5,000,000
4,000,000
3,000,000
2,000,000
1,000,000
0
To
tal N
um
ber
of
HC
V-
Infe
cted
Per
son
s
195
0
196
0
197
0
198
0
200
0
199
0
201
0
203
0
202
0
Peak incidence Peak cirrhosis
40 yrs
Yr
Acute hepatitisCirrhosisEver infectedChronic HCV
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
Cowie BC, et al. AASLD 2013. Abstract 23.
Causes of CLD Death, US 2010
Dea
ths
(%)
50
40
30
20
10
0
41
16
29
14
8
40 39
13
Liver Cancer Cirrhosis
Causes of CLD Death, US
Yr
Dea
ths
(n)
HBVHCV
Liver cancer–HBVCirrhosis–HBV
AlcoholOther
Liver cancer–HCVCirrhosis–HCVLiver cancer–alcoholCirrhosis–alcohol
1990 1995 2000 2005 2010
25,000
20,000
15,000
10,000
5000
0
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
Liv
er
Tra
nsp
lan
ts (
n)
20,000
2013 2018 2023 2028 2033 2038 2043
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
0
Yr in Model
150,617162,559 162,747
24,258 21,994
49,013
91,310
126,296
18,19325,573 27,175 26,207
No treatment
25% treated
50% treated
75% treated
All treated
1. Davis GL, et al. Gastroenterology. 2010;138:513. 2. Desai AP, et al. AASLD 2013. Abstract 1427.
Fibrosis Assessment: Important to Diagnose CirrhosisAASLD/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
Serum Biomarke
rs
Liver biopsy: gold standard
Axial CT/MRI, US can demonstrate cirrhotic morphology, portal hypertension
Serum markers of fibrosis
Elastography: approved in United States
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 TreatmentTreatment 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.
NS3/4A Protease Inhibitors (PI)
High potency
Limited genotypic coverage
Low barrier to resistance
NS5A Inhibitors
High potency
Multigenotypic coverage
Low barrier to resistance
NS5B Nucleos(t)ide Inhibitors (NI)
Intermediate potency
Pangenotypic coverage
High barrier to resistance
NS5B Nonnucleoside Inhibitors (NNI)
Intermediate potency
Limited genotypic coverage
Low barrier to resistance
Direct-Acting Antiviral Agents: Key Characteristics
C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B
Evolving Options for HCV Therapy
New in 2013: beginning of all-oral therapySofosbuvir Simeprevir
New in 2014 and early 2015: all-oral therapy options for allSofosbuvir/ledipasvirParitaprevir/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
AASLD/IDSA HCV Management Guidance. October 2014.
IFN Eligible IFN Ineligible
Preferred Sofosbuvir 400 mg/day + simeprevir 150 mg/day ± weight-based RBV 1000-1200 mg/day for 12 wks*
Alternative
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.
Current AASLD/IDSA Guidance: GT1, Tx-Naive 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
AASLD/IDSA HCV Management Guidance. October 2014.
IFN Eligible IFN Ineligible
Preferred Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks
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*
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)
*Likely less effective than sofosbuvir + simeprevir, particularly among pts with cirrhosis.
SofosbuvirOral, once-daily nucleotide NS5B polymerase inhibitor
Potent antiviral activity; pangenotypic
High barrier to resistance
Pharmacology profileNo significant drug interactions, including tacrolimus or
cyclosporine
Approved for combination treatment of HCV in following settingsGT1-4 HCVHCC meeting Milan criteria; awaiting transplantationHIV 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
Patel K, et al. AASLD 2013. Abstract 1093.
SVR12 by Biopsy Fibrosis Stage SVR12 by FibroTest Stage
SV
R12
(%
)
n/N =
100
80
60
40
20
0
91
78
10089
16/16 124/137 34/38
100
80
60
40
20
0
85
97
79
96
76/78 101/105 46/5432/41 68/86
F0 F1-F2 F3 F4
Cirrhosis Predictive of Relapse With Sofosbuvir + pegIFN/RBV in GT1
Pooled multivariate regression analysis from NEUTRINO and ATOMIC* studies[1]
*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.
SimeprevirOral, once-daily NS3 PI for GT1 HCVImproved adverse effect profile vs previous PIs: no
anemiaFewer 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 HCVScreening for Q80K in GT1a pts recommended
Simeprevir [package insert].
COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV Patients
Randomized phase IIa study
Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV 1000-1200 mg/day.
