Antonio Craxì
Gastroenterologia & Epatologia,
Di.Bi.M.I.S., Università di Palermo
28 Maggio 2013
Trattamento dell’epatite C nel 2014: scelte guidate dalla sostenibilità e dalla disponibilità
Malattia lieve
(epatite cronica F0-F1)
Conoscenza dello
stato di infezione
cronica da HCV
Malattia significativa
(epatite cronica F2-F3;
Cirrosi F4, Child A)
Malattia avanzata
(Cirrosi, Child B-C,
HCC, trapianto)
Infezione da HCV in Italia: distribuzione per stadi o di malattia
• ∼ 7000 patients treated each year with a 10% yearly trend to decrease
• ∼ ¼ of HCV-1 patients were re-treatments: warehousing for triple therapy
• Yearly expenditure (2011) for dual therapy: 220,000,000 €
• Aging population of naives (48 years) with 25-30% of F3/F4
• At least 20,000 patients with previous P/R failures: usually unclassified,
mean age > 55 years and ∼ 40% F3/F4
Treatment of HCV-1 in Italy: current status
Malattia lieve
(epatite cronica F0-F1)
Conoscenza dello
stato di infezione
cronica da HCV
Malattia significativa
(epatite cronica F2-F3;
Cirrosi F4, Child A)
Malattia avanzata
(Cirrosi, Child B-C,
HCC, trapianto)
Infezione da HCV in Italia: chi curiamo oggi
Terapie basate sull’IFN
(PEG IFN + ribavirina)
+/- boceprevir o
telaprevir
� First-generation protease inhibitorsincrease SVR rates in naive and treatment-experienced patients1,2
and may reduce liver-related morbidity and mortality in the long-term1,2
� Modest potential for shorter treatment duration1,2
� Not sufficiently effective in difficultpatients (cirrhosis; OLT; HIV) and in null responders
� Modest potency with developmentof resistance2,3
� Genotype 1 restricted
� Complex regimens, with risk of poor adherence2
� Increased adverse reactions and toxicity burden2
� Increased risk of DDIs2
� Costs
1. Ghany MG, et al. Hepatology 2011; 54: 1433–442. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201
3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51
Advantages Disadvantages
The balance of triple therapy
with boceprevir and telaprevir
-
1.000.000
2.000.000
3.000.000
4.000.000
5.000.000
6.000.000
7.000.000
1 2 3 4 5 6 7 8 9 10 11 12
FRANCE
GERMANY
ITALY
SPAIN
UK
Triple Therapy sales in the first 12 months
after launch in TOP5 UE
Boceprevir
-
2.000.000
4.000.000
6.000.000
8.000.000
10.000.000
12.000.000
14.000.000
16.000.000
18.000.000
1 2 3 4 5 6 7 8 9 10 11 12
FRANCE
GERMANY
ITALY
SPAIN
UK
Telaprevir
Triple therapy regional access: main regions
# Centers able to prescribe: 249/480 ( 52%)
* Starting Therapy Pts; 3.979 Full Year pts
RegionRegional
Decree# Centres
Centres
accreditat
ion
Triple
Therapy
Estimate
Start
Estimate
Triple Pts
Pts. on
treatment
in Triple
Lombardia Yes 34 24 Feb 1000 357
Veneto Yes 9 8 Mar 600 206
Emilia R. Yes 14 9 May 467 121
Piemonte/VA Yes 17 12 Feb 462 286
Toscana Yes 11 10 Mar 450 84
Lazio Yes 14 12 Feb 447 258
Campania Yes 51 23 Feb 444 266
Puglia Yes 19 14 May 397 88
Sicilia Yes 12 8 June 418 108
Other Regions 68 36 1074 310
ITALY 249 156 5759* 2083
46% BOC 54% TEL
28% with
BOC
72% with
TEL
Treat now or wait: issues to consider
Treat now
� Triple therapy increases SVR
� Earlier treatment has higher
success rates
� Successful treatment may arrest
progression of liver disease
� Uncertainty about timelines for
approval and reimbursement of
new DAAs
Defer
� First-generation PIs complex,
associated with adverse events
