Slide 1 of 8
Don’t Blink: The Rapid Evolution
of IFN-Free Therapy for HCV
David L. Wyles, MD
Associate Professor of Medicine
University of California San Diego
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
IAS–USA
Slide 2 of 8
Why do we need IFN-free regimens?
Efficacy
• Poorly interferon responsive 100 HCV RNA+ Patients
– African Americans
– Prior IFN failure
• Null responder cirrhotics
Acceptance and tolerability
• Poor patient acceptance
• Providers reluctance
40 Eligible Patients
– Resource intensive
• Monitoring: toxicity
• Support services
Interferon ineligible populations
• Decompensated ESLD
• Severe psychiatric disease
• Medical co-morbidities
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
28 Treated
5 Cured
60%
Ineligible
30%
refusal
75% dropout
or
nonresponse
Falck-Ytter, Y. Annals, 2002.
Slide 3 of 8
Limitation of first generation PIs
• Complicated dosing regimens and treatment
algorithms
– Food restrictions
• High potential for drug-drug interactions
• Increased side effects (over Peg/RBV)
• Limited efficacy in those with the greatest
medical need
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 4 of 8
Retreatment Success Depends on Fibrosis
Stage and Previous Response
TVR-based therapy; HCV mono-infected
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Zeuzem S. NEJM 2011.
Slide 5 of 8
BOC and TVR Increase Adverse Events
Telaprevir (TVR)
Adverse Event, %
TVR Arms
(n = 727)
PegIFN/RBV Arm
(n = 361)
Pruritus
45-50
36
Nausea
40-43
31
Rash
35-37
24
Anemia
37-39
19
Diarrhea
28-32
22
9
1
BOC Arms
(n = 78)
PegIFN/RBV Arm
(n = 363)
49
29
37-43
18
14
16
Discontinuation due to AE
Boceprevir (BOC)
Adverse Event, %
Anemia
Dysgeusia
Discontinuation due to AE
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA. Jacobson I. NEJM 2011; Poordad F. NEJM 2011.
Slide 6 of 8
SVR
(1a/1b)
Daclatasvir/
Nulls
11
36% (22/100)
NS5A/PI
24 wks
Asunaprevir
IFN intolerant
43
77%
DCV/ASU/
NS5A/PI/N
Naïve
12 wks
16
94%
BMS-791325
NI
Non-cirrhotic
24wks
16
94%$
Naïve
25
84%
SOF/RBV
NI
12 wks
Nulls
10
10%
SOF/RBV
Naïve/intolerant 12 wks
253
67% (97/56)
NI
GT 2/3
Non-responders 12/16 wks 100/95
50/73%
SOF/DCV±RBV
Naïve
24wks
44
93-100%
NI/NS5A
SOF/LDV/RBV
Naïve/Null
12wks
25/9
100/100%
Null
27
96%*
SOF/SMV±RBV
NI/PI
12wks
(F0-F2)
14
93%*
FAL/
Naïve
PI/NNI
28 wks
78
68% (43/83)
BI-207127/RBV
Cirrhosis
Mericitabine/
Naïve
NI/PI
24 wks
64
41% (26/71)
Danoprevir + RBV
(F0-F2)
ABT-450r/267/ PI/NS5A/N
Naïve
79
99%
12
333±RBV
NI
Nulls
45
93%
Drugs
Classes
Population
Duration
N
IFN-Free Regimens for HCV gt1
Lok A. NEJM 2012. Suzuki F. #14 EASL 2012. Everson G. AASLD 2012. Gane EJ AASLD 2012. Gilead press release Feb 2013. Sulkowski
From
DL 2012.
Wyles,
MD,
at Atlanta,
GA:EApril
10, 2013,
IAS-USA
. 2012. Poordad F. EASL 2012. King M. CROI 2013.
M. AASLD
Gane
EJ. CROI
2013. Lawitz
CROI 2013.
Zeuzem
S. #101 EASL
$
SVR4
* SVR8
Slide 7 of 8
Lessons learned with IFN-free therapies
• HCV cure is achievable without IFN
– With much shorter durations
• Subtype matters with less potent regimens
• Ribavirin matters with less potent regimens
• Cirrhotics and null responders can be
effectively treated
• Tolerability and side effects are improved
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.
Slide 8 of 8
Unknowns with IFN-free therapies
• Efficacy in HCV/HIV subjects
– No reason to suspect efficacy will suffer
– Drug-drug interaction limiting factor
• How restrictive will payers be?
– SOF + DCV or SOF + SMV “off label” early 2014
• Impact of selected HCV resistance?
• Decompensated cirrhosis data needed
From DL Wyles, MD, at Atlanta, GA: April 10, 2013, IAS-USA.