Patients With GT1 HCV Cohort 1:
Previous null responders, F0-F2
(N = 80)
Cohort 2:
Naives and previous null responders, F3-F4
(N = 87)
Simeprevir + Sofosbuvir + RBV (n = 54)
Simeprevir + Sofosbuvir (n = 31)
Wk 12 Wk 24
Simeprevir + Sofosbuvir (n = 28)
Simeprevir + Sofosbuvir + RBV (n = 54)
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
Lawitz E, et al. Lancet. 2014;[Epub ahead of print].
Overall
28/30 16/16n/N =
100
80
60
40
20
0
93
25/27 82/87
100
24 Wks
SMV + SOF + RBV
SMV + SOF
12 Wks
SMV + SOF + RBV
SMV + SOF
13/14
SMV + SOF + RBV
93 93 94
SV
R12
(%
)
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)
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
Observation (n = 25)
Sofosbuvir + Ribavirin (n = 25)
Wk 72
Afdhal N, et al. EASL 2014. Abstract O68.
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.
HCV-infected patients with portal HTN ±
decompensated liver disease*
(N = 50)
Wk 24Current analysis
Sofosbuvir + Ribavirin (n = 25)
Wk 48
Sofosbuvir + RBV in Pts With Cirrhosis and Portal HTN: On-Tx Virologic Response
HC
V R
NA
< L
LO
Q (
%)
100
80
60
40
20
0Wk 2 Wk 4 Wk 8 Wk 12
56
10094*
Wk 24
CTP A44
75
100 100 10094 93
CTP B
5/9 9/9n/N = 8/8 7/77/16 12/16 15/16 8/8 15/16 14/15
*1 patient with nonresponse at Wk 8.
Afdhal N, et al. EASL 2014. Abstract O68.
Sofosbuvir + RBV in Pts With Cirrhosis/ Portal HTN: Disease Marker Changes
Platelets (103/µL) Albumin (g/dL)SOF + RBV (n = 25) Observation 24 wks (n = 25)
CTP A CTP B
P = .003
P = NS
P = .001 P = .001
Clinical Events, n
Ascites 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.
201510
50
-5-10-15
17
-9
1
-1
CTP A CTP B
0.60.50.40.30.20.1
0-0.1-0.2
0.50.4
0
-0.1
130
-75-72
ALT (U/L)
CTP A CTP B
20
0
-20
-40
-60
-80
Sofosbuvir/LedipasvirOral, once-daily fixed-dose combination of nucleotide
NS5B polymerase inhibitor and NS5A inhibitorSofosbuvir: potent antiviral activity; pangenotypicLedipasvir: potent antiviral activity against GT1a, 1b,
4a, 5a, 6aCombination has high barrier to resistancePharmacology 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
*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
SOF/LDV + RBV (n = 217)
SOF/LDV (n = 214)
Wk 24
Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Treatment-naive pts with GT1 HCV
(N = 865)
SOF/LDV + RBV (n = 217)
SOF/LDV (n = 217)
Wk 12Stratified by HCV subtype (1a vs 1b) and
cirrhosis
ION-1: SVR12 According to Cirrhosis Status
SVR12 rates did not differ by GT1a vs GT1b in any treatment arm
No cirrhosis
Cirrhosis
179/179
32/33
178/178
33/33
181/182
31/32
179/179
36/36
12 Wks 24 Wks
SOF/LDV + RBV SOF/LDV + RBVSOF/LDV SOF/LDV
SV
R12
(%
)
Afdhal N, et al. N Engl J Med. 2014;370:1889-1898.
100
80
60
40
20
0
100 97 100 100 10010096.999.5
n/N =
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
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
Wk 24
Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day.
Tx-experienced pts with GT1 HCV
(N = 440)
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
Wk 12
Stratified by HCV subtype (1a vs 1b), cirrhosis, and previous
Tx response
ION-2: SVR12 According to Cirrhosis Status
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.
83/87
19/22
89/89
18/22
86/87
22/22
88/89
22/22
12 Wks 24 Wks
SOF/LDV + RBV SOF/LDV + RBVSOF/LDV SOF/LDV
SV
R12
(%
)
100
80
60
40
20
0
95 86 10082
1009910099
n/N =
No cirrhosis
Cirrhosis
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
Safety similar to that observed in pts without cirrhosis AEs more frequent in pts treated with RBV; no other AE or
SAE trends observed 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 CirrhosisHigher SVR rates in GT1 HCV with compensated
cirrhosis with just 12 wks of therapy with sofosbuvir + pegIFN/RBV than with first-generation protease inhibitorsNo 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 regimensSofosbuvir/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
AASLD/IDSA HCV Management Guidance. October 2014.