� Potential for higher SVR, including
difficult populations
� Potential for simpler regimens, QD
or BID, fewer adverse effects,
eventually IFN-free
� Activity in non–genotype 1
Severity of Disease Increases Need for HCV
Therapy but Also Impairs Response
� May not need immediate treatment� BUT
� Easier to treat� High likelihood of response
Advanced fibrosis/ cirrhosis
Mild disease
� Greater need for treatment� BUT
� Response may be impaired
� Perhaps more effective options in future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria
Extrahepatic Clinical Benefits of a SVR in Patients with
Chronic Hepatitis C
Clinical Event Number/Total Patients Reference
SVR (+) SVR (-)
Diabetes 26/1167
(2.2%)
117/1175 (9.9%) Arase et al 2009
Malignant lymphoma 0/2161 (0%) 25/1048
(12.6%)
Kawamura et al 2007
Improved Neurocognitive
Functions*
8/8 100% 0/6 0% Byrnes et al 2012
* Improved Brain Metabolism: basal ganglia Cho/Cr and ml/Cr ratios
Companies and agents in phase 2/3
PI NS5A NNPI NUC
AbbVie ABT-450/r ABT-267 ABT-333
ABT-072
Achillion ACH-1625 ACH-3102
Boehringer Faldaprevir Deleobuvir (PPI-668)
BMS Asunaprevir Daclatasvir BMS-791325
Genentech Danoprevir/r Setrobuvir Mericitabine
Gilead GS-9451 Ledipasvir Tegobuvir;
GS-9669
Sofosbuvir
Janssen/J&J Simeprevir TMC-647055/r
Merck MK-5172
Vaniprevir
MK-8742
Vertex Telaprevir VX-222 ALS-2200
(VX-135)
SAPPHIRE-1 Press release – November 18th, 2013
15
FDA Approval Timeline
End of 2013
2014
2015
Geno-2,3:Sofosbuvir + RBV
Geno-1:Sofosbuvir + PEG/RBV
Simeprevir + PEG/RBV
Geno-1b:Faldaprevir + PEG/RBV
Geno-1:Sofosbuvir + Ledipasvir
ABT450/r+ABT267+ABT333
Daclatasvir + PEG/RBV?
Geno-1:Daclatasvir + Asunaprevir+ BMS791325
Faldaprevir + Deleobuvir+ PPI668
What Is In Our Near Future?
More Triple Therapy
• DAA plus IFN backbone plus ribavirin (RBV)
- Second-generation PIs
- Nucleoside polymerase inhibitors
- Nonstructural protein (NS)5A inhibitors
• Expectations
- RVR >90%
- Sustained virologic response (SVR): 80%
- Tolerability and side effects
- RGT
What Is In Our Near Future?
More Triple Therapy
• DAA plus IFN backbone plus ribavirin (RBV)
- Second-generation PIs
- Nucleoside polymerase inhibitors
- Nonstructural protein (NS)5A inhibitors
• Expectations
- RVR >90%
- Sustained virologic response (SVR): 80%
- Tolerability and side effects
- RGT
QUEST-2: Virologic Response to Simeprevir + P/R
Treatment
Manns M, et al. EASL 2013. Abstract 1413.
SMV Arm: Total
Duration of RGT
91% of pts in SMV arm
met RGT criteria
n/N =
SMV + P/R
P/R
Overall 24 wks 48 wks
100
80
60
40
20
0
SV
R1
2 (
%)
81
50
86
32
209/257 67/134 202/235 7/22
ASPIRE: Simeprevir (PI) + PEG-IFN/RBV
in Treatment Experienced Patients
Zeuzem S, et al. EASL 2012. Abstract 2
TMC 435
+ PEG/R
weeks
0 48
Treatment experienced, G1, includes cirrhotics
PEG-IFN + RBV
12
n=66
TMC 435 +
PEG-IFN/RBVPEG-IFN + RBV
TMC435 +PEG-IFN + RBV
24
n=68
n=66
PEG-IFN + RBV
n=65
100
80
60
40
20
0
85*
SV
R 2
4 (%
)
75*
19
51*
9
37
Relapsers PartialResponders
Null Responders
* Represents pooled TMC duration at 150mg dose
NEUTRINO: SVR12 With Sofosbuvir + P/R
According to Genotype and Fibrosis Level
SV
R1
2 (
%)
92
80
100
80
60
40
20
0No
Cirrhosis
Cirrhosis
252/273 43/54
SVR12 According to
Fibrosis Level
SV
R1
2 (
%)
8996
100100
80
60
40
20
0GT 1 GT 4 GT 5,6
261/292 27/28 7/7
SVR12 According to
Genotype
n/N =
Lawitz E, et al. N Engl J Med. 2013;369:678-9.
NEUTRINO: Adverse Events in ≥15% of Patients
Preferred term, n (%) SOF + Peg-IFN + RBV
(N=327)
Any adverse event 304 (93)
Fatigue 192 (59)
Headache 118 (36)
Nausea 112 (34)
Insomnia 81 (25)
Anemia 68 (21)
Rash 59 (18)
Decreased appetite 58 (18)
Pyrexia 58 (18)
Chills 54 (17)
Neutropenia 54 (17)
Pruritus 54 (17)
Flu-like symptoms 49 (15)
Lawitz E, et al. N Engl J Med. 2013;369:678-9.
What’s the ideal future therapy?
• Characteristics of an ideal therapy:
– Interferon-free
– High barrier to resistance
– Once daily oral combination
– Pan-genotype (genotypes 1-4, at least)
– “Reasonably” safe; minimal DDI
– Short duration (~12 weeks)
– SVR rates >90%
– Affordable
Malattia lieve
(epatite cronica F0-F1)
Conoscenza dello
stato di infezione
cronica da HCV
Malattia significativa
(epatite cronica F2-F3;
Cirrosi F4, Child A)
Malattia avanzata
(Cirrosi, Child B-C,
HCC, trapianto)
Infezione da HCV in Italia: chi cureremo domani
Terapie senza IFN con
DAAs +/- ribavirina
Screening
Costo – beneficio?
ELECTRON study: Once daily sofosbuvir/ledipasvir fixed dose combination (FDC) ± RBV
� FDC of sofosbuvir 400mg (Nuc NS5B) + ledipasvir 90mg (NS5A)
� To explore efficacy and safety of SOF/LDV in difficult-to-treat cirrhotic nonresponder GT 1
� To explore minimum duration of SOF/LDV needed in GT 1 infection
1.Cirrhotic, non-responders � Substituting RBV with GS-9669 prevents Hb drop
Gane EJ, et al. AASLD 2013, Washington DC. #73
Wk 0 8 126
FDC + RBV (n=10)
FDC (n=10) GT 1 Null
F4
Ran
dom
ized
FDC + RBV (n=25)
FDC + GS-9669 (n=26)
GT 1 NonresponderF3/4 (70%F4)
Ran
dom
ized
FDC + RBV (n=25)GT 1 naïve
F0 – F2
� Substituting RBV withGS-9669 maintains SVR12
25/25 26/26
SOF/LDV
SV
R 1
2 (%
)
7/10 9/9SOF/LDV
+ RBV
25/25 26/26SOF/LDV
+ RBVSOF/LDV+ GS-9669
� Adding RBV improvesSVR12 of SOF/LDV
Mea
n he
mog
lobi
n (g
/dL)
1 2 4 6 8 10 12 2 4BL
25
ELECTRON study: Once daily sofosbuvir/ledipasvir fixed dose combination (FDC) ± RBV
2. Treatment-naïve, mild fibrosis� Shortening duration to 6 weeks
� Baseline NS5A RAVs� Present in 6/60 SOF/LDV patients � Only 1 relapsed
� Safety� AEs mild consistent with RBV� 1 SAE, no discontinuation� No toxicity attributed to FDC� No toxicity attributed to GS9669
� In cirrhotic GT1 non-responders, RBV or GS-9669 enhances the efficacy of 12 weeks SOF/LDV FDC
� Efficacy not reduced by baseline NS5A RAVs � Optimal duration of SOF/LDV FDC±RBV is >6 weeks� Further studies to evaluate whether addition of third DAA allows reduced duration to 6 weeks
(see LB#8, Kohli et al)
Gane EJ, et al. AASLD 2013, Washington DC. #73
SV
R 1
2 (%
)
25/25 20/20 17/25
100 100
68
0
20
40
60
80
100
SOF/LDV+ RBV*
SOF/LDV+ RBV†
SOF/LDV+ RBV
12 weeksELECTRON
*Gane, EASL 2013
8 weeksLONESTAR
†Lawitz, EASL 2013
6 weeks
26
LONESTAR trial: Once daily sofosbuvir/ledipasvir fixed dose combination ± RBV in patients with HCV GT1, including patientswith cirrhosis
� Single center, genotype 1� Platelets>50,000, no upper BMI or age� Baseline NS5A resistance : 9%� PI failures 55% cirrhotic� Mean platelet 106,000� Mean albumin 3.8
� Safety:� Nausea(5-14%); headache 5-10%;
anemia in 24% (all on RBV)� No discontinuations due to AE’s
� Resistance: � Baseline� NS5A: 7/9 achieved SVR� NS3: 29/29 achieved SVR
� Emergent� Single S282T+ NS5A resistance
(8wk SOF/LDV) that achieved SVR on retreatment (SOF/LDV/RBV x24 wks)
Lawitz E, et al. AASLD 2013, Washington DC. #215 Lawitz E, et al. Lancet. 2013 Nov 1. doi:pii: S0140-6736(13)62121-2.