Genotype 2 Genotype 3
Recommended Sofosbuvir 400 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
Alternative (if IFN eligible)
Previous nonresponders only: Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks
Sofosbuvir 400 mg/day + weight-based RBV 1000-1200 mg/day + wkly pegIFN for 12 wks
*Previous nonresponders to pegIFN/RBV with cirrhosis may benefit from extending treatment to 16 wks.
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
Treatment-naive patients with
GT2/3 HCV(N = 499)
Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day
(n = 256)
PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day(n = 243)
Wk 24Wk 12
Stratified by HCV GT (2 vs 3), HCV RNA (< vs ≥ 106 IU/mL),
cirrhosis (yes vs no)
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
FISSION: SVR12 According toGenotype and Fibrosis Level
Gane E, et al. EASL 2013. Abstract 5.
Genotype 2 Genotype 3
SV
R12
(%
)
No cirrhosis No cirrhosisCirrhosis Cirrhosis
58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37n/N =
100
80
60
40
20
0
98
8291
62 6171
34 30
Sofosbuvir + RBV PegIFN + RBV
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
Tx-experienced pts with GT2/3 HCV
(N = 201)
Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day
(n = 103)
Sofosbuvir 400 mg/day + RBV 1000-1200 mg/day
(n = 98)
Wk 16Wk 12
Placebo
Stratified by HCV GT (2 vs 3),
cirrhosis (yes vs no)
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
FUSION: SVR12 According to Genotype and Fibrosis Level
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks
100
6/10 5/26
SV
R12
(%
)
25/26 7/923/
2314/38
14/23
25/40
No cirrhosis No cirrhosisCirrhosis Cirrhosis
Genotype 2 Genotype 3
19
6163
37
n/N =
100
80
60
40
20
0
96
60
78
100
80
60
40
20
0
SV
R12
(%
)
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*
HCV-infected
Tx-naive or exp’d pts(N = 323)
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)
Wk 24Wk 12
GT2
GT3
*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
No increase in AEs seen with longer duration treatmentAEs consistent with RBV
GT2 12-Wk Treatment(n = 73)
GT3 24-Wk Treatment(n = 250)
100
80
60
40
20
0
SV
R12
(%
)
SV
R12
(%
)
100
80
60
40
20
0Naive,
NoncirrhoticNaive,
Cirrhotic
97 10094
78
Exp’d Noncirrhotic
Exp’d, Cirrhotic
29/30 2/2 30/32 7/9
95 92 87
62
Naive, Noncirrhotic
Naive, Cirrhotic
Exp’d Noncirrhotic
Exp’d, Cirrhotic
87/92 12/13 85/98 29/47n/N = n/N =
Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001.
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
Lawitz E, et al. AASLD 2013. Abstract LB-4.
Pts with GT2 or GT3 HCV
and previous treatment
failure with P/R
(N = 47)
Sofosbuvir 400 mg/day +PegIFN 180 µg once wkly
+RBV 1000 mg or 1200
mg/day
Wk 12
No cirrhosis
93
10/ 12
SV
R12
(%
)
9/ 9
13/ 14
GT2 GT3
n/N =
100
80
60
40
20
0
100
83 83
10/ 12
Cirrhosis
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)
AASLD/IDSA HCV Management Guidance. October 2014.
Treatment Wk 4 8 12/EOT 16* 20* 24* SVR 12
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) X X
HCV RNA X X X X*If using a 24-wk treatment option.
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* SVR 12
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) X
HCV RNA 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.
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)
AASLD/IDSA HCV Management Guidance. October 2014.
Treatment Wk 4 8 12 16 20 24/EOT
SVR 12
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) X X
HCV RNA X X X 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 inhibitorDasabuvir 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
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV(n = 172)
Paritaprevir/RTV/Ombitasvir + Dasabuvir +
RBV(n = 208)
Wk 24
Poordad F, et al . N Engl J Med. 2014;370:1973-1982.
Paritaprevir/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.
DAA-naive cirrhotic pts with GT1 HCV
(N = 380)
Wk 12
TURQUOISE-II: ITT SVR12
Superiority threshold: 54%[1]
Noninferiority threshold: 43%[1]
High SVR12 rates regardless of sex, age, BMI, or baseline HCV RNA in subgroup analyses[2]
Pts with platelet counts < 100,000/mm3: 89% to 97%
Pts with serum albumin < 3.5 g/dL: 84% to 89%
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.