95 100 95 95 100
0
20
40
60
80
100
- + - - +
19/20 21/21 18/19 21/2118/19
8 8 12 12 12Duration(week)
RBV
Treatment naïve(no cirrhosis)
PI failures(50% cirrhosis)
1 relapse 1 relapse
1 lost to follow up
after SVR8
Pat
ient
s (%
)
Ran
dom
ized
1:
1
Treatment naïve
(non-cirrhotic)
PI failures(50%
cirrhotic)
Cohort 1(n=60)
Cohort 2(n=40)
Ran
dom
ized
1:
1:1
Wk 0 8 12
SOF/LDV
SOF/LDV + RBV
SOF/LDV
SOF/LDV
SOF/LDV + RBV
27
LONESTAR trial: Once daily sofosbuvir/ledipasvir fixed dose combination ± RBV in patients with HCV GT1, including patientswith cirrhosis
� 8 and 12 weeks were equally highly effective in genotype 1 noncirrhotics� PI failure cirrhotics were efficiently treated with FDC + RBV for 12 weeks� Proof of principle that retreating failure with s282T can still achieve SVR with FDC+RBV� Safe and effective but needs larger confirmatory study
95 100 100 10091
100
0
20
40
60
80
100
- + - + - +12Duration
(week)
RBV
Overall
Pat
ient
s (%
)
1819
2121
88
1010
1011
1111
12
No cirrhosis
12
CirrhosisPost-
treatment
0
5
HC
V R
NA
(log 1
0IU
/mL)
6
4
3
2
1
7
Post-treatment
SOF/LDV8 weeks
Retreatment:SOF/LDV+RBV
24 weeks
SVR12LLOQ-TD
LLOQ-TND
NS5A: L31M 21.45%NS5B: No RAVs
NS5A: Q30L (3.47%)L31M (94.38%)L31V (4.67%)Y93H (98.19%)
NS5B: S282T (8.00%)
NS5A: Q30L (4.50%)L31M (>99%)Y93H (96.74%)
NS5B: S282T (91.24%)
28Lawitz E, et al. AASLD 2013, Washington DC. #215 Lawitz E, et al. Lancet. 2013 Nov 1. doi:pii: S0140-6736(13)62121-2.
SVR24
• SVR4 rates with 12-wk regimens
– SVR12 in all 68 pts who have reached
time point
SVR Rates With 12 or 24 Wks of
Daclatasvir + Sofosbuvir ± RBV• SVR24 rates with all 24-wk regimens
Sulkowski MS, et al. AASLD 2012. Abstract LB-2.
SOF + DCV + RBVSOF LI + DCV SOF + DCV SOF + DCV (12 wk)
SOF + DCV + RBV (12 wk)
93
GT2/3
8893 94
GT1
HC
V R
NA
< LL
OQ
(%)
100
80
60
40
20
0
100
80
60
40
20
EOT* SVR4
98 95100 100
EOT* SVR24 EOT*
100 100100 100100 100 100 100
0
*EOT includes pts who discontinued early, with last visit considered EOT.
COSMOS study: SVR results of a once-daily regimen of simeprevir plus sofosbuvir ± RBV in cirrhotic and non-cirrhotic GT1 treatment-naive and prior null responder patients
� Two cohorts: � F0–2 (n=80, all null responders)� F3–4 (n=87, 46% naive, 54% null)� 47% cirrhosis
� 78% GT1a
� Safety: � Discontinued for AEs = 2.4%
� Fatigue, headache, nausea
� Rash 4–15%, pruritus 3–17%, photosensitivity/sunburn (gr 1/2) 3–7%
� Anemia mostly related to RBV andbilirubin elevations – more common with RBV
� Cohort 1: prior null responders(METAVIR F0–F2) ITT population
Jacobson IM, et al. AASLD 2013, Washington DC. #LB-3
SMV+SOF
SMV+SOF+RBVVSMV+SOF
SMV+SOF+RBV
24 wks
12 weeks
24 weeks
12 wks
24-week treatment
14/1519/24
SMV/SOF/RBV
100
Pat
ient
s, %
1/244/24
1/15
80
60
40
20
0SMV/SOF
100
80
60
40
20
0
Pat
ient
s, %
12-week treatment
13/1426/27
1/141/27
SMV/SOF/RBV SMV/SOF
SVR12 Non-virologicfailureRelapse
30
� PI + nuc appears similar to NS5A + nuc� No apparent impact of RBV or 24 vs. 12 weeks� Q80K may have impact but most Q80K still have SVR;
final data needed for full assessment� Potential utility as first DAA regimen in 2014
� COSMOS may have cosmic implications in the upcoming months
� Cohort 2: Naïve and prior null responders (METAVIR F3–F4) SVR4 interim analysis, ITT population
COSMOS study: SVR results of a once-daily regimen of simeprevir plus sofosbuvir ± RBV in cirrhotic and non-cirrhotic GT1 treatment-naive and prior null responder patients
� SVR rates according to HCV subtype: Cohorts 1 + 2 (excludes non-virologic failures)
31Jacobson IM, et al. AASLD 2013, Washington DC. #LB-3
100 100 10096,3 100 93.3
0
20
40
60
80
100
Total Naives Nulls
Pat
ient
s, %
1/2712-week treatment
1/15
1414
2627
77
1212
77
1415
SVR4 (SMV/SOF)SVR4 (SMV/SOF/RBV)
Relapse
88,9100 100
0
20
40
60
80
100
1 2 3
24/27 30/30 17/17
SVR12 Cohort 1 (12 + 24 week arms)
GT1a withQ80K
GT1a withoutQ80K
GT1b
90100 100
0
20
40
60
80
100
1 2 3
10/11 21/21 8/8
SVR4 Cohort 2 (12 week arm)
GT1a withQ80K
GT1a withoutQ80K
GT1b
*
*
*Q80K present in all four relapsers thus far
AVIATOR: SVR12 Rates With
ABT-450/ RTV, ABT-267, ABT-333, and RBV
8 wks 12 wks 12 wks
8286
0
20
40
60
80
100
SV
R12
(%)
96100 100 100 100 100
8496
56 24
79
100
29 12
85
100
52 27
83
96
52 25
96 100
54 25
81
100
26 18
89100
28 17
Observed data (above bar)
ITT (within bar)
n =
81
988888
10089
1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1bABT-450ABT-267ABT-333
RBV
ABT-450ABT-333
RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-333
ABT-450ABT-267ABT-333
RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-333
RBV
Treatment-Naive Patients Null Responders
Kowdley KV, et al. EASL 2013. Abstract 3
ABT-450: Protease/RTV QD
ABT-267: NS5A QD
ABT-333: NNPI BID
88 83 89 87 96 89 93
100 97,6 97,6 95,297,5 97,5 92,5 90
020
406080
100
Week 4 Week 12(EOTR)
SVR4 SVR12
� 42 treatment naïve and 40 null respondersto P/R
� ABT-450/r (PI) + ABT-267 (NS5A inhibitor)
� 12 weeks
� No cirrhosis
� Efficacy (%):
3940
3940
3740
3640
4242
4142
4142
4042
ABT-450/r + ABT-267 in HCV GT1b-infected treatment-naïve patients and prior null responders
� Virologic failure (n=4): naïve 0/2, null responder 4/4
� 3 relapse, 1 breakthrough