SV
R12
(%
)
n/N =
100
80
60
40
20
0
96
165/172
92
191/208
12 wks 24 wks
P = .09
Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV
TURQUOISE II: SVR12 According to GT1 HCV Subtype and Treatment Experience
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
12 wks24 wks 100 100
Naive Relapse
100 100 85.7100 100 100
PR NullResponse
GT1b
Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
SV
R12
(%
)
Naive Relapse PR NullResponse
GT1a
59/64
14/15
52/56
13/13
11/11
40/50
10/10
39/42
100
80
60
40
20
0
92.292.9 93.3100 100 100
80.0
92.9100
80
60
40
20
0
22/22
25/25
18/18
20/20
6/7 14/14
3/3 10/10n/N =
TURQUOISE-II: Laboratory Abnormalities
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%)
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
Hemoglobin, % < 10 g/dL 7.2 11.0 < 8.0 g/dL 1.4 0.6
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
SV
R (
%)
100
80
60
40
20
0
67
SOF +SMV
12 Wks
1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1898. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
COSMOS[1]
100 100 100ION-1[2] TURQUOISE-II[3]
SOF +SMV +
RBV12 Wks
SOF +SMV
24 Wks
SOF +SMV +
RBV24 Wks
SOF/ LDV
12 Wks
SOF/ LDV
24 Wks
SOF/ LDV + RBV
12 Wks
SOF/ LDV + RBV
24 Wks
3DAA + RBV
12 Wks
3DAA + RBV
24 Wks
32/33 33/33 31/32 36/36
97100 100
97
n/N =
95
70/74
94
81/862/3 6/6 6/6 3/3
GT1 HCV SVR Summary: Treatment-Experienced Patients With Cirrhosis
SV
R (
%)
80
SOF +SMV
12 Wks
100 100
90
SOF +SMV +
RBV12 Wks
SOF +SMV
24 Wks
SOF +SMV +
RBV24 Wks
100 97
95/ 98
90
110/ 122
4/4 4/5 4/49/ 10
19/22
18/22
22/22
22/22
8682
100
3DAA + RBV
12 Wks
3DAA + RBV
24 Wks
SOF/ LDV
12 Wks
SOF/ LDV
24 Wks
SOF/ LDV + RBV
12 Wks
SOF/ LDV + RBV
24 Wks
COSMOS[1] ION-2[2] TURQUOISE-II[3]
100
80
60
40
20
0
n/N =
1. Lawitz E, et al. Lancet. 2014;[Epub ahead of print]. 2. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493. 3. Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
ELECTRON 2: SOF/LDV FDC ± RBV in Diverse Hard-to-Treat PatientsPartially randomized, open-label phase II
trial
Gane EJ, et al. EASL 2014. Abstract O6.
SOF/LDV FDC (n = 20)
Wk 12
Sofosbuvir/ledipasvir 400/90 mg FDC tablet once daily; weight-based RBV 1000-1200 mg/day
GT1 and CTP class B cirrhosis(N = 20)
SVR12: 65% (13/20); 7 relapses
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 dataCTP B: 89% with 12 wks, 92% with 24 wksCTP 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 study14% of patients with GT2/3 HCV had cirrhosis (specific
number for GT3 not reported)
Tx-naive pts with GT3 HCV
(N = 18)
Daclatasvir 60 mg QD + Sofosbuvir 400 mg QD*
(n = 13)
Wk 24
Daclatasvir 60 mg QD + Sofosbuvir 400 mg QD +
RBV 1000 mg or 1200 mg/day(n = 5)
Sulkowski MS, et al. N Engl J Med. 2014;370:211-221.
*7 patients received 4-week lead-in with sofosbuvir 400 mg QD alone before addition of daclatasvir.
AI444-040: SVR12 in GT3 by Treatment Arm
A potential option for cirrhotic GT3 pts, more data required in cirrhotic nonresponders
SV
R12
(%
)
n/N =
100
80
60
40
20
0
100
5/5
85
11/13
All GT3 Pts (Including Pts With Cirrhosis)
Daclatasvir + sofosbuvir + RBVDaclatasvir + sofosbuvir
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 requiredRBV-free therapies now availableMore data needed in decompensated liver disease
GT2: High SVR rates regardless of cirrhosisGT3: High SVR rates in treatment-naive patients
Additional strategies needed for cirrhotic nonresponders