� 2/4 virologic failures had baseline NS5A resistance (Y93H)
� Safety:
� Naïve: headache (33%), nausea (19%),dry skin (17%)
� Null: headache (25%)
� 2x grade 3 AST/ALT (1 naïve/1 null)� Failure associated with 2 class resistance
Lawitz E, et al. AASLD 2013, Washington DC. #75
� 2 DAA regimen highly effective in genotype 1b non cirrhotics without ribavirin� Baseline NS5A resistance (Y93H) associated with virologic failure� Cirrhotic cohorts and genotype 4 cohorts to be studies� Studies in larger and more diverse patient populations should be undertaken
Naïve patientsPrior null responders
33
SAPPHIRE-1: 3DAA + RBV x 12 weeks versus placebo
34
AbbVie Press Release November 18th ,2013
20%
40%
60%
80%
100%96% 98%
95%
G1 G1b G1a
455473
148 151
307 322
N= 631 G1 non cirrhotic patients3D: N=473 / Placebo: n=158
SVR12
Safety:- Most common AEs in 3D and Placebo: Fatigue, Headache,
Nausea- Discontinuation for AE:
- Active treatment : 0,6% - Placebo: 0,6%
Efficacy
Breakthrough and relapse rates:- 1,7%
Patients with missing values were considered treatment failures
Phase 2b study of the IFN-free and RBV-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks intreatment-naïve patients with chronic HCV GT1 infection
� Treatment-naïve patients with and without cirrhosis (n=166 patients)� 82% HCV-1a, 33% IL28B CC GT
� Randomization by HCV-1 subtype (a/b) and absence/presence of cirrhosis
� Treatment schedule:
� DCV 30 mg BID, ASV 200 mg BID, BMS-791325 75 or 150 mg BID for 12 weeks
� 3 SAEs (all unrelated to study drug) � AEs: headache, fatigue, nausea
� Grade 3 elevated AST (n=1)and total bilirubin (n=1)
Everson GT, et al. AASLD 2013, Washington DC. #LB-1
n/N (%) BMS-791325 75mg BMS-791325 150mg
Observed Cirrhotic Observed Cirrhotic
EOT 78/80 (97.5) - 81/86 (94.2) -
SVR12 71/77 (92.2)* 8/8 (100) 77/84 (91.7) 5/7 (71)
On-treatment virologic breakthrough (n)
2 3
Posttreatment relapse (n) 4 2
� Three-drug IFN-free combination regimen with high SVR rates in HCV-1 infected patients, supporting initiation of Phase 3 trials
36
� New 3 DAA regimen ± weight-based RBV
� 12 week, all oral regimen
� Faldaprevir, FDV – 120 mg qd
� PPI-668 (NS5A) – 200 mg qd
� Deleobuvir, DEL (non-nuc) – 400/600 mg bid
� Arms (n=12 in each arm): 12 weeks treatment� FDV, PPI-668, DEL 600 mg bid, RBV� FDV, PPI-668, DEL 400 mg bid, RBV� FDV, PPI-668, DEL 600 mg bid
� Treatment naive; no cirrhosis
� All G1a; <33% IL28B CC
� Baseline Q80K common, several patientsbaseline NS5A and/or NNI substitutions
� Efficacy (graph): 81% LLOD by week 4
� Safety� Rashes� GI side effects (1 discontinuation at week 9)� Elevated bilirubin
Phase 2 trial of new all-oral combination of faldaprevir, deleobuvir, and PPI-668, ± RBV, in GT1a patients
Lalezari JP, et al. AASLD 2013, Washington DC. #LB-20
� Breakthrough in 1 patient w/ baseline NS5A substitutions (Q30L+Y93H) and NS5B A421V; high level resistant variants to all 3 classes at breakthrough
� More evidence for highly effective nuc-free regimens in GT1a
� Still not clear if RBV dispensable for maximum SVR rates to be attained
� Hint of occasional impact of baseline variants,needs further study with similar regimens
<L
LO
Q/<
LLO
D (%
)
12 12 12 9 8 N/A 7 6 N/A
HCV RNA categorical responses
Treatment of Genotype 2 and 3:
Sofosbuvir + Ribavirin Summary
Patient
Population
N SVR12
Overall
N
Cirrhosis
SVR12
Cirrhosis
Rx Naive 70 97% 11 91%
Rx Limited 109 92% 17 94%
Genotype 2 Treatment
Experienced:
12 weeks 36 88% 10 60%
16 weeks 32 94% 9 78%
Rx Naive 183 56% 38 34%
Genotype 3 Rx Limited 98 68% 14 32%
Treatment
Experienced:
12 weeks 64 30% 26 19%
16 weeks 63 62% 23 61%
VALENCE trial: SOF + RBV for 12 or 24 weeks for patients with HCV GT2 or 3
� European study� SOF 400 mg + weight based
RBV naïve or experienced GT2 or 3
� 20% with cirrhosis; platelets >50,000� 12 weeks GT2� 24 weeks GT3: following
emergent data � (11 GT3 patients completed
12 weeks)
Zeuzem S, et al. AASLD 2013, Washington DC. #1085
PBO (n=85)
SOF+RBV (n=334)
GT2/3
GT2/3
0 12 24 36Weeks
SVR12
SVR12
SVR12, SVR 12 wks after treatment end
SOF+RBV (n=73)*
SOF+RBV (n=250)
GT2
GT3
0 12 24 36Weeks
SVR12
SVR12
*An additional 11 patients with GT3 had completed treatment before treatment could be extended in an amended protocol; for safety analyses, they were included with GT2 patients; for efficacy, they were analyzed separately
VALENCE: Initial study design
VALENCE: Amended study design
39
VALENCE trial: SOF + RBV for 12 or 24 weeks for patients with HCV GT2 or 3
� Multivariate analysis: no factor associated with relapse in TE cirrhotic group� No S282T mutation detected at relapse� AEs observed in >15% were: headache, fatigue, pruritus, asthenia, nausea, insomnia� Overall safety: SAE 2% and 4% GT2 12 weeks and GT3 24 weeks, respectively� AE leading to discontinuation: 1 and <1%, respectively
Zeuzem S, et al. AASLD 2013, Washington DC. #1085
� SVR >90% in GT3 naïve patients, irrespective of presence absence cirrhosis� Benefit of longer duration for GT3� Most difficult group: GT3 cirrhosis, experienced: 60% SVR� Why difference in naïve and experienced patients when common denominator cirrhosis?
68/73 212/250
*3/11 patients (27%) with HCV GT3 who received 12 wks of SOF+RBV achieved SVR12
SVR12 in GT2 and 3 patients*
SV
R1
2 (%
)
29/302/2
30/33 7/8
SVR12 in GT2 patients treated for 12 wks
SVR12 in GT3 patients treated for 24 wks
86/92 12/13 87/100
27/45
40
PHOTON-1: All-oral therapy with SOF + RBV for the treatment of HCV GT1, 2, and 3 infection in patients co-infected with HIV
41Sulkowski MS, et al. AASLD 2013, Washington DC. #212
� Coinfected HCV GT1–3� SOF 400 mg RBV 1000–1200 mg/day
� GT1 treated 24 weeks
� GT2/3 treated 12 weeks
� Multiple ART permitted� Compensated cirrhosis permitted
GT1 (N=114)
GT2(N=26)
GT3 (N=42)
Baseline Character-
istics
Male, n (%) 93 (82) 21 (81) 34 (81)Black, n (%) 37 (33) 6 (23) 2 (5)IL28B CC
genotype, n (%)30 (27) 10 (39) 15 (36)
Cirrhosis, n (%) 5 (4) 1 (4) 6 (14)Log10 HCV RNA (IU/mL), mean
(SD)6.6 (0.8) 6.5 (0.6) 6.2 (0.6)
CD4 T-cell count (cells/µL), mean
(SD)636 (251) 627
(278)559
(224)
On ART, n (%) 112 (98) 22 (85) 39 (93)
ART Regimen: Tenofovir/
Emtricitabine PLUS
Efavirenz, n (%) 42 (37) 7 (27) 13 (31)Atazanavir/ritonavi,
n (%)24 (21) 4 (15) 3 (7)
Darunavir/ritonavir, n (%)
15 (13) 6 (23) 11 (26)
Raltegravir, n (%) 21 (18) 2 (8) 6 (14)Other, n (%) 10 (9) 3 (12) 6 (14)
Virologic responses
Week 4 HCV RNA <25 IU/mL, n/N
(%)
109/113 (96)
25/26 (96)
41/41 (100)
SVR12, n/N (%) [To be presented]
21/26 (81)
28/42 (67)
21/26 28/42109/114
**Wk 4 <25 IU/mL
SVR12
Initial evaluation of the sofosbuvir compassionate use program for patients with severe recurrent HCV followingliver transplantation
� Compassionate use program for severerecurrent HCV after LT (up to 48 wks)
� Treated for ≤48 wks:
� SOF + RBV (32)
� SOF + RBV + PegIFN (12)� 20 had FCH
� Baseline:
� Bilirubin mean 7.9 (no IFN group)2.6 (IFN group) mg/dL
� ALT mean 81–124 IU/L
� Albumin mean 3.2–3.4 mg/dL
� INR mean 1.2–1.4
� Clinical condition improved in 64%
� Rapid improvement occurred in some� Improvement in ALT, INR and/or bilirubin
� Resolution of ascites
� Decreased episodes of encephalopathy
� ≥8 died from complications of disease
� SAEs 50% SOF/R, 42% SOF/PR� 1 treatment-related SAE, 3 d/c for AE
Forns X, et al. AASLD 2013, Washington DC. #1084
28/36
� High degree of viral suppression though notthe ~100% noted in other populations
� SVR may be attainable in ≥50%� Clinical improvement with viral suppression has
major potential implications for treatment ofpatients with advanced liver disease, not onlypost-transplant but potentially pre-transplant
2/2
Undetectable HCV RNA
SOF + RBV n/N (%)
SOF + PR n/N (%)
On-treatment response
Wk 4 22/32 (69) 8/12 (67)
Wk 12 29/32 (91) 9/12 (75)
Wk 24 24/29* (83) 7/11* (64)
Post-treatment response
SVR 4 20/27 (74) 5/9 (56)
SVR 12 12/20 (60) 4/8 (50)
*3 early termination pts (Wk 12, 12, 22) not counted in denominator
EF
FIC
AC
Y
TOLERABILITY/SAFETY
Peg IFN +
RBV
Peg/RBV +
BOC/TVR
Peg/RBV +
Two DAAs
Peg/RBV +
2nd gen DAA
IFN free NON NUC-
Based DAAs combo
Evolution (2014-2018) of HCV treatment is not linear
IFN free NUC-
Based DAAs comboOff label
IFN free
combos
<50%
<70%
80%
90%
100%
modest fair excellent
HCV PATIENT PROTOTYPES: indications for
treatment 2014
•I: Prototypes to be treated with P/R (all naives):
•a) Gt 1, "easy to cure": F1 to F2 plus IL 28 cc or RVR after lead-in,
no factors reducing IFN responsiveness (obesity, metabolic
syndrome)
•b) Gt 2 and 3, F2 to F4
•c) Gt 4, 5, 6, F2 to F4
•I: Prototypes to be treated with P/R and a first generation protease inhibitor (boceprevir
or telaprevir):
•a) Naive Gt 1, "difficult to cure": F2 to F4 plus IL 28 non cc or no RVR after lead-in,
presence of factors reducing IFN responsiveness (obesity, metabolic syndrome)
•b) All Gt 1 relapsers to P/R, regardless of stage
•c) Gt 1 partial or null responders to P/R, F2 to F4
•d) Gt 1 with HIV coinfection, F2 to F4
•e) Gt1 with severe post-OLT relapse (compassionate sofosbuvir available)
HCV PATIENT PROTOTYPES: indications for
treatment 2014
•I: Prototypes to be deferred for new regimens (mostly for IFN free DAAs):
•a) Naive, all genotypes, F0 to F1
•b) P/R treatment failures, all non-1 genotypes
•c) Gt 1, F4, compensated, naive or P/R experienced, with no response to lead in
•d) All decompensated patients
•e) Gt 1, failures of triple therapy with P/R plus PI
HCV PATIENT PROTOTYPES: indications for
treatment 2014
"“There are decades where nothing happens; and
then there are weeks where decades happen.”
Vladimir Ilyich Lenin
